Case Reports

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

Beau lines are palpable transverse depressions on the dorsal aspect of the nail plate that result from a temporary slowing of nail plate production by the proximal nail matrix. Onychomadesis is a separation of the proximal nail plate from the distal nail plate leading to shedding of the nail. It occurs due to a complete growth arrest in the nail matrix and is thought to be on a continuum with Beau lines. The etiologies of these 2 conditions overlap and include trauma, inflammatory diseases, systemic illnesses, hereditary conditions, and infections.^1-5 In almost all cases of both conditions, normal nail plate production ensues upon identification and removal of the inciting agent or recuperation from the causal illness.^3,4,6 Beau lines will move distally as the nail grows out and can be clipped. In onychomadesis, the affected nails will be shed with time. Resolution of these nail defects can be estimated from average nail growth rates (1 mm/mo for fingernails and 2–3 mm/mo for toenails).⁷

Retronychia is defined as a proximal ingrowing of the nail plate into the ventral surface of the proximal nail fold.^4,6 It is thought to occur via vertical progression of the nail plate into the proximal nail fold, repetitive nail matrix trauma, or shearing forces, resulting in inflammation that leads to nail plate stacking.^8,9 Although conservative treatment using topical corticosteroids may be attempted, proximal nail plate avulsion typically is required for treatment.¹⁰

Braswell et al¹ suggested a unifying hypothesis for a common pathophysiologic basis for these 3 conditions; that is, nail matrix injury results in slowing and/or cessation of nail plate production, followed by recommencement of nail plate production by the nail matrix after removal of the insult. We report a case of a patient presenting with concurrent Beau lines, onychomadesis, and retronychia following scurvy, thus supporting the hypothesis that these 3 nail conditions lie on a continuum.

Case Report

A 41-year-old woman with a history of thyroiditis, gastroesophageal reflux disease, endometriosis, osteoarthritis, gastric ulcer, pancreatitis, fatty liver, and polycystic ovarian syndrome presented with lines on the toenails and no growth of the right second toenail of several months’ duration. She denied any pain or prior trauma to the nails, participation in sports activities, or wearing tight or high-heeled shoes. She had presented 6 months prior for evaluation of perifollicular erythema on the posterior thighs, legs, and abdomen, as well as gingival bleeding.¹¹ At that time, one of the authors (S.R.L.) found that she was vitamin C deficient, and a diagnosis of scurvy was made. The rash and gingival bleeding resolved with vitamin C supplementation.¹¹

At the current presentation, physical examination revealed transverse grooves involving several fingernails but most evident on the left thumbnail (Figure, A). The grooves did not span the entire breadth of the nail, which was consistent with Beau lines. Several toenails had parallel transverse grooves spanning the entire width of the nail plate such that the proximal nail plate was discontinuous with the distal nail plate, which was consistent with onychomadesis (Figure, B). The right second toenail was yellow and thickened with layered nail plates, indicative of retronychia (Figure, B). Histopathology of a nail plate clipping from the right second toenail was negative for fungal hyphae, and a radiograph was negative for bony changes or exostosis.

Comment

The nail matrix is responsible for nail plate production, and the newly formed nail plate then moves outward over the nail bed. It is hypothesized that the pathophysiologic basis for Beau lines, onychomadesis, and retronychia lies on a continuum such that all 3 conditions are caused by an insult to the nail matrix that results in slowing and/or halting of nail plate growth. Beau lines result from slowing or disruption in cell growth from the nail matrix, whereas onychomadesis is associated with a complete halt in nail plate production.^1,3 In retronychia, the new nail growing from the matrix pushes the old one upward, interrupting the longitudinal growth of the nail and leading to nail plate stacking.¹⁰

Our patient presented with concurrent Beau lines, onychomadesis, and retronychia. Although Beau lines and onychomadesis have been reported together in some instances,^12-14 retronychia is not commonly reported with either of these conditions. The exact incidence of each condition has not been studied, but Beau lines are relatively common, onychomadesis is less common, and retronychia is seen infrequently; therefore, the concurrent presentation of these 3 conditions in the same patient is exceedingly rare. Thus, it was most likely that one etiology accounted for all 3 nail findings.

Because the patient had been diagnosed with scurvy 6 months prior to presentation, we hypothesized that the associated vitamin C deficiency caused a systemic insult to the nail matrix, which resulted in cessation of nail growth. The mechanism of nail matrix arrest in the setting of systemic disease is thought to be due to inhibition of cellular proliferation or a change in the quality of the newly manufactured nail plate, which becomes thinner and more dystrophic.¹⁵ Vitamin C (ascorbic acid) deficiency causes scurvy, which is characterized by cutaneous signs such as perifollicular hemorrhage and purpura, corkscrew hairs, bruising, gingivitis, arthralgia, and impaired wound healing.¹⁶ These clinical manifestations are due to impaired collagen synthesis and disordered connective tissue. Ascorbic acid also is involved in fatty acid transport, neurotransmitter synthesis, prostaglandin metabolism, and nitric oxide synthesis.¹⁷ Ascorbic acid has not been studied for its role in nail plate synthesis¹⁸; however, given the role that ascorbic acid plays in a myriad of biologic processes, the deficiency associated with scurvy likely had a considerable systemic effect in our patient that halted nail plate synthesis and resulted in the concurrent presentation of Beau lines, onychomadesis, and retronychia.

Beau lines are palpable transverse depressions on the dorsal aspect of the nail plate that result from a temporary slowing of nail plate production by the proximal nail matrix. Onychomadesis is a separation of the proximal nail plate from the distal nail plate leading to shedding of the nail. It occurs due to a complete growth arrest in the nail matrix and is thought to be on a continuum with Beau lines. The etiologies of these 2 conditions overlap and include trauma, inflammatory diseases, systemic illnesses, hereditary conditions, and infections.^1-5 In almost all cases of both conditions, normal nail plate production ensues upon identification and removal of the inciting agent or recuperation from the causal illness.^3,4,6 Beau lines will move distally as the nail grows out and can be clipped. In onychomadesis, the affected nails will be shed with time. Resolution of these nail defects can be estimated from average nail growth rates (1 mm/mo for fingernails and 2–3 mm/mo for toenails).⁷

Retronychia is defined as a proximal ingrowing of the nail plate into the ventral surface of the proximal nail fold.^4,6 It is thought to occur via vertical progression of the nail plate into the proximal nail fold, repetitive nail matrix trauma, or shearing forces, resulting in inflammation that leads to nail plate stacking.^8,9 Although conservative treatment using topical corticosteroids may be attempted, proximal nail plate avulsion typically is required for treatment.¹⁰

Braswell et al¹ suggested a unifying hypothesis for a common pathophysiologic basis for these 3 conditions; that is, nail matrix injury results in slowing and/or cessation of nail plate production, followed by recommencement of nail plate production by the nail matrix after removal of the insult. We report a case of a patient presenting with concurrent Beau lines, onychomadesis, and retronychia following scurvy, thus supporting the hypothesis that these 3 nail conditions lie on a continuum.

Case Report

A 41-year-old woman with a history of thyroiditis, gastroesophageal reflux disease, endometriosis, osteoarthritis, gastric ulcer, pancreatitis, fatty liver, and polycystic ovarian syndrome presented with lines on the toenails and no growth of the right second toenail of several months’ duration. She denied any pain or prior trauma to the nails, participation in sports activities, or wearing tight or high-heeled shoes. She had presented 6 months prior for evaluation of perifollicular erythema on the posterior thighs, legs, and abdomen, as well as gingival bleeding.¹¹ At that time, one of the authors (S.R.L.) found that she was vitamin C deficient, and a diagnosis of scurvy was made. The rash and gingival bleeding resolved with vitamin C supplementation.¹¹

At the current presentation, physical examination revealed transverse grooves involving several fingernails but most evident on the left thumbnail (Figure, A). The grooves did not span the entire breadth of the nail, which was consistent with Beau lines. Several toenails had parallel transverse grooves spanning the entire width of the nail plate such that the proximal nail plate was discontinuous with the distal nail plate, which was consistent with onychomadesis (Figure, B). The right second toenail was yellow and thickened with layered nail plates, indicative of retronychia (Figure, B). Histopathology of a nail plate clipping from the right second toenail was negative for fungal hyphae, and a radiograph was negative for bony changes or exostosis.

Comment

The nail matrix is responsible for nail plate production, and the newly formed nail plate then moves outward over the nail bed. It is hypothesized that the pathophysiologic basis for Beau lines, onychomadesis, and retronychia lies on a continuum such that all 3 conditions are caused by an insult to the nail matrix that results in slowing and/or halting of nail plate growth. Beau lines result from slowing or disruption in cell growth from the nail matrix, whereas onychomadesis is associated with a complete halt in nail plate production.^1,3 In retronychia, the new nail growing from the matrix pushes the old one upward, interrupting the longitudinal growth of the nail and leading to nail plate stacking.¹⁰

Our patient presented with concurrent Beau lines, onychomadesis, and retronychia. Although Beau lines and onychomadesis have been reported together in some instances,^12-14 retronychia is not commonly reported with either of these conditions. The exact incidence of each condition has not been studied, but Beau lines are relatively common, onychomadesis is less common, and retronychia is seen infrequently; therefore, the concurrent presentation of these 3 conditions in the same patient is exceedingly rare. Thus, it was most likely that one etiology accounted for all 3 nail findings.

Because the patient had been diagnosed with scurvy 6 months prior to presentation, we hypothesized that the associated vitamin C deficiency caused a systemic insult to the nail matrix, which resulted in cessation of nail growth. The mechanism of nail matrix arrest in the setting of systemic disease is thought to be due to inhibition of cellular proliferation or a change in the quality of the newly manufactured nail plate, which becomes thinner and more dystrophic.¹⁵ Vitamin C (ascorbic acid) deficiency causes scurvy, which is characterized by cutaneous signs such as perifollicular hemorrhage and purpura, corkscrew hairs, bruising, gingivitis, arthralgia, and impaired wound healing.¹⁶ These clinical manifestations are due to impaired collagen synthesis and disordered connective tissue. Ascorbic acid also is involved in fatty acid transport, neurotransmitter synthesis, prostaglandin metabolism, and nitric oxide synthesis.¹⁷ Ascorbic acid has not been studied for its role in nail plate synthesis¹⁸; however, given the role that ascorbic acid plays in a myriad of biologic processes, the deficiency associated with scurvy likely had a considerable systemic effect in our patient that halted nail plate synthesis and resulted in the concurrent presentation of Beau lines, onychomadesis, and retronychia.

Beau lines are palpable transverse depressions on the dorsal aspect of the nail plate that result from a temporary slowing of nail plate production by the proximal nail matrix. Onychomadesis is a separation of the proximal nail plate from the distal nail plate leading to shedding of the nail. It occurs due to a complete growth arrest in the nail matrix and is thought to be on a continuum with Beau lines. The etiologies of these 2 conditions overlap and include trauma, inflammatory diseases, systemic illnesses, hereditary conditions, and infections.^1-5 In almost all cases of both conditions, normal nail plate production ensues upon identification and removal of the inciting agent or recuperation from the causal illness.^3,4,6 Beau lines will move distally as the nail grows out and can be clipped. In onychomadesis, the affected nails will be shed with time. Resolution of these nail defects can be estimated from average nail growth rates (1 mm/mo for fingernails and 2–3 mm/mo for toenails).⁷

Retronychia is defined as a proximal ingrowing of the nail plate into the ventral surface of the proximal nail fold.^4,6 It is thought to occur via vertical progression of the nail plate into the proximal nail fold, repetitive nail matrix trauma, or shearing forces, resulting in inflammation that leads to nail plate stacking.^8,9 Although conservative treatment using topical corticosteroids may be attempted, proximal nail plate avulsion typically is required for treatment.¹⁰

Braswell et al¹ suggested a unifying hypothesis for a common pathophysiologic basis for these 3 conditions; that is, nail matrix injury results in slowing and/or cessation of nail plate production, followed by recommencement of nail plate production by the nail matrix after removal of the insult. We report a case of a patient presenting with concurrent Beau lines, onychomadesis, and retronychia following scurvy, thus supporting the hypothesis that these 3 nail conditions lie on a continuum.

Case Report

A 41-year-old woman with a history of thyroiditis, gastroesophageal reflux disease, endometriosis, osteoarthritis, gastric ulcer, pancreatitis, fatty liver, and polycystic ovarian syndrome presented with lines on the toenails and no growth of the right second toenail of several months’ duration. She denied any pain or prior trauma to the nails, participation in sports activities, or wearing tight or high-heeled shoes. She had presented 6 months prior for evaluation of perifollicular erythema on the posterior thighs, legs, and abdomen, as well as gingival bleeding.¹¹ At that time, one of the authors (S.R.L.) found that she was vitamin C deficient, and a diagnosis of scurvy was made. The rash and gingival bleeding resolved with vitamin C supplementation.¹¹

At the current presentation, physical examination revealed transverse grooves involving several fingernails but most evident on the left thumbnail (Figure, A). The grooves did not span the entire breadth of the nail, which was consistent with Beau lines. Several toenails had parallel transverse grooves spanning the entire width of the nail plate such that the proximal nail plate was discontinuous with the distal nail plate, which was consistent with onychomadesis (Figure, B). The right second toenail was yellow and thickened with layered nail plates, indicative of retronychia (Figure, B). Histopathology of a nail plate clipping from the right second toenail was negative for fungal hyphae, and a radiograph was negative for bony changes or exostosis.

Comment

The nail matrix is responsible for nail plate production, and the newly formed nail plate then moves outward over the nail bed. It is hypothesized that the pathophysiologic basis for Beau lines, onychomadesis, and retronychia lies on a continuum such that all 3 conditions are caused by an insult to the nail matrix that results in slowing and/or halting of nail plate growth. Beau lines result from slowing or disruption in cell growth from the nail matrix, whereas onychomadesis is associated with a complete halt in nail plate production.^1,3 In retronychia, the new nail growing from the matrix pushes the old one upward, interrupting the longitudinal growth of the nail and leading to nail plate stacking.¹⁰

Our patient presented with concurrent Beau lines, onychomadesis, and retronychia. Although Beau lines and onychomadesis have been reported together in some instances,^12-14 retronychia is not commonly reported with either of these conditions. The exact incidence of each condition has not been studied, but Beau lines are relatively common, onychomadesis is less common, and retronychia is seen infrequently; therefore, the concurrent presentation of these 3 conditions in the same patient is exceedingly rare. Thus, it was most likely that one etiology accounted for all 3 nail findings.

Because the patient had been diagnosed with scurvy 6 months prior to presentation, we hypothesized that the associated vitamin C deficiency caused a systemic insult to the nail matrix, which resulted in cessation of nail growth. The mechanism of nail matrix arrest in the setting of systemic disease is thought to be due to inhibition of cellular proliferation or a change in the quality of the newly manufactured nail plate, which becomes thinner and more dystrophic.¹⁵ Vitamin C (ascorbic acid) deficiency causes scurvy, which is characterized by cutaneous signs such as perifollicular hemorrhage and purpura, corkscrew hairs, bruising, gingivitis, arthralgia, and impaired wound healing.¹⁶ These clinical manifestations are due to impaired collagen synthesis and disordered connective tissue. Ascorbic acid also is involved in fatty acid transport, neurotransmitter synthesis, prostaglandin metabolism, and nitric oxide synthesis.¹⁷ Ascorbic acid has not been studied for its role in nail plate synthesis¹⁸; however, given the role that ascorbic acid plays in a myriad of biologic processes, the deficiency associated with scurvy likely had a considerable systemic effect in our patient that halted nail plate synthesis and resulted in the concurrent presentation of Beau lines, onychomadesis, and retronychia.

Skin injuries caused by spines of various species of cactus are common in the southwestern United States and Mexico and have been described worldwide.¹ Effects of injury vary depending on localization, surface extension, and skin conditions (eg, preexisting erosions, ulcerations, sunburns).

Case Report

A 22-year-old woman presented to the outpatient department with extremely painful, erythematous papules on the second, third, and fourth fingers of the left hand, as well as diffuse swelling of the entire metacarpophalangeal and interphalangeal joints (Figure 1). She reported accidentally falling on a cholla cactus (genus Cylindropuntia) 2 weeks earlier while walking on a cholla cactus trail during a vacation in California. She reported that the symptoms had worsened over the last week. Class 3 corticosteroid ointments did not provide benefit. The patient had no comorbidities and was allergic to penicillin.

Radiographs of the left hand excluded concomitant fracture. Digital dermoscopy showed multiple white homogeneous areas with a central pustule (Figure 2A). Frequency-domain optical coherence tomography (OCT) displayed round hyperrefractive structures in the dermis suggestive of granulomas, as well as a small needlelike hyperrefractive structure, a foreign body (Figure 2B).

One week later, pain, erythema, and swelling had disappeared; no additional lesions had developed (Figure 3). Follow-up OCT showed no foreign bodies. At 4-week follow-up, the inflammatory component had disappeared, and no granulomas were evident. Six months later, the lesions healed with minimal scarring that could later be treated with fractional laser therapy (Figure 4).

Comment

Pathogenesis and Presentation
Cactus spines are included in the possible causes of foreign body granulomas of the skin (eTable).^2,3 However, granulomatous inflammation after cactus spine injury rarely has been described in the medical literature. In the first known case report in 1955, Winer and Zeilenga⁴ described a woman who developed multiple hand granulomas that were partially removed by curettage, while the spines underwent slow spontaneous expulsion.

In 1971, Schreiber et al⁵ hypothesized a type 2 allergic response to cactus spines based on the variability of reactions in different cases. Doctoroff et al⁶ proposed an unroofing technique based on the removal of spines under microscopy, which brought faster (2–4 months) healing. Madkan et al⁷ reported that complete response is possible only with punch excision of the largest lesions.

The cholla (Cylindropuntia) cactus has been described as the species most commonly implicated in granulomatous reactions to cactus spines.^8,9 Two principal pathogenic mechanisms have been described—foreign body granuloma and allergic reaction to cactus antigens—because not every patient develops granulomatous lesions.

Sequelae
Complications of injury from cactus spines are common, especially when spines are not completely removed, including local inflammation, superinfection, necrosis, allergic reactions, granulomas, scarring, and chronic pain. Rare consequences of cactus injury include bacterial infection with Staphylococcus aureus; Enterobacter species; atypical mycobacteria, including Mycobacterium marinum; Nocardia species; and Clostridium tetani, as well as deep fungal infection, especially in immunocompromised patients.¹⁰ In our case, bacterial culture and polymerase chain reaction testing for mycobacteria were negative.

Diagnosis
Cactus spine injuries usually are easy to diagnose based on the clear-cut anamnesis and clinical picture; however, it might be interesting to assess the presence of foreign body granulomas without biopsy. Optical coherence tomography is a noninvasive optical imaging technique based on low-coherence interferometry that uses a low-intensity, 1310-nm infrared laser. Widespread in ophthalmology, OCT has gained importance in dermatologic diagnostics, especially for nonmelanoma skin cancer.¹¹ Moreover, it has demonstrated its usefulness in various dermatologic fields, including granulomatous lesions.¹² Further methods include reflectance confocal microscopy, based on a near-infrared laser, and 7.5-MHz ultrasonography. In our experience, however, 7.5-MHz ultrasonography has been ineffective in detecting cactus spines in the current patient as well as others. Preoperative and postoperative monitoring with dermoscopy and OCT helped us evaluate the nature, size, and location of spines and lesions and effective healing.

Treatment
Management strategies are still debated and include watchful waiting, corticosteroid ointment, partial removal of spines, and unroofing.^{1,2,4-10,13-18} We treated our patient with an innovative radical surgical approach using punch excision for granulomas that developed after cholla cactus spine injury. Our approach resulted in rapid relief of pain and reduced complications, a good aesthetic result, and no recurrence.

Skin injuries caused by spines of various species of cactus are common in the southwestern United States and Mexico and have been described worldwide.¹ Effects of injury vary depending on localization, surface extension, and skin conditions (eg, preexisting erosions, ulcerations, sunburns).

Case Report

A 22-year-old woman presented to the outpatient department with extremely painful, erythematous papules on the second, third, and fourth fingers of the left hand, as well as diffuse swelling of the entire metacarpophalangeal and interphalangeal joints (Figure 1). She reported accidentally falling on a cholla cactus (genus Cylindropuntia) 2 weeks earlier while walking on a cholla cactus trail during a vacation in California. She reported that the symptoms had worsened over the last week. Class 3 corticosteroid ointments did not provide benefit. The patient had no comorbidities and was allergic to penicillin.

Radiographs of the left hand excluded concomitant fracture. Digital dermoscopy showed multiple white homogeneous areas with a central pustule (Figure 2A). Frequency-domain optical coherence tomography (OCT) displayed round hyperrefractive structures in the dermis suggestive of granulomas, as well as a small needlelike hyperrefractive structure, a foreign body (Figure 2B).

One week later, pain, erythema, and swelling had disappeared; no additional lesions had developed (Figure 3). Follow-up OCT showed no foreign bodies. At 4-week follow-up, the inflammatory component had disappeared, and no granulomas were evident. Six months later, the lesions healed with minimal scarring that could later be treated with fractional laser therapy (Figure 4).

Comment

Pathogenesis and Presentation
Cactus spines are included in the possible causes of foreign body granulomas of the skin (eTable).^2,3 However, granulomatous inflammation after cactus spine injury rarely has been described in the medical literature. In the first known case report in 1955, Winer and Zeilenga⁴ described a woman who developed multiple hand granulomas that were partially removed by curettage, while the spines underwent slow spontaneous expulsion.

In 1971, Schreiber et al⁵ hypothesized a type 2 allergic response to cactus spines based on the variability of reactions in different cases. Doctoroff et al⁶ proposed an unroofing technique based on the removal of spines under microscopy, which brought faster (2–4 months) healing. Madkan et al⁷ reported that complete response is possible only with punch excision of the largest lesions.

The cholla (Cylindropuntia) cactus has been described as the species most commonly implicated in granulomatous reactions to cactus spines.^8,9 Two principal pathogenic mechanisms have been described—foreign body granuloma and allergic reaction to cactus antigens—because not every patient develops granulomatous lesions.

Sequelae
Complications of injury from cactus spines are common, especially when spines are not completely removed, including local inflammation, superinfection, necrosis, allergic reactions, granulomas, scarring, and chronic pain. Rare consequences of cactus injury include bacterial infection with Staphylococcus aureus; Enterobacter species; atypical mycobacteria, including Mycobacterium marinum; Nocardia species; and Clostridium tetani, as well as deep fungal infection, especially in immunocompromised patients.¹⁰ In our case, bacterial culture and polymerase chain reaction testing for mycobacteria were negative.

Diagnosis
Cactus spine injuries usually are easy to diagnose based on the clear-cut anamnesis and clinical picture; however, it might be interesting to assess the presence of foreign body granulomas without biopsy. Optical coherence tomography is a noninvasive optical imaging technique based on low-coherence interferometry that uses a low-intensity, 1310-nm infrared laser. Widespread in ophthalmology, OCT has gained importance in dermatologic diagnostics, especially for nonmelanoma skin cancer.¹¹ Moreover, it has demonstrated its usefulness in various dermatologic fields, including granulomatous lesions.¹² Further methods include reflectance confocal microscopy, based on a near-infrared laser, and 7.5-MHz ultrasonography. In our experience, however, 7.5-MHz ultrasonography has been ineffective in detecting cactus spines in the current patient as well as others. Preoperative and postoperative monitoring with dermoscopy and OCT helped us evaluate the nature, size, and location of spines and lesions and effective healing.

Treatment
Management strategies are still debated and include watchful waiting, corticosteroid ointment, partial removal of spines, and unroofing.^{1,2,4-10,13-18} We treated our patient with an innovative radical surgical approach using punch excision for granulomas that developed after cholla cactus spine injury. Our approach resulted in rapid relief of pain and reduced complications, a good aesthetic result, and no recurrence.

Skin injuries caused by spines of various species of cactus are common in the southwestern United States and Mexico and have been described worldwide.¹ Effects of injury vary depending on localization, surface extension, and skin conditions (eg, preexisting erosions, ulcerations, sunburns).

Case Report

A 22-year-old woman presented to the outpatient department with extremely painful, erythematous papules on the second, third, and fourth fingers of the left hand, as well as diffuse swelling of the entire metacarpophalangeal and interphalangeal joints (Figure 1). She reported accidentally falling on a cholla cactus (genus Cylindropuntia) 2 weeks earlier while walking on a cholla cactus trail during a vacation in California. She reported that the symptoms had worsened over the last week. Class 3 corticosteroid ointments did not provide benefit. The patient had no comorbidities and was allergic to penicillin.

Radiographs of the left hand excluded concomitant fracture. Digital dermoscopy showed multiple white homogeneous areas with a central pustule (Figure 2A). Frequency-domain optical coherence tomography (OCT) displayed round hyperrefractive structures in the dermis suggestive of granulomas, as well as a small needlelike hyperrefractive structure, a foreign body (Figure 2B).

One week later, pain, erythema, and swelling had disappeared; no additional lesions had developed (Figure 3). Follow-up OCT showed no foreign bodies. At 4-week follow-up, the inflammatory component had disappeared, and no granulomas were evident. Six months later, the lesions healed with minimal scarring that could later be treated with fractional laser therapy (Figure 4).

Comment

Pathogenesis and Presentation
Cactus spines are included in the possible causes of foreign body granulomas of the skin (eTable).^2,3 However, granulomatous inflammation after cactus spine injury rarely has been described in the medical literature. In the first known case report in 1955, Winer and Zeilenga⁴ described a woman who developed multiple hand granulomas that were partially removed by curettage, while the spines underwent slow spontaneous expulsion.

In 1971, Schreiber et al⁵ hypothesized a type 2 allergic response to cactus spines based on the variability of reactions in different cases. Doctoroff et al⁶ proposed an unroofing technique based on the removal of spines under microscopy, which brought faster (2–4 months) healing. Madkan et al⁷ reported that complete response is possible only with punch excision of the largest lesions.

The cholla (Cylindropuntia) cactus has been described as the species most commonly implicated in granulomatous reactions to cactus spines.^8,9 Two principal pathogenic mechanisms have been described—foreign body granuloma and allergic reaction to cactus antigens—because not every patient develops granulomatous lesions.

Sequelae
Complications of injury from cactus spines are common, especially when spines are not completely removed, including local inflammation, superinfection, necrosis, allergic reactions, granulomas, scarring, and chronic pain. Rare consequences of cactus injury include bacterial infection with Staphylococcus aureus; Enterobacter species; atypical mycobacteria, including Mycobacterium marinum; Nocardia species; and Clostridium tetani, as well as deep fungal infection, especially in immunocompromised patients.¹⁰ In our case, bacterial culture and polymerase chain reaction testing for mycobacteria were negative.

Diagnosis
Cactus spine injuries usually are easy to diagnose based on the clear-cut anamnesis and clinical picture; however, it might be interesting to assess the presence of foreign body granulomas without biopsy. Optical coherence tomography is a noninvasive optical imaging technique based on low-coherence interferometry that uses a low-intensity, 1310-nm infrared laser. Widespread in ophthalmology, OCT has gained importance in dermatologic diagnostics, especially for nonmelanoma skin cancer.¹¹ Moreover, it has demonstrated its usefulness in various dermatologic fields, including granulomatous lesions.¹² Further methods include reflectance confocal microscopy, based on a near-infrared laser, and 7.5-MHz ultrasonography. In our experience, however, 7.5-MHz ultrasonography has been ineffective in detecting cactus spines in the current patient as well as others. Preoperative and postoperative monitoring with dermoscopy and OCT helped us evaluate the nature, size, and location of spines and lesions and effective healing.

Treatment
Management strategies are still debated and include watchful waiting, corticosteroid ointment, partial removal of spines, and unroofing.^{1,2,4-10,13-18} We treated our patient with an innovative radical surgical approach using punch excision for granulomas that developed after cholla cactus spine injury. Our approach resulted in rapid relief of pain and reduced complications, a good aesthetic result, and no recurrence.

THE CASE

A 5-year-old boy was brought into his primary care clinic by his mother, who expressed concern about her son’s increasing impulsiveness, aggression, and difficulty staying on task at preschool and at home. The child’s medical history was unremarkable, and he was taking no medications. The family history was negative for hepatic or metabolic disease and positive for attention deficit-hyperactivity disorder (ADHD; father).

The child’s growth was normal. His physical exam was remarkable for a liver edge 1 cm below his costal margin. No Kayser-Fleischer rings were present. 

Screening included a complete metabolic panel. Notable results included an alanine aminotransferase (ALT) level of 208 U/dL (normal range, < 30 U/dL), an aspartate transaminase (AST) level of 125 U/dL (normal range, 10-34 U/dL), and an alkaline phosphatase (ALP) of 470 U/dL (normal range, 93-309 U/dL). Subsequent repeat laboratory testing confirmed these elevations (ALT, 248 U/dL; AST, 137 U/dL; ALP, 462 U/dL). Ceruloplasmin levels were low (11 mg/dL; normal range, 18-35 mg/dL), and 24-hour urinary copper was not obtainable. Prothrombin/partial thromboplastin time, ammonia, lactate, total and direct bilirubin, and gamma-glutamyltransferase levels were normal.

Further evaluation included abdominal ultrasound and brain magnetic resonance imaging, both of which yielded normal results. Testing for Epstein-Barr virus; ­cytomegalovirus; hepatitis A, B, and C titers; and antinuclear, anti-smooth muscle, and anti–liver-kidney microsomal antibodies was negative.

THE DIAGNOSIS

The patient’s low ceruloplasmin prompted referral to Pediatric Gastroenterology for consultation and liver biopsy due to concern for Wilson disease. Biopsy results were consistent with, and quantitative liver copper confirmatory for, this diagnosis (FIGURE).

Genetic testing for mutations in the ATP7B gene was performed on the patient, his mother, and his siblings (his father was unavailable). The patient, his mother, and his sister were all positive for His1069Gln mutation; only the patient was positive for a 3990_3993 del mutation (his half-brother was negative for both mutations). The presence of 2 different mutant alleles for the ATP7B gene, one on each chromosome—the common substitution mutation, His1069Gln, in exon 14 and a 3990_3993 del TTAT mutation in exon 19—qualified the patient as a compound heterozygote.

The 3990_3993 del TTAT mutation—which to our knowledge has not been previously reported—produced a translational frame shift and premature stop codon. As others have pointed out, frame shift and missense mutations produce a more severe phenotype.¹

Continue to: Further testing was prompted...

Further testing was prompted by a report suggesting that codon 129 mutations of the human prion gene (HPG) influence Wilson disease.² Compared with patients who are heterozygous (M129V) or homozygous (V129V) for valine, those who are homozygous for methionine (M129M) have delayed symptom onset.² Our patient was heterozygous (M129V). It is interesting to speculate that HPG heterozygosity, combined with a mutation causing a stop codon, predisposed our patient to more rapid accumulation of copper and earlier age of onset.  

DISCUSSION

Wilson disease is an inherited disorder of copper metabolism.³ An inherent difficulty in its recognition, diagnosis, and management is its rarity: global prevalence is estimated as 1/30,000, although this varies by geographic location.¹ In contrast, ADHD has a prevalence of 7.2%,⁴ making it 2400 times more prevalent than Wilson disease. Furthermore, abnormal liver function tests are common in children; the differential diagnosis includes etiologies such as infection (both viral and nonviral), immune-mediated inflammatory disease, drug toxicity (iatrogenic or medication-induced), anatomic abnormalities, and nonalcoholic fatty liver disease.⁵

Wilson disease is remarkable, however, for being easily treatable if detected and devastating if not. Although liver abnormalities often improve with treatment, delayed diagnosis and management significantly impact neurologic recovery: An 18-month delay results in 38% of patients continuing to have major neurologic disabilities.⁶ Untreated, Wilson disease may be fatal within 5 years of development of neurologic symptoms.⁷ Thus, it has been suggested that evaluation for Wilson disease be considered in any child older than 1 year who presents with unexplained liver disease, including asymptomatic elevations of serum transaminases.⁸

Mutations in ATP7B on chromosome 13 are responsible for the pathology of Wilson disease⁹; more than 250 mutations have been identified, including substitutions, deletions, and missense mutations.¹⁰ Affected patients may be compound heterozygotes¹¹ and/or may possess new mutations, as seen in our patient.

Although copper absorption is normal, impaired excretion causes toxic accumulation in affected organs. ATP7B’s product, ATPase 2, regulates copper excretion, as well as copper binding to apoceruloplasmin to form the carrier protein ceruloplasmin. An ATP7B abnormality would prevent the latter—making ceruloplasmin a useful screening biomarker and a reliable marker for Wilson disease by age 1 year.⁸

Continue to: Hepatic and neurocognitive effects

Hepatic and neurocognitive effects. Excess copper in hepatocytes causes oxidative damage and release of copper into the circulation, with accumulation in susceptible organs (eg, brain, kidneys). Hepatocyte apoptosis is accelerated by copper’s negative effect on inhibitor of apoptosis protein.^12,13 Renal tubular damage leads to Fanconi syndrome,¹⁴ in which substances such as glucose, phosphates, and potassium are excreted in urine rather than absorbed into the bloodstream by the kidneys. Excess copper deposition in the Descemet membrane may lead to Kayser-Fleisher ring formation.¹⁵ In the brain, copper deposition may occur in the lenticular nuclei,³ as well as in the thalamus, subthalamus, brainstem, and frontal cortex—resulting in extrapyramidal, cerebral, and mild cerebellar symptoms.⁶  

Cognitive impairment, which may be subtle, includes increased impulsivity, impaired judgment, apathy, poor decision making, decreased attention, increased lability, slowed thinking, and memory loss.⁶ Behavioral manifestations include changes in school or work performance and outbursts mimicking ADHD^12,16,17 as well as paranoia, depression, and bizarre behaviors.^16,18 Neuropsychiatric abnormalities include personality changes, pseudoparkinsonism, dyskinesia/dysarthria, and ataxia/tremor. Younger patients with psychiatric symptoms may be labelled with depression, anxiety, obsessive-compulsive disorder, bipolar disorder, or antisocial disorder.^6,16,18

Hepatic disease manifestations range from asymptomatic elevations in AST/ALT to acute hepatitis, mimicking infectious processes. Cirrhosis is the end result of untreated Wilson disease, with liver transplantation required if end-stage liver disease results. Rarely, patients present in fulminant hepatic failure, with death occurring if emergent liver transplantation is not performed.^6,8,10

In this case, routine screening saved the day.

Of note, before age 10, > 80% of patients with Wilson disease present with hepatic symptoms; those ages 10 to 18 often manifest psychiatric changes.¹⁷ Kayser-Fleisher rings are common in patients with neurologic manifestations but less so in those who have hepatic presentations or are presymptomatic.^6,15

Effective disease-mitigating treatment is indicated and available for both symptomatic and asymptomatic individuals and includes the copper chelators D-penicillamine (starting dose, 150-300 mg/d with a gradual weekly increase to 20 mg/kg/d) and trientine hydrochloride (a heavy metal chelating compound; starting dose, 20 mg/kg/d to a maximum of 1000 mg/d in young adults). Adverse effects of D-penicillamine include cutaneous eruptions, neutropenia, thrombocytopenia, proteinuria, and a lupus-like syndrome; therefore, trientine is increasingly being used as first-line therapy.⁸

Continue to: For asymptomatic...

For asymptomatic patients who have had effective chelation therapy and proven de-coppering, zinc salts are a useful follow-on therapy. Zinc’s proposed mechanism of action is induction of metallothionein in enterocytes, which promotes copper trapping and eventual excretion into the lumen. Importantly, treatment for Wilson disease is lifelong and monitoring of compliance is essential.⁸

Our 5-year-old patient was started on oral trientine at 20 mg/kg/d and a low copper diet. In response to this initial treatment, the patient’s liver function tests (LFTs) normalized, and he was switched to 25 mg tid of a zinc chelate, with continuation of the low copper diet. His LFTs have remained normal, although his urine copper levels are still elevated. He continues to be monitored periodically with LFTs and measurement of urine copper levels. He is also being treated for ADHD, as his presenting behavioral abnormalities suggestive of ADHD have not resolved.

THE TAKEAWAY

Although children presenting with symptoms consistent with ADHD often have ADHD, as was true in this case, it is important to consider other diagnoses. Unexplained elevations of liver function test values in children older than 1 year should prompt screening for Wilson disease.^5,8 Additionally, other family members should be evaluated; if they have the disease, treatment should be started by age 2 years, even if the patient is asymptomatic.

In our patient’s case, routine screening saved the day. The complete metabolic panel revealed elevated ALT and AST levels, prompting further evaluation. Without this testing, his diagnosis likely would have been delayed, leading to progressive liver and central nervous system disease. With early identification and treatment, it is possible to stop the progression of Wilson disease.

CORRESPONDENCE
Jeffrey Taylor, MD, MS, Evangelical Community Hospital, Department of Pediatrics, 1 Hospital Drive, Lewisburg PA, 17837; [email protected].

THE CASE

A 5-year-old boy was brought into his primary care clinic by his mother, who expressed concern about her son’s increasing impulsiveness, aggression, and difficulty staying on task at preschool and at home. The child’s medical history was unremarkable, and he was taking no medications. The family history was negative for hepatic or metabolic disease and positive for attention deficit-hyperactivity disorder (ADHD; father).

The child’s growth was normal. His physical exam was remarkable for a liver edge 1 cm below his costal margin. No Kayser-Fleischer rings were present. 

Screening included a complete metabolic panel. Notable results included an alanine aminotransferase (ALT) level of 208 U/dL (normal range, < 30 U/dL), an aspartate transaminase (AST) level of 125 U/dL (normal range, 10-34 U/dL), and an alkaline phosphatase (ALP) of 470 U/dL (normal range, 93-309 U/dL). Subsequent repeat laboratory testing confirmed these elevations (ALT, 248 U/dL; AST, 137 U/dL; ALP, 462 U/dL). Ceruloplasmin levels were low (11 mg/dL; normal range, 18-35 mg/dL), and 24-hour urinary copper was not obtainable. Prothrombin/partial thromboplastin time, ammonia, lactate, total and direct bilirubin, and gamma-glutamyltransferase levels were normal.

Further evaluation included abdominal ultrasound and brain magnetic resonance imaging, both of which yielded normal results. Testing for Epstein-Barr virus; ­cytomegalovirus; hepatitis A, B, and C titers; and antinuclear, anti-smooth muscle, and anti–liver-kidney microsomal antibodies was negative.

THE DIAGNOSIS

The patient’s low ceruloplasmin prompted referral to Pediatric Gastroenterology for consultation and liver biopsy due to concern for Wilson disease. Biopsy results were consistent with, and quantitative liver copper confirmatory for, this diagnosis (FIGURE).

Genetic testing for mutations in the ATP7B gene was performed on the patient, his mother, and his siblings (his father was unavailable). The patient, his mother, and his sister were all positive for His1069Gln mutation; only the patient was positive for a 3990_3993 del mutation (his half-brother was negative for both mutations). The presence of 2 different mutant alleles for the ATP7B gene, one on each chromosome—the common substitution mutation, His1069Gln, in exon 14 and a 3990_3993 del TTAT mutation in exon 19—qualified the patient as a compound heterozygote.

The 3990_3993 del TTAT mutation—which to our knowledge has not been previously reported—produced a translational frame shift and premature stop codon. As others have pointed out, frame shift and missense mutations produce a more severe phenotype.¹

Continue to: Further testing was prompted...

Further testing was prompted by a report suggesting that codon 129 mutations of the human prion gene (HPG) influence Wilson disease.² Compared with patients who are heterozygous (M129V) or homozygous (V129V) for valine, those who are homozygous for methionine (M129M) have delayed symptom onset.² Our patient was heterozygous (M129V). It is interesting to speculate that HPG heterozygosity, combined with a mutation causing a stop codon, predisposed our patient to more rapid accumulation of copper and earlier age of onset.  

DISCUSSION

Wilson disease is an inherited disorder of copper metabolism.³ An inherent difficulty in its recognition, diagnosis, and management is its rarity: global prevalence is estimated as 1/30,000, although this varies by geographic location.¹ In contrast, ADHD has a prevalence of 7.2%,⁴ making it 2400 times more prevalent than Wilson disease. Furthermore, abnormal liver function tests are common in children; the differential diagnosis includes etiologies such as infection (both viral and nonviral), immune-mediated inflammatory disease, drug toxicity (iatrogenic or medication-induced), anatomic abnormalities, and nonalcoholic fatty liver disease.⁵

Wilson disease is remarkable, however, for being easily treatable if detected and devastating if not. Although liver abnormalities often improve with treatment, delayed diagnosis and management significantly impact neurologic recovery: An 18-month delay results in 38% of patients continuing to have major neurologic disabilities.⁶ Untreated, Wilson disease may be fatal within 5 years of development of neurologic symptoms.⁷ Thus, it has been suggested that evaluation for Wilson disease be considered in any child older than 1 year who presents with unexplained liver disease, including asymptomatic elevations of serum transaminases.⁸

Mutations in ATP7B on chromosome 13 are responsible for the pathology of Wilson disease⁹; more than 250 mutations have been identified, including substitutions, deletions, and missense mutations.¹⁰ Affected patients may be compound heterozygotes¹¹ and/or may possess new mutations, as seen in our patient.

Although copper absorption is normal, impaired excretion causes toxic accumulation in affected organs. ATP7B’s product, ATPase 2, regulates copper excretion, as well as copper binding to apoceruloplasmin to form the carrier protein ceruloplasmin. An ATP7B abnormality would prevent the latter—making ceruloplasmin a useful screening biomarker and a reliable marker for Wilson disease by age 1 year.⁸

Continue to: Hepatic and neurocognitive effects

Hepatic and neurocognitive effects. Excess copper in hepatocytes causes oxidative damage and release of copper into the circulation, with accumulation in susceptible organs (eg, brain, kidneys). Hepatocyte apoptosis is accelerated by copper’s negative effect on inhibitor of apoptosis protein.^12,13 Renal tubular damage leads to Fanconi syndrome,¹⁴ in which substances such as glucose, phosphates, and potassium are excreted in urine rather than absorbed into the bloodstream by the kidneys. Excess copper deposition in the Descemet membrane may lead to Kayser-Fleisher ring formation.¹⁵ In the brain, copper deposition may occur in the lenticular nuclei,³ as well as in the thalamus, subthalamus, brainstem, and frontal cortex—resulting in extrapyramidal, cerebral, and mild cerebellar symptoms.⁶  

Cognitive impairment, which may be subtle, includes increased impulsivity, impaired judgment, apathy, poor decision making, decreased attention, increased lability, slowed thinking, and memory loss.⁶ Behavioral manifestations include changes in school or work performance and outbursts mimicking ADHD^12,16,17 as well as paranoia, depression, and bizarre behaviors.^16,18 Neuropsychiatric abnormalities include personality changes, pseudoparkinsonism, dyskinesia/dysarthria, and ataxia/tremor. Younger patients with psychiatric symptoms may be labelled with depression, anxiety, obsessive-compulsive disorder, bipolar disorder, or antisocial disorder.^6,16,18

Hepatic disease manifestations range from asymptomatic elevations in AST/ALT to acute hepatitis, mimicking infectious processes. Cirrhosis is the end result of untreated Wilson disease, with liver transplantation required if end-stage liver disease results. Rarely, patients present in fulminant hepatic failure, with death occurring if emergent liver transplantation is not performed.^6,8,10

In this case, routine screening saved the day.

Of note, before age 10, > 80% of patients with Wilson disease present with hepatic symptoms; those ages 10 to 18 often manifest psychiatric changes.¹⁷ Kayser-Fleisher rings are common in patients with neurologic manifestations but less so in those who have hepatic presentations or are presymptomatic.^6,15

Effective disease-mitigating treatment is indicated and available for both symptomatic and asymptomatic individuals and includes the copper chelators D-penicillamine (starting dose, 150-300 mg/d with a gradual weekly increase to 20 mg/kg/d) and trientine hydrochloride (a heavy metal chelating compound; starting dose, 20 mg/kg/d to a maximum of 1000 mg/d in young adults). Adverse effects of D-penicillamine include cutaneous eruptions, neutropenia, thrombocytopenia, proteinuria, and a lupus-like syndrome; therefore, trientine is increasingly being used as first-line therapy.⁸

Continue to: For asymptomatic...

For asymptomatic patients who have had effective chelation therapy and proven de-coppering, zinc salts are a useful follow-on therapy. Zinc’s proposed mechanism of action is induction of metallothionein in enterocytes, which promotes copper trapping and eventual excretion into the lumen. Importantly, treatment for Wilson disease is lifelong and monitoring of compliance is essential.⁸

Our 5-year-old patient was started on oral trientine at 20 mg/kg/d and a low copper diet. In response to this initial treatment, the patient’s liver function tests (LFTs) normalized, and he was switched to 25 mg tid of a zinc chelate, with continuation of the low copper diet. His LFTs have remained normal, although his urine copper levels are still elevated. He continues to be monitored periodically with LFTs and measurement of urine copper levels. He is also being treated for ADHD, as his presenting behavioral abnormalities suggestive of ADHD have not resolved.

THE TAKEAWAY

Although children presenting with symptoms consistent with ADHD often have ADHD, as was true in this case, it is important to consider other diagnoses. Unexplained elevations of liver function test values in children older than 1 year should prompt screening for Wilson disease.^5,8 Additionally, other family members should be evaluated; if they have the disease, treatment should be started by age 2 years, even if the patient is asymptomatic.

In our patient’s case, routine screening saved the day. The complete metabolic panel revealed elevated ALT and AST levels, prompting further evaluation. Without this testing, his diagnosis likely would have been delayed, leading to progressive liver and central nervous system disease. With early identification and treatment, it is possible to stop the progression of Wilson disease.

CORRESPONDENCE
Jeffrey Taylor, MD, MS, Evangelical Community Hospital, Department of Pediatrics, 1 Hospital Drive, Lewisburg PA, 17837; [email protected].

THE CASE

A 5-year-old boy was brought into his primary care clinic by his mother, who expressed concern about her son’s increasing impulsiveness, aggression, and difficulty staying on task at preschool and at home. The child’s medical history was unremarkable, and he was taking no medications. The family history was negative for hepatic or metabolic disease and positive for attention deficit-hyperactivity disorder (ADHD; father).

The child’s growth was normal. His physical exam was remarkable for a liver edge 1 cm below his costal margin. No Kayser-Fleischer rings were present. 

Screening included a complete metabolic panel. Notable results included an alanine aminotransferase (ALT) level of 208 U/dL (normal range, < 30 U/dL), an aspartate transaminase (AST) level of 125 U/dL (normal range, 10-34 U/dL), and an alkaline phosphatase (ALP) of 470 U/dL (normal range, 93-309 U/dL). Subsequent repeat laboratory testing confirmed these elevations (ALT, 248 U/dL; AST, 137 U/dL; ALP, 462 U/dL). Ceruloplasmin levels were low (11 mg/dL; normal range, 18-35 mg/dL), and 24-hour urinary copper was not obtainable. Prothrombin/partial thromboplastin time, ammonia, lactate, total and direct bilirubin, and gamma-glutamyltransferase levels were normal.

Further evaluation included abdominal ultrasound and brain magnetic resonance imaging, both of which yielded normal results. Testing for Epstein-Barr virus; ­cytomegalovirus; hepatitis A, B, and C titers; and antinuclear, anti-smooth muscle, and anti–liver-kidney microsomal antibodies was negative.

THE DIAGNOSIS

The patient’s low ceruloplasmin prompted referral to Pediatric Gastroenterology for consultation and liver biopsy due to concern for Wilson disease. Biopsy results were consistent with, and quantitative liver copper confirmatory for, this diagnosis (FIGURE).

Genetic testing for mutations in the ATP7B gene was performed on the patient, his mother, and his siblings (his father was unavailable). The patient, his mother, and his sister were all positive for His1069Gln mutation; only the patient was positive for a 3990_3993 del mutation (his half-brother was negative for both mutations). The presence of 2 different mutant alleles for the ATP7B gene, one on each chromosome—the common substitution mutation, His1069Gln, in exon 14 and a 3990_3993 del TTAT mutation in exon 19—qualified the patient as a compound heterozygote.

The 3990_3993 del TTAT mutation—which to our knowledge has not been previously reported—produced a translational frame shift and premature stop codon. As others have pointed out, frame shift and missense mutations produce a more severe phenotype.¹

Continue to: Further testing was prompted...

Further testing was prompted by a report suggesting that codon 129 mutations of the human prion gene (HPG) influence Wilson disease.² Compared with patients who are heterozygous (M129V) or homozygous (V129V) for valine, those who are homozygous for methionine (M129M) have delayed symptom onset.² Our patient was heterozygous (M129V). It is interesting to speculate that HPG heterozygosity, combined with a mutation causing a stop codon, predisposed our patient to more rapid accumulation of copper and earlier age of onset.  

DISCUSSION

Wilson disease is an inherited disorder of copper metabolism.³ An inherent difficulty in its recognition, diagnosis, and management is its rarity: global prevalence is estimated as 1/30,000, although this varies by geographic location.¹ In contrast, ADHD has a prevalence of 7.2%,⁴ making it 2400 times more prevalent than Wilson disease. Furthermore, abnormal liver function tests are common in children; the differential diagnosis includes etiologies such as infection (both viral and nonviral), immune-mediated inflammatory disease, drug toxicity (iatrogenic or medication-induced), anatomic abnormalities, and nonalcoholic fatty liver disease.⁵

Wilson disease is remarkable, however, for being easily treatable if detected and devastating if not. Although liver abnormalities often improve with treatment, delayed diagnosis and management significantly impact neurologic recovery: An 18-month delay results in 38% of patients continuing to have major neurologic disabilities.⁶ Untreated, Wilson disease may be fatal within 5 years of development of neurologic symptoms.⁷ Thus, it has been suggested that evaluation for Wilson disease be considered in any child older than 1 year who presents with unexplained liver disease, including asymptomatic elevations of serum transaminases.⁸

Mutations in ATP7B on chromosome 13 are responsible for the pathology of Wilson disease⁹; more than 250 mutations have been identified, including substitutions, deletions, and missense mutations.¹⁰ Affected patients may be compound heterozygotes¹¹ and/or may possess new mutations, as seen in our patient.

Although copper absorption is normal, impaired excretion causes toxic accumulation in affected organs. ATP7B’s product, ATPase 2, regulates copper excretion, as well as copper binding to apoceruloplasmin to form the carrier protein ceruloplasmin. An ATP7B abnormality would prevent the latter—making ceruloplasmin a useful screening biomarker and a reliable marker for Wilson disease by age 1 year.⁸

Continue to: Hepatic and neurocognitive effects

Hepatic and neurocognitive effects. Excess copper in hepatocytes causes oxidative damage and release of copper into the circulation, with accumulation in susceptible organs (eg, brain, kidneys). Hepatocyte apoptosis is accelerated by copper’s negative effect on inhibitor of apoptosis protein.^12,13 Renal tubular damage leads to Fanconi syndrome,¹⁴ in which substances such as glucose, phosphates, and potassium are excreted in urine rather than absorbed into the bloodstream by the kidneys. Excess copper deposition in the Descemet membrane may lead to Kayser-Fleisher ring formation.¹⁵ In the brain, copper deposition may occur in the lenticular nuclei,³ as well as in the thalamus, subthalamus, brainstem, and frontal cortex—resulting in extrapyramidal, cerebral, and mild cerebellar symptoms.⁶  

Cognitive impairment, which may be subtle, includes increased impulsivity, impaired judgment, apathy, poor decision making, decreased attention, increased lability, slowed thinking, and memory loss.⁶ Behavioral manifestations include changes in school or work performance and outbursts mimicking ADHD^12,16,17 as well as paranoia, depression, and bizarre behaviors.^16,18 Neuropsychiatric abnormalities include personality changes, pseudoparkinsonism, dyskinesia/dysarthria, and ataxia/tremor. Younger patients with psychiatric symptoms may be labelled with depression, anxiety, obsessive-compulsive disorder, bipolar disorder, or antisocial disorder.^6,16,18

Hepatic disease manifestations range from asymptomatic elevations in AST/ALT to acute hepatitis, mimicking infectious processes. Cirrhosis is the end result of untreated Wilson disease, with liver transplantation required if end-stage liver disease results. Rarely, patients present in fulminant hepatic failure, with death occurring if emergent liver transplantation is not performed.^6,8,10

In this case, routine screening saved the day.

Of note, before age 10, > 80% of patients with Wilson disease present with hepatic symptoms; those ages 10 to 18 often manifest psychiatric changes.¹⁷ Kayser-Fleisher rings are common in patients with neurologic manifestations but less so in those who have hepatic presentations or are presymptomatic.^6,15

Effective disease-mitigating treatment is indicated and available for both symptomatic and asymptomatic individuals and includes the copper chelators D-penicillamine (starting dose, 150-300 mg/d with a gradual weekly increase to 20 mg/kg/d) and trientine hydrochloride (a heavy metal chelating compound; starting dose, 20 mg/kg/d to a maximum of 1000 mg/d in young adults). Adverse effects of D-penicillamine include cutaneous eruptions, neutropenia, thrombocytopenia, proteinuria, and a lupus-like syndrome; therefore, trientine is increasingly being used as first-line therapy.⁸

Continue to: For asymptomatic...

For asymptomatic patients who have had effective chelation therapy and proven de-coppering, zinc salts are a useful follow-on therapy. Zinc’s proposed mechanism of action is induction of metallothionein in enterocytes, which promotes copper trapping and eventual excretion into the lumen. Importantly, treatment for Wilson disease is lifelong and monitoring of compliance is essential.⁸

Our 5-year-old patient was started on oral trientine at 20 mg/kg/d and a low copper diet. In response to this initial treatment, the patient’s liver function tests (LFTs) normalized, and he was switched to 25 mg tid of a zinc chelate, with continuation of the low copper diet. His LFTs have remained normal, although his urine copper levels are still elevated. He continues to be monitored periodically with LFTs and measurement of urine copper levels. He is also being treated for ADHD, as his presenting behavioral abnormalities suggestive of ADHD have not resolved.

THE TAKEAWAY

Although children presenting with symptoms consistent with ADHD often have ADHD, as was true in this case, it is important to consider other diagnoses. Unexplained elevations of liver function test values in children older than 1 year should prompt screening for Wilson disease.^5,8 Additionally, other family members should be evaluated; if they have the disease, treatment should be started by age 2 years, even if the patient is asymptomatic.

In our patient’s case, routine screening saved the day. The complete metabolic panel revealed elevated ALT and AST levels, prompting further evaluation. Without this testing, his diagnosis likely would have been delayed, leading to progressive liver and central nervous system disease. With early identification and treatment, it is possible to stop the progression of Wilson disease.

CORRESPONDENCE
Jeffrey Taylor, MD, MS, Evangelical Community Hospital, Department of Pediatrics, 1 Hospital Drive, Lewisburg PA, 17837; [email protected].

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

THE CASE

A 56-year-old woman presented with a 3-day complaint of worsening left upper arm pain. She denied having any specific initiating factors but reported receiving an influenza vaccination in the arm a few days prior to the onset of pain. The patient did not have any associated numbness or tingling in the arm. She reported that the pain was worse with movement—especially abduction. The patient reported taking an over-the-counter nonsteroidal anti-­inflammatory drug (NSAID) without much relief.

On physical examination, the patient had difficulty with active range of motion and had erythema, swelling, and tenderness to palpation along the subacromial space and the proximal deltoid. Further examination of the shoulder revealed a positive Neer Impingement Test and a positive Hawkins–Kennedy Test. (For more on these tests, visit “MSK Clinic: Evaluating shoulder pain using IPASS.”). The patient demonstrated full passive range of motion, but her pain was exacerbated with abduction.

THE DIAGNOSIS

In light of the soft-tissue findings and the absence of trauma, magnetic resonance imaging (MRI), rather than an ­x-ray, of the upper extremity was ordered. ­Imaging revealed subacromial subdeltoid bursal inflammation (FIGURE).

DISCUSSION

Shoulder injury related to vaccine administration (SIRVA) is the result of accidental injection of a vaccine into the tissue lying underneath the deltoid muscle or joint space, leading to a suspected immune-mediated inflammatory reaction.

A report from the National Vaccine Advisory Committee of the US ­Department of Health & Human Services showed an increase in the number of reported cases of SIRVA (59 reported cases in 2011-2014 and 202 cases reported in 2016).¹ Additionally, in 2016 more than $29 million was awarded in compensation to patients with SIRVA.^1,2 In a 2011 report, an Institute of Medicine committee found convincing evidence of a causal relationship between injection of vaccine, independent of the antigen involved, and deltoid bursitis, or frozen shoulder, characterized by shoulder pain and loss of motion.³

A review of 13 cases revealed that 50% of the patients reported pain immediately after the injection and 90% had developed pain within 24 hours.² On physical exam, a limited range of motion and pain were the most common findings, while weakness and sensory changes were uncommon. In some cases, the pain lasted several years and 30% of the patients required surgery. Forty-six percent of the patients reported apprehension concerning the administration of the vaccine, specifically that the injection was administered “too high” into the deltoid.²

In the review of cases, routine x-rays of the shoulder did not provide beneficial diagnostic information; however, when an MRI was performed, it revealed fluid collections in the deep deltoid or overlying the rotator cuff tendons; bursitis; tendonitis; and rotator cuff tears.²

Continue to: Management of SIRVA

Management of SIRVA is similar to that of other shoulder injuries. Treatment may include icing the shoulder, NSAIDs, intra­-articular steroid injections, and physical therapy. If conservative management does not resolve the patient’s pain and improve function, then a consult with an orthopedic surgeon is recommended to determine if surgical intervention is required.

Vaccines should be injected at a 90° angle into the central and thickest portion of the deltoid muscle approximately 2” below the acromion process.

Another case report from Japan reported that a 45-year-old woman developed acute pain following a third injection of ­Cervarix, the prophylactic human papillomavirus-16/18 vaccine. An x-ray was ordered and was normal, but an MRI revealed acute subacromial bursitis. In an attempt to relieve the pain and improve her mobility, multiple cortisone injections were administered and physical therapy was performed. Despite the conservative treatment efforts, she continued to have pain and limited mobility in the shoulder 6 months following the onset of symptoms. As a result, the patient underwent arthroscopic synovectomy and subacromial decompression. One week following the surgery, the patient’s pain improved and at 1 year she had no pain and full range of motion.⁴

Prevention of SIRVA

By using appropriate techniques when administering intramuscular vaccinations, SIRVA can be prevented. The manufacturer recommended route of administration is based on studies showing maximum safety and immunogenicity, and should therefore be followed by the individual administering the vaccine.⁵ The Centers for Disease Control and Prevention recommends using a 22- to 25-gauge needle that is long enough to reach into the muscle and may range from ⅝" to 1½" depending on the patient’s weight.⁶ The vaccine should be injected at a 90° angle into the central and thickest portion of the deltoid muscle, about 2" below the acromion process and above the level of the axilla.⁵

Our patient’s outcome. The patient’s symptoms resolved within 10 days of receiving a steroid injection into the subacromial space. Although this case was the result of the influenza vaccine, any intramuscularly injected vaccine could lead to SIRVA.

THE TAKEAWAY

Inappropriate administration of routine intramuscularly injected vaccinations can lead to significant patient harm, including pain and disability. It is important for physicians to be aware of SIRVA and to be able to identify the signs and symptoms. Although an MRI of the shoulder is helpful in confirming the diagnosis, it is not necessary if the physician takes a thorough history and performs a comprehensive shoulder exam. Routine x-rays do not provide any beneficial clinical information.

CORRESPONDENCE
Bryan Farford, DO, Department of Family Medicine, Mayo Clinic, Davis Building, 4500 San Pablo Road South #358, Jacksonville, FL 32224; [email protected]

THE CASE

A 56-year-old woman presented with a 3-day complaint of worsening left upper arm pain. She denied having any specific initiating factors but reported receiving an influenza vaccination in the arm a few days prior to the onset of pain. The patient did not have any associated numbness or tingling in the arm. She reported that the pain was worse with movement—especially abduction. The patient reported taking an over-the-counter nonsteroidal anti-­inflammatory drug (NSAID) without much relief.

On physical examination, the patient had difficulty with active range of motion and had erythema, swelling, and tenderness to palpation along the subacromial space and the proximal deltoid. Further examination of the shoulder revealed a positive Neer Impingement Test and a positive Hawkins–Kennedy Test. (For more on these tests, visit “MSK Clinic: Evaluating shoulder pain using IPASS.”). The patient demonstrated full passive range of motion, but her pain was exacerbated with abduction.

THE DIAGNOSIS

In light of the soft-tissue findings and the absence of trauma, magnetic resonance imaging (MRI), rather than an ­x-ray, of the upper extremity was ordered. ­Imaging revealed subacromial subdeltoid bursal inflammation (FIGURE).

DISCUSSION

Shoulder injury related to vaccine administration (SIRVA) is the result of accidental injection of a vaccine into the tissue lying underneath the deltoid muscle or joint space, leading to a suspected immune-mediated inflammatory reaction.

A report from the National Vaccine Advisory Committee of the US ­Department of Health & Human Services showed an increase in the number of reported cases of SIRVA (59 reported cases in 2011-2014 and 202 cases reported in 2016).¹ Additionally, in 2016 more than $29 million was awarded in compensation to patients with SIRVA.^1,2 In a 2011 report, an Institute of Medicine committee found convincing evidence of a causal relationship between injection of vaccine, independent of the antigen involved, and deltoid bursitis, or frozen shoulder, characterized by shoulder pain and loss of motion.³

A review of 13 cases revealed that 50% of the patients reported pain immediately after the injection and 90% had developed pain within 24 hours.² On physical exam, a limited range of motion and pain were the most common findings, while weakness and sensory changes were uncommon. In some cases, the pain lasted several years and 30% of the patients required surgery. Forty-six percent of the patients reported apprehension concerning the administration of the vaccine, specifically that the injection was administered “too high” into the deltoid.²

In the review of cases, routine x-rays of the shoulder did not provide beneficial diagnostic information; however, when an MRI was performed, it revealed fluid collections in the deep deltoid or overlying the rotator cuff tendons; bursitis; tendonitis; and rotator cuff tears.²

Continue to: Management of SIRVA

Management of SIRVA is similar to that of other shoulder injuries. Treatment may include icing the shoulder, NSAIDs, intra­-articular steroid injections, and physical therapy. If conservative management does not resolve the patient’s pain and improve function, then a consult with an orthopedic surgeon is recommended to determine if surgical intervention is required.

Vaccines should be injected at a 90° angle into the central and thickest portion of the deltoid muscle approximately 2” below the acromion process.

Another case report from Japan reported that a 45-year-old woman developed acute pain following a third injection of ­Cervarix, the prophylactic human papillomavirus-16/18 vaccine. An x-ray was ordered and was normal, but an MRI revealed acute subacromial bursitis. In an attempt to relieve the pain and improve her mobility, multiple cortisone injections were administered and physical therapy was performed. Despite the conservative treatment efforts, she continued to have pain and limited mobility in the shoulder 6 months following the onset of symptoms. As a result, the patient underwent arthroscopic synovectomy and subacromial decompression. One week following the surgery, the patient’s pain improved and at 1 year she had no pain and full range of motion.⁴

Prevention of SIRVA

By using appropriate techniques when administering intramuscular vaccinations, SIRVA can be prevented. The manufacturer recommended route of administration is based on studies showing maximum safety and immunogenicity, and should therefore be followed by the individual administering the vaccine.⁵ The Centers for Disease Control and Prevention recommends using a 22- to 25-gauge needle that is long enough to reach into the muscle and may range from ⅝" to 1½" depending on the patient’s weight.⁶ The vaccine should be injected at a 90° angle into the central and thickest portion of the deltoid muscle, about 2" below the acromion process and above the level of the axilla.⁵

Our patient’s outcome. The patient’s symptoms resolved within 10 days of receiving a steroid injection into the subacromial space. Although this case was the result of the influenza vaccine, any intramuscularly injected vaccine could lead to SIRVA.

THE TAKEAWAY

Inappropriate administration of routine intramuscularly injected vaccinations can lead to significant patient harm, including pain and disability. It is important for physicians to be aware of SIRVA and to be able to identify the signs and symptoms. Although an MRI of the shoulder is helpful in confirming the diagnosis, it is not necessary if the physician takes a thorough history and performs a comprehensive shoulder exam. Routine x-rays do not provide any beneficial clinical information.

CORRESPONDENCE
Bryan Farford, DO, Department of Family Medicine, Mayo Clinic, Davis Building, 4500 San Pablo Road South #358, Jacksonville, FL 32224; [email protected]

THE CASE

A 56-year-old woman presented with a 3-day complaint of worsening left upper arm pain. She denied having any specific initiating factors but reported receiving an influenza vaccination in the arm a few days prior to the onset of pain. The patient did not have any associated numbness or tingling in the arm. She reported that the pain was worse with movement—especially abduction. The patient reported taking an over-the-counter nonsteroidal anti-­inflammatory drug (NSAID) without much relief.

On physical examination, the patient had difficulty with active range of motion and had erythema, swelling, and tenderness to palpation along the subacromial space and the proximal deltoid. Further examination of the shoulder revealed a positive Neer Impingement Test and a positive Hawkins–Kennedy Test. (For more on these tests, visit “MSK Clinic: Evaluating shoulder pain using IPASS.”). The patient demonstrated full passive range of motion, but her pain was exacerbated with abduction.

THE DIAGNOSIS

In light of the soft-tissue findings and the absence of trauma, magnetic resonance imaging (MRI), rather than an ­x-ray, of the upper extremity was ordered. ­Imaging revealed subacromial subdeltoid bursal inflammation (FIGURE).

DISCUSSION

Shoulder injury related to vaccine administration (SIRVA) is the result of accidental injection of a vaccine into the tissue lying underneath the deltoid muscle or joint space, leading to a suspected immune-mediated inflammatory reaction.

A report from the National Vaccine Advisory Committee of the US ­Department of Health & Human Services showed an increase in the number of reported cases of SIRVA (59 reported cases in 2011-2014 and 202 cases reported in 2016).¹ Additionally, in 2016 more than $29 million was awarded in compensation to patients with SIRVA.^1,2 In a 2011 report, an Institute of Medicine committee found convincing evidence of a causal relationship between injection of vaccine, independent of the antigen involved, and deltoid bursitis, or frozen shoulder, characterized by shoulder pain and loss of motion.³

A review of 13 cases revealed that 50% of the patients reported pain immediately after the injection and 90% had developed pain within 24 hours.² On physical exam, a limited range of motion and pain were the most common findings, while weakness and sensory changes were uncommon. In some cases, the pain lasted several years and 30% of the patients required surgery. Forty-six percent of the patients reported apprehension concerning the administration of the vaccine, specifically that the injection was administered “too high” into the deltoid.²

In the review of cases, routine x-rays of the shoulder did not provide beneficial diagnostic information; however, when an MRI was performed, it revealed fluid collections in the deep deltoid or overlying the rotator cuff tendons; bursitis; tendonitis; and rotator cuff tears.²

Continue to: Management of SIRVA

Management of SIRVA is similar to that of other shoulder injuries. Treatment may include icing the shoulder, NSAIDs, intra­-articular steroid injections, and physical therapy. If conservative management does not resolve the patient’s pain and improve function, then a consult with an orthopedic surgeon is recommended to determine if surgical intervention is required.

Vaccines should be injected at a 90° angle into the central and thickest portion of the deltoid muscle approximately 2” below the acromion process.

Another case report from Japan reported that a 45-year-old woman developed acute pain following a third injection of ­Cervarix, the prophylactic human papillomavirus-16/18 vaccine. An x-ray was ordered and was normal, but an MRI revealed acute subacromial bursitis. In an attempt to relieve the pain and improve her mobility, multiple cortisone injections were administered and physical therapy was performed. Despite the conservative treatment efforts, she continued to have pain and limited mobility in the shoulder 6 months following the onset of symptoms. As a result, the patient underwent arthroscopic synovectomy and subacromial decompression. One week following the surgery, the patient’s pain improved and at 1 year she had no pain and full range of motion.⁴

Prevention of SIRVA

By using appropriate techniques when administering intramuscular vaccinations, SIRVA can be prevented. The manufacturer recommended route of administration is based on studies showing maximum safety and immunogenicity, and should therefore be followed by the individual administering the vaccine.⁵ The Centers for Disease Control and Prevention recommends using a 22- to 25-gauge needle that is long enough to reach into the muscle and may range from ⅝" to 1½" depending on the patient’s weight.⁶ The vaccine should be injected at a 90° angle into the central and thickest portion of the deltoid muscle, about 2" below the acromion process and above the level of the axilla.⁵

Our patient’s outcome. The patient’s symptoms resolved within 10 days of receiving a steroid injection into the subacromial space. Although this case was the result of the influenza vaccine, any intramuscularly injected vaccine could lead to SIRVA.

THE TAKEAWAY

Inappropriate administration of routine intramuscularly injected vaccinations can lead to significant patient harm, including pain and disability. It is important for physicians to be aware of SIRVA and to be able to identify the signs and symptoms. Although an MRI of the shoulder is helpful in confirming the diagnosis, it is not necessary if the physician takes a thorough history and performs a comprehensive shoulder exam. Routine x-rays do not provide any beneficial clinical information.

CORRESPONDENCE
Bryan Farford, DO, Department of Family Medicine, Mayo Clinic, Davis Building, 4500 San Pablo Road South #358, Jacksonville, FL 32224; [email protected]

THE CASE

A 33-year-old Hispanic man with no significant past medical history presented to the emergency department with generalized flaccid paralysis in both arms and legs. Two days before, he had been working on a construction site in hot weather. The following day, he woke up with very little energy or strength to perform his daily activities, and he had pain in the inguinal area and both calves. He denied taking any medications or supplements.

The patient had complete muscle weakness and was unable to move his arms and legs. He reported dysphagia and an unintentional weight loss of 30 lb during the previous month.

On physical examination, the patient’s vital signs were within the normal range, and mild thyromegaly without nodules was present. Neurologic examination revealed decreased deep tendon reflexes with intact sensation. Muscle strength in his arms and legs was 0/5.

Initial laboratory test results included a potassium level of 2.2 mEq/L (normal range, 3.5–5 mEq/L) and normal acid-basic status that was confirmed by an arterial blood gas measurement. Serum magnesium was 1.6 mg/dL (normal range, 1.6–2.5 mg/dL); phosphorus, 1.9 mg/dL (normal range, 2.7–4.5 mg/dL); and random urinary potassium, 16 mEq/L (normal range, 25–125 mEq/L). An initial chest x-ray was normal, and an electrocardiogram showed a prolonged QT interval, flattening of the T wave, and a prominent U wave consistent with hypokalemia.

THE DIAGNOSIS

The initial clinical diagnosis was hypokalemic paralysis. The patient was treated with intravenous (IV) potassium chloride 40 mEq; however, his potassium level decreased further, to 1.8 mEq/L. Potassium chloride administration was continued and potassium levels were monitored. Normal saline 1 L was also administered, and other electrolyte abnormalities were corrected.

Evaluation of the patient’s hypokalemia revealed the following: thyroid-stimulating hormone (TSH) level, < 0.01 microIU/mL (normal range, 0.27–4.2 microIU/mL); free T4 (thyroxine) level, 4.47 ng/dL (normal range, 0.08–1.70 ng/dL); total T3 (triiodothyronine) level, 17.5 ng/dL (normal range, 2.6–4.4 ng/dL).

The patient was diagnosed with hypokalemic periodic paralysis (HPP) secondary to thyrotoxicosis, also known as thyrotoxicosis periodic paralysis (TPP). His hyperthyroidism was treated with oral atenolol 25 mg/d and oral methimazole 10 mg tid.

Continue to: Within a few hours...

Within a few hours of this treatment, the patient experienced significant improvement in muscle strength and complete resolution of weakness in his arms and legs. Serial measurements of potassium levels normalized.

Further workup revealed that the patient’s thyroid-stimulating immunoglobulin (TSI) was 4.2 on the TSI index (normal, ≤ 1.3) and his thyroid peroxidase (TPO) antibody level was 133.4 IU/mL (normal, < 34 IU/mL). Ultrasonography showed decreased echogenicity of the thyroid gland, consistent with the acute phase of Hashimoto thyroiditis or Graves disease.

The patient was unaware that he had any thyroid disorder previously. He was a private-pay, undocumented immigrant and did not have a regular primary care physician. On discharge, he was referred to a local primary care physician as well as an endocrinologist. He was discharged on atenolol and methimazole.

DISCUSSION

A rare neuromuscular disorder known as periodic paralysis can be precipitated by a hypokalemic or hyperkalemic state; HPP is more common and can be either familial (a defect in the gene) or acquired (secondary to thyrotoxicosis; TPP).^1,2 In both forms of periodic paralysis, patients present with hypokalemia and paralysis. Physicians need to look closely at thyroid lab test results so as not to miss the cause of the paralysis.  

TPP is most commonly seen in Asian populations, and 95% of cases reported occur in males, despite the higher incidence of hyperthyroidism in females.³ TPP can be precipitated by emotional stress, steroid use, beta-adrenergic bronchodilators, heavy exercise, fasting, or high-carbohydrate meals.^2-4 In our patient, heavy exercise and fasting likely were the triggers.

Continue to: The pathophysiology for the hypokalemia...

Failure to correct the potassium deficit in thyrotoxicosis periodic paralysis could cause severe complications, such as respiratory failure and psychosis.

The pathophysiology for the hypokalemia in TPP is thought to involve the sodium/potassium–adenosine triphosphatase (Na+/K+–ATPase) pump. This pump activity is increased in skeletal muscle and platelets in patients with TPP vs patients with thyrotoxicosis alone.^3,5

The role of Hashimoto thyrotoxicosis. Most acquired cases of TPP are mainly secondary to Graves disease with elevated levels of TSI and mildly elevated or normal levels of TPO. In this case, the patient was in the acute phase of Hashimoto thyrotoxicosis (“hashitoxicosis”) with elevated levels of TPO and only mildly elevated TSI.Imaging studies to support the diagnosis, such as a thyroid uptake scan or ultrasonography, are not necessary to determine the cause of thyrotoxicosis. In the absence of test results for TPO and TSI antibodies, however, a scan can be helpful.^6,7

Treatment of TPP consists of early recognition and supportive management by correcting the potassium deficit; failure to do so could cause severe complications, such as respiratory failure and psychosis.⁸ Because of the risk for rebound hyperkalemia, serial potassium levels must be measured until a stable potassium level in the normal range is achieved.

Nonselective beta-blockers, such as propranolol (3 mg/kg) 4 times per day, have been reported to ameliorate the periodic paralysis and prevent rebound hyperkalemia.⁹ Finally, restoring a euthyroid state will prevent the patient from experiencing future attacks.

THE TAKEAWAY

Few medical conditions result in complete muscle paralysis in a matter of hours. Clinicians should consider the possibility of TPP in any patient who presents with acute onset of paralysis.

CORRESPONDENCE
Jorge Luis Chavez, MD; 8405 E. San Pedro Drive, Scottsdale, AZ 85258; [email protected].

THE CASE

A 33-year-old Hispanic man with no significant past medical history presented to the emergency department with generalized flaccid paralysis in both arms and legs. Two days before, he had been working on a construction site in hot weather. The following day, he woke up with very little energy or strength to perform his daily activities, and he had pain in the inguinal area and both calves. He denied taking any medications or supplements.

The patient had complete muscle weakness and was unable to move his arms and legs. He reported dysphagia and an unintentional weight loss of 30 lb during the previous month.

On physical examination, the patient’s vital signs were within the normal range, and mild thyromegaly without nodules was present. Neurologic examination revealed decreased deep tendon reflexes with intact sensation. Muscle strength in his arms and legs was 0/5.

Initial laboratory test results included a potassium level of 2.2 mEq/L (normal range, 3.5–5 mEq/L) and normal acid-basic status that was confirmed by an arterial blood gas measurement. Serum magnesium was 1.6 mg/dL (normal range, 1.6–2.5 mg/dL); phosphorus, 1.9 mg/dL (normal range, 2.7–4.5 mg/dL); and random urinary potassium, 16 mEq/L (normal range, 25–125 mEq/L). An initial chest x-ray was normal, and an electrocardiogram showed a prolonged QT interval, flattening of the T wave, and a prominent U wave consistent with hypokalemia.

THE DIAGNOSIS

The initial clinical diagnosis was hypokalemic paralysis. The patient was treated with intravenous (IV) potassium chloride 40 mEq; however, his potassium level decreased further, to 1.8 mEq/L. Potassium chloride administration was continued and potassium levels were monitored. Normal saline 1 L was also administered, and other electrolyte abnormalities were corrected.

Evaluation of the patient’s hypokalemia revealed the following: thyroid-stimulating hormone (TSH) level, < 0.01 microIU/mL (normal range, 0.27–4.2 microIU/mL); free T4 (thyroxine) level, 4.47 ng/dL (normal range, 0.08–1.70 ng/dL); total T3 (triiodothyronine) level, 17.5 ng/dL (normal range, 2.6–4.4 ng/dL).

The patient was diagnosed with hypokalemic periodic paralysis (HPP) secondary to thyrotoxicosis, also known as thyrotoxicosis periodic paralysis (TPP). His hyperthyroidism was treated with oral atenolol 25 mg/d and oral methimazole 10 mg tid.

Continue to: Within a few hours...

Within a few hours of this treatment, the patient experienced significant improvement in muscle strength and complete resolution of weakness in his arms and legs. Serial measurements of potassium levels normalized.

Further workup revealed that the patient’s thyroid-stimulating immunoglobulin (TSI) was 4.2 on the TSI index (normal, ≤ 1.3) and his thyroid peroxidase (TPO) antibody level was 133.4 IU/mL (normal, < 34 IU/mL). Ultrasonography showed decreased echogenicity of the thyroid gland, consistent with the acute phase of Hashimoto thyroiditis or Graves disease.

The patient was unaware that he had any thyroid disorder previously. He was a private-pay, undocumented immigrant and did not have a regular primary care physician. On discharge, he was referred to a local primary care physician as well as an endocrinologist. He was discharged on atenolol and methimazole.

DISCUSSION

A rare neuromuscular disorder known as periodic paralysis can be precipitated by a hypokalemic or hyperkalemic state; HPP is more common and can be either familial (a defect in the gene) or acquired (secondary to thyrotoxicosis; TPP).^1,2 In both forms of periodic paralysis, patients present with hypokalemia and paralysis. Physicians need to look closely at thyroid lab test results so as not to miss the cause of the paralysis.  

TPP is most commonly seen in Asian populations, and 95% of cases reported occur in males, despite the higher incidence of hyperthyroidism in females.³ TPP can be precipitated by emotional stress, steroid use, beta-adrenergic bronchodilators, heavy exercise, fasting, or high-carbohydrate meals.^2-4 In our patient, heavy exercise and fasting likely were the triggers.

Continue to: The pathophysiology for the hypokalemia...

Failure to correct the potassium deficit in thyrotoxicosis periodic paralysis could cause severe complications, such as respiratory failure and psychosis.

The pathophysiology for the hypokalemia in TPP is thought to involve the sodium/potassium–adenosine triphosphatase (Na+/K+–ATPase) pump. This pump activity is increased in skeletal muscle and platelets in patients with TPP vs patients with thyrotoxicosis alone.^3,5

The role of Hashimoto thyrotoxicosis. Most acquired cases of TPP are mainly secondary to Graves disease with elevated levels of TSI and mildly elevated or normal levels of TPO. In this case, the patient was in the acute phase of Hashimoto thyrotoxicosis (“hashitoxicosis”) with elevated levels of TPO and only mildly elevated TSI.Imaging studies to support the diagnosis, such as a thyroid uptake scan or ultrasonography, are not necessary to determine the cause of thyrotoxicosis. In the absence of test results for TPO and TSI antibodies, however, a scan can be helpful.^6,7

Treatment of TPP consists of early recognition and supportive management by correcting the potassium deficit; failure to do so could cause severe complications, such as respiratory failure and psychosis.⁸ Because of the risk for rebound hyperkalemia, serial potassium levels must be measured until a stable potassium level in the normal range is achieved.

Nonselective beta-blockers, such as propranolol (3 mg/kg) 4 times per day, have been reported to ameliorate the periodic paralysis and prevent rebound hyperkalemia.⁹ Finally, restoring a euthyroid state will prevent the patient from experiencing future attacks.

THE TAKEAWAY

Few medical conditions result in complete muscle paralysis in a matter of hours. Clinicians should consider the possibility of TPP in any patient who presents with acute onset of paralysis.

CORRESPONDENCE
Jorge Luis Chavez, MD; 8405 E. San Pedro Drive, Scottsdale, AZ 85258; [email protected].

THE CASE

A 33-year-old Hispanic man with no significant past medical history presented to the emergency department with generalized flaccid paralysis in both arms and legs. Two days before, he had been working on a construction site in hot weather. The following day, he woke up with very little energy or strength to perform his daily activities, and he had pain in the inguinal area and both calves. He denied taking any medications or supplements.

The patient had complete muscle weakness and was unable to move his arms and legs. He reported dysphagia and an unintentional weight loss of 30 lb during the previous month.

On physical examination, the patient’s vital signs were within the normal range, and mild thyromegaly without nodules was present. Neurologic examination revealed decreased deep tendon reflexes with intact sensation. Muscle strength in his arms and legs was 0/5.

Initial laboratory test results included a potassium level of 2.2 mEq/L (normal range, 3.5–5 mEq/L) and normal acid-basic status that was confirmed by an arterial blood gas measurement. Serum magnesium was 1.6 mg/dL (normal range, 1.6–2.5 mg/dL); phosphorus, 1.9 mg/dL (normal range, 2.7–4.5 mg/dL); and random urinary potassium, 16 mEq/L (normal range, 25–125 mEq/L). An initial chest x-ray was normal, and an electrocardiogram showed a prolonged QT interval, flattening of the T wave, and a prominent U wave consistent with hypokalemia.

THE DIAGNOSIS

The initial clinical diagnosis was hypokalemic paralysis. The patient was treated with intravenous (IV) potassium chloride 40 mEq; however, his potassium level decreased further, to 1.8 mEq/L. Potassium chloride administration was continued and potassium levels were monitored. Normal saline 1 L was also administered, and other electrolyte abnormalities were corrected.

Evaluation of the patient’s hypokalemia revealed the following: thyroid-stimulating hormone (TSH) level, < 0.01 microIU/mL (normal range, 0.27–4.2 microIU/mL); free T4 (thyroxine) level, 4.47 ng/dL (normal range, 0.08–1.70 ng/dL); total T3 (triiodothyronine) level, 17.5 ng/dL (normal range, 2.6–4.4 ng/dL).

The patient was diagnosed with hypokalemic periodic paralysis (HPP) secondary to thyrotoxicosis, also known as thyrotoxicosis periodic paralysis (TPP). His hyperthyroidism was treated with oral atenolol 25 mg/d and oral methimazole 10 mg tid.

Continue to: Within a few hours...

Within a few hours of this treatment, the patient experienced significant improvement in muscle strength and complete resolution of weakness in his arms and legs. Serial measurements of potassium levels normalized.

Further workup revealed that the patient’s thyroid-stimulating immunoglobulin (TSI) was 4.2 on the TSI index (normal, ≤ 1.3) and his thyroid peroxidase (TPO) antibody level was 133.4 IU/mL (normal, < 34 IU/mL). Ultrasonography showed decreased echogenicity of the thyroid gland, consistent with the acute phase of Hashimoto thyroiditis or Graves disease.

The patient was unaware that he had any thyroid disorder previously. He was a private-pay, undocumented immigrant and did not have a regular primary care physician. On discharge, he was referred to a local primary care physician as well as an endocrinologist. He was discharged on atenolol and methimazole.

DISCUSSION

A rare neuromuscular disorder known as periodic paralysis can be precipitated by a hypokalemic or hyperkalemic state; HPP is more common and can be either familial (a defect in the gene) or acquired (secondary to thyrotoxicosis; TPP).^1,2 In both forms of periodic paralysis, patients present with hypokalemia and paralysis. Physicians need to look closely at thyroid lab test results so as not to miss the cause of the paralysis.  

TPP is most commonly seen in Asian populations, and 95% of cases reported occur in males, despite the higher incidence of hyperthyroidism in females.³ TPP can be precipitated by emotional stress, steroid use, beta-adrenergic bronchodilators, heavy exercise, fasting, or high-carbohydrate meals.^2-4 In our patient, heavy exercise and fasting likely were the triggers.

Continue to: The pathophysiology for the hypokalemia...

Failure to correct the potassium deficit in thyrotoxicosis periodic paralysis could cause severe complications, such as respiratory failure and psychosis.

The pathophysiology for the hypokalemia in TPP is thought to involve the sodium/potassium–adenosine triphosphatase (Na+/K+–ATPase) pump. This pump activity is increased in skeletal muscle and platelets in patients with TPP vs patients with thyrotoxicosis alone.^3,5

The role of Hashimoto thyrotoxicosis. Most acquired cases of TPP are mainly secondary to Graves disease with elevated levels of TSI and mildly elevated or normal levels of TPO. In this case, the patient was in the acute phase of Hashimoto thyrotoxicosis (“hashitoxicosis”) with elevated levels of TPO and only mildly elevated TSI.Imaging studies to support the diagnosis, such as a thyroid uptake scan or ultrasonography, are not necessary to determine the cause of thyrotoxicosis. In the absence of test results for TPO and TSI antibodies, however, a scan can be helpful.^6,7

Treatment of TPP consists of early recognition and supportive management by correcting the potassium deficit; failure to do so could cause severe complications, such as respiratory failure and psychosis.⁸ Because of the risk for rebound hyperkalemia, serial potassium levels must be measured until a stable potassium level in the normal range is achieved.

Nonselective beta-blockers, such as propranolol (3 mg/kg) 4 times per day, have been reported to ameliorate the periodic paralysis and prevent rebound hyperkalemia.⁹ Finally, restoring a euthyroid state will prevent the patient from experiencing future attacks.

THE TAKEAWAY

Few medical conditions result in complete muscle paralysis in a matter of hours. Clinicians should consider the possibility of TPP in any patient who presents with acute onset of paralysis.

CORRESPONDENCE
Jorge Luis Chavez, MD; 8405 E. San Pedro Drive, Scottsdale, AZ 85258; [email protected].

Calciphylaxis, otherwise known as calcific uremic arteriolopathy, is characterized by calcification of the tunica media of the small- to medium-sized blood vessels of the dermis and subcutis, leading to ischemia and necrosis.¹ It is a deadly disease with a 1-year mortality rate of more than 50%.² End-stage renal disease (ESRD) is the most common risk factor for calciphylaxis, with a prevalence of 1% to 4% of hemodialysis patients with calciphylaxis in the United States.^2-5 However, nonuremic calciphylaxis (NUC) has been increasingly reported in the literature and has risk factors other than ESRD, including but not limited to obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, and underlying malignancy.^3,6-9 Triggers for calciphylaxis in at-risk patients include use of corticosteroids or warfarin, iron or albumin infusions, and rapid weight loss.^3,6,9-11 We report an unusual case of NUC that most likely was triggered by rapid weight loss and hypotension in a patient with multiple risk factors for calciphylaxis.

Case Report

A 75-year-old white woman with history of morbid obesity (body mass index, 40 kg/m²), unexplained weight loss of 70 lb over the last year, and polymyalgia rheumatica requiring chronic prednisone therapy presented with painful lesions on the thighs, buttocks, and right shoulder of 4 months’ duration. She had multiple hospital admissions preceding the onset of lesions for severe infections resulting in sepsis with hypotension, including Enterococcus faecalis endocarditis, extended-spectrum beta-lactamase bacteremia, and Pseudomonas aeruginosa pneumonia. Physical examination revealed large well-demarcated ulcers and necrotic eschars with surrounding violaceous induration and stellate erythema on the anterior, medial, and posterior thighs and buttocks that were exquisitely tender (Figures 1 and 2).

Notable laboratory results included hypoalbuminemia (1.3 g/dL [reference range, 3.5–5.0 g/dL]) with normal renal function, a corrected calcium level of 9.7 mg/dL (reference range, 8.2–10.2 mg/dL), a serum phosphorus level of 3.5 mg/dL (reference range, 2.3–4.7 mg/dL), a calcium-phosphate product of 27.3 mg²/dL² (reference range, <55 mg²/dL²), and a parathyroid hormone level of 49.3 pg/mL (reference range, 10–65 pg/mL). Antinuclear antibodies were negative. A hypercoagulability evaluation showed normal protein C and S levels, negative lupus anticoagulant, and negative anticardiolipin antibodies.

Telescoping punch biopsies of the indurated borders of the eschars showed prominent calcification of the small- and medium-sized vessels in the mid and deep dermis, intravascular thrombi, and necrosis of the epidermis and subcutaneous fat consistent with calciphylaxis (Figure 3).

Comment

Background on Calciphylaxis
Calciphylaxis is a rare but deadly disease that affects both ESRD patients receiving dialysis and patients without ESRD who have known risk factors for calciphylaxis, including female gender, white race, obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, underlying malignancy, protein C or S deficiency, corticosteroid use, warfarin use, diabetes, iron or albumin infusions, and rapid weight loss.^3,6-9,11 Although the molecular pathogenesis of calciphylaxis is not completely understood, it is believed to be caused by local deposition of calcium in the tunica media of small- to medium-sized arterioles and venules in the skin.¹² This deposition leads to intimal proliferation and progressive narrowing of the vessels with resultant thrombosis, ischemia, and necrosis. The cutaneous manifestations and histopathology of calciphylaxis classically follow its pathogenesis. Calciphylaxis typically presents with livedo reticularis as vessels narrow and then progresses to purpura, bullae, necrosis, and eschar formation with the onset of acute thrombosis and ischemia. Histopathology is characterized by small- and medium-sized vessel calcification and thrombus, dermal necrosis, and septal panniculitis, though the histology can be highly variable.¹² Unfortunately, the already poor prognosis for calciphylaxis worsens when lesions become either ulcerative or present on the proximal extremities and trunk.^4,13 Sepsis is the leading cause of death in calciphylaxis patients, affecting more than 50% of patients.^2,3,14 The differential diagnoses for calciphylactic-appearing lesions include warfarin-induced skin necrosis, disseminated intravascular coagulation, pyoderma gangrenosum, cholesterol emboli, and various vasculitides and coagulopathies.

Risk Factors
Our case demonstrates the importance of risk factor minimization, trigger avoidance, and early intervention due to the high mortality rate of calciphylaxis. Selye et al¹⁵ coined the term calciphylaxis in 1961 based on experiments that induced calciphylaxis in rat models. Their research concluded that there were certain sensitizers (ie, risk factors) that predisposed patients to medial calcium deposition in blood vessels and other challengers (ie, triggers) that acted as inciting events to calcium deposition. Our patient presented with multiple known risk factors for calciphylaxis, including obesity (body mass index, 40 kg/m²), female gender, white race, hypoalbuminemia, and chronic corticosteroid use.¹⁶ In the presence of a milieu of risk factors, the patient’s rapid weight loss and episodes of hypotension likely were triggers for calciphylaxis.

Other case reports in the literature have suggested weight loss as a trigger for NUC. One morbidly obese patient with inactive rheumatoid arthritis had onset of calciphylaxis lesions after unintentional weight loss of approximately 50% body weight in 1 year¹⁷; however, the weight loss does not have to be drastic to trigger calciphylaxis. Another study of 16 patients with uremic calciphylaxis found that 7 of 16 (44%) patients lost 10 to 50 kg in the 6 months prior to calciphylaxis onset.¹⁴ One proposed mechanism by Munavalli et al¹⁰ is that elevated levels of matrix metalloproteinases during catabolic weight loss states enhance the deposition of calcium into elastic fibers of small vessels. The authors found elevated serum levels of matrix metalloproteinases in their patients with NUC induced by rapid weight loss.¹⁰

A meta-analysis by Nigwekar et al³ found a history of prior corticosteroid use in 61% (22/36) of NUC cases reviewed. However, it is unclear whether it is the use of corticosteroids or chronic inflammation that is implicated in NUC pathogenesis. Chronic inflammation causes downregulation of anticalcification signaling pathways.^18-20 The role of 2 vascular calcification inhibitors has been evaluated in the pathogenesis of calciphylaxis: fetuin-A and matrix gla protein (MGP).²¹ The activity of these proteins is decreased not only in calciphylaxis but also in other inflammatory states and chronic renal failure.^18-20 One study found lower fetuin-A levels in 312 hemodialysis patients compared to healthy controls and an association between low fetuin-A levels and increased C-reactive protein levels.²² Reduced fetuin-A and MGP levels may be the result of several calciphylaxis risk factors. Warfarin is believed to trigger calciphylaxis via inhibition of gamma-carboxylation of MGP, which is necessary for its anticalcification activity.²³ Hypoalbuminemia and alcoholic liver disease also are risk factors that may be explained by the fact that fetuin-A is synthesized in the liver.²⁴ Therefore, liver disease results in decreased production of fetuin-A that is permissive to vascular calcification in calciphylaxis patients.

There have been other reports of calciphylaxis patients who were originally hospitalized due to hypotension, which may serve as a trigger for calciphylaxis onset.²⁵ Because calciphylaxis lesions are more likely to occur in the fatty areas of the abdomen and proximal thighs where blood flow is slower, hypotension likely accentuates the slowing of blood flow and subsequent blood vessel calcification. This theory is supported by studies showing that established calciphylactic lesions worsen more quickly in the presence of systemic hypotension.²⁶ One patient with ESRD and calciphylaxis of the breasts had consistent systolic blood pressure readings in the high 60s to low 70s between dialysis sessions.²⁷ Due to this association, we recommend that patients with calciphylaxis have close blood pressure monitoring to aid in preventing disease progression.²⁸

Management
Calciphylaxis treatment has not yet been standardized, as it is an uncommon disease whose pathogenesis is not fully understood. Current management strategies aim to normalize metabolic abnormalities such as hypercalcemia if they are present and remove inciting agents such as warfarin and corticosteroids.²⁹ Other medical treatments that have been successfully used include sodium thiosulfate, oral steroids, and adjunctive bisphosphonates.^29-31 Sodium thiosulfate is known to cause metabolic acidosis by generating thiosulfuric acid in vivo in patients with or without renal disease; therefore, patients on sodium thiosulfate therapy should be monitored for development of metabolic acidosis and treated with oral sodium bicarbonate or dialysis as needed.^30,32 Wound care also is an important element of calciphylaxis treatment; however, the debridement of wounds is controversial. Some argue that dry intact eschars serve to protect against sepsis, which is the leading cause of death in calciphylaxis.^2,14,33 In contrast, a retrospective study of 63 calciphylaxis patients found a 1-year survival rate of 61.6% in 17 patients receiving wound debridement vs 27.4% in 46 patients who did not.² The current consensus is that debridement should be considered on a case-by-case basis, factoring in the presence of wound infection, size of wounds, stability of eschars, and treatment goals of the patient.³⁴ Future studies should be aimed at this issue, with special focus on how these factors and the decision to debride or not impact patient outcomes.

Conclusion

Calciphylaxis is a potentially fatal disease that impacts both patients with ESRD and those with nonuremic risk factors. The term calcific uremic arteriolopathy should be disregarded, as nonuremic causes are being reported with increased frequency in the literature. In such cases, patients often have multiple risk factors, including obesity, primary hyperparathyroidism, alcoholic liver disease, and underlying malignancy, among others. Certain triggers for onset of calciphylaxis should be avoided in at-risk patients, including the use of corticosteroids or warfarin; iron and albumin infusions; hypotension; and rapid weight loss. Our fatal case of NUC is a reminder to dermatologists treating at-risk patients to avoid these triggers and to keep calciphylaxis in the differential diagnosis when encountering early lesions such as livedo reticularis, as progression of these lesions has a 1-year mortality rate of more than 50% with the therapies being utilized at this time.

Calciphylaxis, otherwise known as calcific uremic arteriolopathy, is characterized by calcification of the tunica media of the small- to medium-sized blood vessels of the dermis and subcutis, leading to ischemia and necrosis.¹ It is a deadly disease with a 1-year mortality rate of more than 50%.² End-stage renal disease (ESRD) is the most common risk factor for calciphylaxis, with a prevalence of 1% to 4% of hemodialysis patients with calciphylaxis in the United States.^2-5 However, nonuremic calciphylaxis (NUC) has been increasingly reported in the literature and has risk factors other than ESRD, including but not limited to obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, and underlying malignancy.^3,6-9 Triggers for calciphylaxis in at-risk patients include use of corticosteroids or warfarin, iron or albumin infusions, and rapid weight loss.^3,6,9-11 We report an unusual case of NUC that most likely was triggered by rapid weight loss and hypotension in a patient with multiple risk factors for calciphylaxis.

Case Report

A 75-year-old white woman with history of morbid obesity (body mass index, 40 kg/m²), unexplained weight loss of 70 lb over the last year, and polymyalgia rheumatica requiring chronic prednisone therapy presented with painful lesions on the thighs, buttocks, and right shoulder of 4 months’ duration. She had multiple hospital admissions preceding the onset of lesions for severe infections resulting in sepsis with hypotension, including Enterococcus faecalis endocarditis, extended-spectrum beta-lactamase bacteremia, and Pseudomonas aeruginosa pneumonia. Physical examination revealed large well-demarcated ulcers and necrotic eschars with surrounding violaceous induration and stellate erythema on the anterior, medial, and posterior thighs and buttocks that were exquisitely tender (Figures 1 and 2).

Notable laboratory results included hypoalbuminemia (1.3 g/dL [reference range, 3.5–5.0 g/dL]) with normal renal function, a corrected calcium level of 9.7 mg/dL (reference range, 8.2–10.2 mg/dL), a serum phosphorus level of 3.5 mg/dL (reference range, 2.3–4.7 mg/dL), a calcium-phosphate product of 27.3 mg²/dL² (reference range, <55 mg²/dL²), and a parathyroid hormone level of 49.3 pg/mL (reference range, 10–65 pg/mL). Antinuclear antibodies were negative. A hypercoagulability evaluation showed normal protein C and S levels, negative lupus anticoagulant, and negative anticardiolipin antibodies.

Telescoping punch biopsies of the indurated borders of the eschars showed prominent calcification of the small- and medium-sized vessels in the mid and deep dermis, intravascular thrombi, and necrosis of the epidermis and subcutaneous fat consistent with calciphylaxis (Figure 3).

Comment

Background on Calciphylaxis
Calciphylaxis is a rare but deadly disease that affects both ESRD patients receiving dialysis and patients without ESRD who have known risk factors for calciphylaxis, including female gender, white race, obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, underlying malignancy, protein C or S deficiency, corticosteroid use, warfarin use, diabetes, iron or albumin infusions, and rapid weight loss.^3,6-9,11 Although the molecular pathogenesis of calciphylaxis is not completely understood, it is believed to be caused by local deposition of calcium in the tunica media of small- to medium-sized arterioles and venules in the skin.¹² This deposition leads to intimal proliferation and progressive narrowing of the vessels with resultant thrombosis, ischemia, and necrosis. The cutaneous manifestations and histopathology of calciphylaxis classically follow its pathogenesis. Calciphylaxis typically presents with livedo reticularis as vessels narrow and then progresses to purpura, bullae, necrosis, and eschar formation with the onset of acute thrombosis and ischemia. Histopathology is characterized by small- and medium-sized vessel calcification and thrombus, dermal necrosis, and septal panniculitis, though the histology can be highly variable.¹² Unfortunately, the already poor prognosis for calciphylaxis worsens when lesions become either ulcerative or present on the proximal extremities and trunk.^4,13 Sepsis is the leading cause of death in calciphylaxis patients, affecting more than 50% of patients.^2,3,14 The differential diagnoses for calciphylactic-appearing lesions include warfarin-induced skin necrosis, disseminated intravascular coagulation, pyoderma gangrenosum, cholesterol emboli, and various vasculitides and coagulopathies.

Risk Factors
Our case demonstrates the importance of risk factor minimization, trigger avoidance, and early intervention due to the high mortality rate of calciphylaxis. Selye et al¹⁵ coined the term calciphylaxis in 1961 based on experiments that induced calciphylaxis in rat models. Their research concluded that there were certain sensitizers (ie, risk factors) that predisposed patients to medial calcium deposition in blood vessels and other challengers (ie, triggers) that acted as inciting events to calcium deposition. Our patient presented with multiple known risk factors for calciphylaxis, including obesity (body mass index, 40 kg/m²), female gender, white race, hypoalbuminemia, and chronic corticosteroid use.¹⁶ In the presence of a milieu of risk factors, the patient’s rapid weight loss and episodes of hypotension likely were triggers for calciphylaxis.

Other case reports in the literature have suggested weight loss as a trigger for NUC. One morbidly obese patient with inactive rheumatoid arthritis had onset of calciphylaxis lesions after unintentional weight loss of approximately 50% body weight in 1 year¹⁷; however, the weight loss does not have to be drastic to trigger calciphylaxis. Another study of 16 patients with uremic calciphylaxis found that 7 of 16 (44%) patients lost 10 to 50 kg in the 6 months prior to calciphylaxis onset.¹⁴ One proposed mechanism by Munavalli et al¹⁰ is that elevated levels of matrix metalloproteinases during catabolic weight loss states enhance the deposition of calcium into elastic fibers of small vessels. The authors found elevated serum levels of matrix metalloproteinases in their patients with NUC induced by rapid weight loss.¹⁰

A meta-analysis by Nigwekar et al³ found a history of prior corticosteroid use in 61% (22/36) of NUC cases reviewed. However, it is unclear whether it is the use of corticosteroids or chronic inflammation that is implicated in NUC pathogenesis. Chronic inflammation causes downregulation of anticalcification signaling pathways.^18-20 The role of 2 vascular calcification inhibitors has been evaluated in the pathogenesis of calciphylaxis: fetuin-A and matrix gla protein (MGP).²¹ The activity of these proteins is decreased not only in calciphylaxis but also in other inflammatory states and chronic renal failure.^18-20 One study found lower fetuin-A levels in 312 hemodialysis patients compared to healthy controls and an association between low fetuin-A levels and increased C-reactive protein levels.²² Reduced fetuin-A and MGP levels may be the result of several calciphylaxis risk factors. Warfarin is believed to trigger calciphylaxis via inhibition of gamma-carboxylation of MGP, which is necessary for its anticalcification activity.²³ Hypoalbuminemia and alcoholic liver disease also are risk factors that may be explained by the fact that fetuin-A is synthesized in the liver.²⁴ Therefore, liver disease results in decreased production of fetuin-A that is permissive to vascular calcification in calciphylaxis patients.

There have been other reports of calciphylaxis patients who were originally hospitalized due to hypotension, which may serve as a trigger for calciphylaxis onset.²⁵ Because calciphylaxis lesions are more likely to occur in the fatty areas of the abdomen and proximal thighs where blood flow is slower, hypotension likely accentuates the slowing of blood flow and subsequent blood vessel calcification. This theory is supported by studies showing that established calciphylactic lesions worsen more quickly in the presence of systemic hypotension.²⁶ One patient with ESRD and calciphylaxis of the breasts had consistent systolic blood pressure readings in the high 60s to low 70s between dialysis sessions.²⁷ Due to this association, we recommend that patients with calciphylaxis have close blood pressure monitoring to aid in preventing disease progression.²⁸

Management
Calciphylaxis treatment has not yet been standardized, as it is an uncommon disease whose pathogenesis is not fully understood. Current management strategies aim to normalize metabolic abnormalities such as hypercalcemia if they are present and remove inciting agents such as warfarin and corticosteroids.²⁹ Other medical treatments that have been successfully used include sodium thiosulfate, oral steroids, and adjunctive bisphosphonates.^29-31 Sodium thiosulfate is known to cause metabolic acidosis by generating thiosulfuric acid in vivo in patients with or without renal disease; therefore, patients on sodium thiosulfate therapy should be monitored for development of metabolic acidosis and treated with oral sodium bicarbonate or dialysis as needed.^30,32 Wound care also is an important element of calciphylaxis treatment; however, the debridement of wounds is controversial. Some argue that dry intact eschars serve to protect against sepsis, which is the leading cause of death in calciphylaxis.^2,14,33 In contrast, a retrospective study of 63 calciphylaxis patients found a 1-year survival rate of 61.6% in 17 patients receiving wound debridement vs 27.4% in 46 patients who did not.² The current consensus is that debridement should be considered on a case-by-case basis, factoring in the presence of wound infection, size of wounds, stability of eschars, and treatment goals of the patient.³⁴ Future studies should be aimed at this issue, with special focus on how these factors and the decision to debride or not impact patient outcomes.

Conclusion

Calciphylaxis is a potentially fatal disease that impacts both patients with ESRD and those with nonuremic risk factors. The term calcific uremic arteriolopathy should be disregarded, as nonuremic causes are being reported with increased frequency in the literature. In such cases, patients often have multiple risk factors, including obesity, primary hyperparathyroidism, alcoholic liver disease, and underlying malignancy, among others. Certain triggers for onset of calciphylaxis should be avoided in at-risk patients, including the use of corticosteroids or warfarin; iron and albumin infusions; hypotension; and rapid weight loss. Our fatal case of NUC is a reminder to dermatologists treating at-risk patients to avoid these triggers and to keep calciphylaxis in the differential diagnosis when encountering early lesions such as livedo reticularis, as progression of these lesions has a 1-year mortality rate of more than 50% with the therapies being utilized at this time.

Calciphylaxis, otherwise known as calcific uremic arteriolopathy, is characterized by calcification of the tunica media of the small- to medium-sized blood vessels of the dermis and subcutis, leading to ischemia and necrosis.¹ It is a deadly disease with a 1-year mortality rate of more than 50%.² End-stage renal disease (ESRD) is the most common risk factor for calciphylaxis, with a prevalence of 1% to 4% of hemodialysis patients with calciphylaxis in the United States.^2-5 However, nonuremic calciphylaxis (NUC) has been increasingly reported in the literature and has risk factors other than ESRD, including but not limited to obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, and underlying malignancy.^3,6-9 Triggers for calciphylaxis in at-risk patients include use of corticosteroids or warfarin, iron or albumin infusions, and rapid weight loss.^3,6,9-11 We report an unusual case of NUC that most likely was triggered by rapid weight loss and hypotension in a patient with multiple risk factors for calciphylaxis.

Case Report

A 75-year-old white woman with history of morbid obesity (body mass index, 40 kg/m²), unexplained weight loss of 70 lb over the last year, and polymyalgia rheumatica requiring chronic prednisone therapy presented with painful lesions on the thighs, buttocks, and right shoulder of 4 months’ duration. She had multiple hospital admissions preceding the onset of lesions for severe infections resulting in sepsis with hypotension, including Enterococcus faecalis endocarditis, extended-spectrum beta-lactamase bacteremia, and Pseudomonas aeruginosa pneumonia. Physical examination revealed large well-demarcated ulcers and necrotic eschars with surrounding violaceous induration and stellate erythema on the anterior, medial, and posterior thighs and buttocks that were exquisitely tender (Figures 1 and 2).

Notable laboratory results included hypoalbuminemia (1.3 g/dL [reference range, 3.5–5.0 g/dL]) with normal renal function, a corrected calcium level of 9.7 mg/dL (reference range, 8.2–10.2 mg/dL), a serum phosphorus level of 3.5 mg/dL (reference range, 2.3–4.7 mg/dL), a calcium-phosphate product of 27.3 mg²/dL² (reference range, <55 mg²/dL²), and a parathyroid hormone level of 49.3 pg/mL (reference range, 10–65 pg/mL). Antinuclear antibodies were negative. A hypercoagulability evaluation showed normal protein C and S levels, negative lupus anticoagulant, and negative anticardiolipin antibodies.

Telescoping punch biopsies of the indurated borders of the eschars showed prominent calcification of the small- and medium-sized vessels in the mid and deep dermis, intravascular thrombi, and necrosis of the epidermis and subcutaneous fat consistent with calciphylaxis (Figure 3).

Comment

Background on Calciphylaxis
Calciphylaxis is a rare but deadly disease that affects both ESRD patients receiving dialysis and patients without ESRD who have known risk factors for calciphylaxis, including female gender, white race, obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, underlying malignancy, protein C or S deficiency, corticosteroid use, warfarin use, diabetes, iron or albumin infusions, and rapid weight loss.^3,6-9,11 Although the molecular pathogenesis of calciphylaxis is not completely understood, it is believed to be caused by local deposition of calcium in the tunica media of small- to medium-sized arterioles and venules in the skin.¹² This deposition leads to intimal proliferation and progressive narrowing of the vessels with resultant thrombosis, ischemia, and necrosis. The cutaneous manifestations and histopathology of calciphylaxis classically follow its pathogenesis. Calciphylaxis typically presents with livedo reticularis as vessels narrow and then progresses to purpura, bullae, necrosis, and eschar formation with the onset of acute thrombosis and ischemia. Histopathology is characterized by small- and medium-sized vessel calcification and thrombus, dermal necrosis, and septal panniculitis, though the histology can be highly variable.¹² Unfortunately, the already poor prognosis for calciphylaxis worsens when lesions become either ulcerative or present on the proximal extremities and trunk.^4,13 Sepsis is the leading cause of death in calciphylaxis patients, affecting more than 50% of patients.^2,3,14 The differential diagnoses for calciphylactic-appearing lesions include warfarin-induced skin necrosis, disseminated intravascular coagulation, pyoderma gangrenosum, cholesterol emboli, and various vasculitides and coagulopathies.

Risk Factors
Our case demonstrates the importance of risk factor minimization, trigger avoidance, and early intervention due to the high mortality rate of calciphylaxis. Selye et al¹⁵ coined the term calciphylaxis in 1961 based on experiments that induced calciphylaxis in rat models. Their research concluded that there were certain sensitizers (ie, risk factors) that predisposed patients to medial calcium deposition in blood vessels and other challengers (ie, triggers) that acted as inciting events to calcium deposition. Our patient presented with multiple known risk factors for calciphylaxis, including obesity (body mass index, 40 kg/m²), female gender, white race, hypoalbuminemia, and chronic corticosteroid use.¹⁶ In the presence of a milieu of risk factors, the patient’s rapid weight loss and episodes of hypotension likely were triggers for calciphylaxis.

Other case reports in the literature have suggested weight loss as a trigger for NUC. One morbidly obese patient with inactive rheumatoid arthritis had onset of calciphylaxis lesions after unintentional weight loss of approximately 50% body weight in 1 year¹⁷; however, the weight loss does not have to be drastic to trigger calciphylaxis. Another study of 16 patients with uremic calciphylaxis found that 7 of 16 (44%) patients lost 10 to 50 kg in the 6 months prior to calciphylaxis onset.¹⁴ One proposed mechanism by Munavalli et al¹⁰ is that elevated levels of matrix metalloproteinases during catabolic weight loss states enhance the deposition of calcium into elastic fibers of small vessels. The authors found elevated serum levels of matrix metalloproteinases in their patients with NUC induced by rapid weight loss.¹⁰

A meta-analysis by Nigwekar et al³ found a history of prior corticosteroid use in 61% (22/36) of NUC cases reviewed. However, it is unclear whether it is the use of corticosteroids or chronic inflammation that is implicated in NUC pathogenesis. Chronic inflammation causes downregulation of anticalcification signaling pathways.^18-20 The role of 2 vascular calcification inhibitors has been evaluated in the pathogenesis of calciphylaxis: fetuin-A and matrix gla protein (MGP).²¹ The activity of these proteins is decreased not only in calciphylaxis but also in other inflammatory states and chronic renal failure.^18-20 One study found lower fetuin-A levels in 312 hemodialysis patients compared to healthy controls and an association between low fetuin-A levels and increased C-reactive protein levels.²² Reduced fetuin-A and MGP levels may be the result of several calciphylaxis risk factors. Warfarin is believed to trigger calciphylaxis via inhibition of gamma-carboxylation of MGP, which is necessary for its anticalcification activity.²³ Hypoalbuminemia and alcoholic liver disease also are risk factors that may be explained by the fact that fetuin-A is synthesized in the liver.²⁴ Therefore, liver disease results in decreased production of fetuin-A that is permissive to vascular calcification in calciphylaxis patients.

There have been other reports of calciphylaxis patients who were originally hospitalized due to hypotension, which may serve as a trigger for calciphylaxis onset.²⁵ Because calciphylaxis lesions are more likely to occur in the fatty areas of the abdomen and proximal thighs where blood flow is slower, hypotension likely accentuates the slowing of blood flow and subsequent blood vessel calcification. This theory is supported by studies showing that established calciphylactic lesions worsen more quickly in the presence of systemic hypotension.²⁶ One patient with ESRD and calciphylaxis of the breasts had consistent systolic blood pressure readings in the high 60s to low 70s between dialysis sessions.²⁷ Due to this association, we recommend that patients with calciphylaxis have close blood pressure monitoring to aid in preventing disease progression.²⁸

Management
Calciphylaxis treatment has not yet been standardized, as it is an uncommon disease whose pathogenesis is not fully understood. Current management strategies aim to normalize metabolic abnormalities such as hypercalcemia if they are present and remove inciting agents such as warfarin and corticosteroids.²⁹ Other medical treatments that have been successfully used include sodium thiosulfate, oral steroids, and adjunctive bisphosphonates.^29-31 Sodium thiosulfate is known to cause metabolic acidosis by generating thiosulfuric acid in vivo in patients with or without renal disease; therefore, patients on sodium thiosulfate therapy should be monitored for development of metabolic acidosis and treated with oral sodium bicarbonate or dialysis as needed.^30,32 Wound care also is an important element of calciphylaxis treatment; however, the debridement of wounds is controversial. Some argue that dry intact eschars serve to protect against sepsis, which is the leading cause of death in calciphylaxis.^2,14,33 In contrast, a retrospective study of 63 calciphylaxis patients found a 1-year survival rate of 61.6% in 17 patients receiving wound debridement vs 27.4% in 46 patients who did not.² The current consensus is that debridement should be considered on a case-by-case basis, factoring in the presence of wound infection, size of wounds, stability of eschars, and treatment goals of the patient.³⁴ Future studies should be aimed at this issue, with special focus on how these factors and the decision to debride or not impact patient outcomes.

Conclusion

Calciphylaxis is a potentially fatal disease that impacts both patients with ESRD and those with nonuremic risk factors. The term calcific uremic arteriolopathy should be disregarded, as nonuremic causes are being reported with increased frequency in the literature. In such cases, patients often have multiple risk factors, including obesity, primary hyperparathyroidism, alcoholic liver disease, and underlying malignancy, among others. Certain triggers for onset of calciphylaxis should be avoided in at-risk patients, including the use of corticosteroids or warfarin; iron and albumin infusions; hypotension; and rapid weight loss. Our fatal case of NUC is a reminder to dermatologists treating at-risk patients to avoid these triggers and to keep calciphylaxis in the differential diagnosis when encountering early lesions such as livedo reticularis, as progression of these lesions has a 1-year mortality rate of more than 50% with the therapies being utilized at this time.