Cutis

Proteus syndrome is characterized by asymmetric disproportionate enlargement of the limbs, skull, or vertebrae, associated with a number of cutaneous lesions. The variability in clinical presentation often results in misdiagnosis, and currently no diagnostic test exists. Although not seen in every patient, cerebriform connective tissue nevi, most commonly located on the plantar foot, are almost pathognomonic for the condition. While on a US Navy humanitarian mission in Southeast Asia, 2 patients with Proteus syndrome were identified. Herein, the clinical findings of 2 patients are presented and the current clinical diagnostic criteria are reviewed. 

Case Reports
Patient 1—A 19-year-old man from Nias Island, Indonesia, presented for evaluation of a progressively enlarging left foot. The patient's father noted that his son had a small vascular lesion on his left calf at birth, but the father was unaware of a discrepancy in foot size until his son was a year old. Over the years, the vascular malformation increased proportionately to the son's growth; the foot, however, enlarged in a disproportionate fashion. At approximately 7 years of age, the plantar foot began to progressively thicken, resulting in pain and difficulty walking. On examination, the patient had a substantially enlarged and distorted left foot with a large cerebriform connective tissue nevus on the plantar foot (Figure 1). A plain lateral radiograph of the foot confirmed enlargement of the bones and soft tissues (Figure 2). In addition, the patient's left calf was larger than the right calf and had an underlying vascular malformation (Figure 3). The patient did not have any café au lait spots, port-wine stains, varicosities, lipomas, or epidermal nevi. It was not possible to obtain a computed tomographic scan or magnetic resonance image to evaluate if there was involvement of other organ systems.

Patient 2—A 10-year-old boy presented for evaluation of a vascular lesion on his right chest. His mother noted that the lesion was present at birth and gradually had increased in size. On examination, the patient had asymmetric enlargement of his right chest associated with a poorly delineated vascular malformation that extended from his right chest and involved his upper abdomen and flank (Figure 4). The lower aspect of the lesion consisted of verrucous papules that intermittently bled and/or drained serosanguineous fluid. In addition, the patient had substantial cervical scoliosis and multiple large lipomas on his back and flank (Figure 5). No epidermal or connective tissue nevi were identified.

Comment
In 1979, Cohen and Hayden1 described 2 patients with overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. Subsequently, Wiedemann et al2 named the condition Proteus syndrome after the Greek god Proteus to denote its polymorphous clinical presentation. Awareness of the syndrome was heightened when Joseph Merrick, known as "The Elephant Man," was diagnosed with Proteus syndrome rather than neurofibromatosis type 1, which previously was believed to be the cause of his deformity. It has been suggested that Proteus syndrome is caused by a phosphatase and tensin homolog (PTEN) mutation; however, the patients cited did not fulfill the current diagnostic criteria that have been established for Proteus syndrome. Subsequently, 34 cases of bona fide Proteus syndrome were studied and none were shown to have a PTEN defect.3 Although the etiology of the condition remains unknown, Happle4 postulated that Proteus syndrome most likely arises from a post-zygotic mutation caused by a dominant lethal gene that survived by mosaicism. Proteus syndrome is relatively rare, and although there are approximately 250 cases reported in the literature, the actual number of confirmed cases of Proteus syndrome is less than 100 if the current diagnostic criteria are applied. The syndrome can occur in individuals of any race and shows a male predominance, with a male to female ratio of 1.9:1.5 Because of the variability in clinical presentation, Proteus syndrome has a high rate of misdiagnosis. Therefore, at the First National Conference on Proteus Syndrome for Parents and Families held at the National Institutes of Health in March 1998, specific diagnostic criteria were established.6 Regardless of the presence of other clinical findings, the following 3 criteria were believed to be mandatory to make the diagnosis: the lesions must have a mosaic distribution, follow a progressive course, and be inherited in a sporadic fashion.5,6 In addition to the aforementioned criteria, a patient may have either a connective tissue nevus, with the cerebriform variant being almost pathognomonic (category A); 2 of 3 lesions in category B (epidermal nevus; asymmetric disproportionate tissue overgrowth; or specific tumors before the end of the second decade, namely ovarian cystadenoma, meningioma, testicular tumor, or parotid monomorphic adenoma); or all 3 criteria in category C (dysregulated adipose tissue growth, vascular malformations, or specific facial phenotype).6 Currently, it is not recommended to combine partial criteria from categories B and C to diagnose Proteus syndrome.5,6 Other common findings include ophthalmologic abnormalities (42% of patients), central nervous system manifestations inclusive of mental retardation (40% of patients), cystic lung malformations (12%–13% of patients), and urologic abnormalities (9% of patients).3,5,6 It also is important to be cognizant of the fact that approximately 20% of patients will have premature deaths because of pneumonia, surgical complications, or pulmonary embolism from deep vein thrombosis.3 When the lesions of Proteus syndrome are fully developed, the diagnosis is not difficult; however, early in childhood, the tissue overgrowth and cutaneous lesions may not be present. One review5 showed that only 43% (42/97) of patients with Proteus syndrome had vascular malformations or epidermal nevi at birth, but even if present, these findings also can be seen in other syndromes or occur in isolation; consequently, the clinical findings may not be immediately associated with a diagnosis of Proteus syndrome. Furthermore, the characteristic asymmetric disproportionate tissue overgrowth is only seen in 17.5% (17/97) of patients at birth; therefore, diagnosis often is delayed until the lesions are fully expressed later in childhood or adolescence.3,5 The most striking feature of Proteus syndrome is asymmetric disproportionate tissue overgrowth with involvement of bones and soft tissues. The overgrowth most often affects an extremity but also commonly involves the skull or vertebrae. The asymmetric bony hyperplasia can result in scoliosis or may be so substantial that bone invades a joint space, resulting in reduced mobility. Characteristically, the overgrowth is progressive, but after adolescence, it tends to plateau.3 Overgrowth of various organs also can occur, particularly the thymus or spleen; however, it is an uncommon finding. The most common cutaneous lesions in Proteus syndrome are lipomas, vascular malformations, connective tissue nevi, epidermal nevi, hyperostoses, and focal areas of dermal and/or lipohypoplasia.3,6,7 The unique combination of tissue overgrowth with focal atrophy results in a body habitus characterized by wasting of the upper body with an elongated thorax and neck and muscular hypertrophy of the lower extremities. The lipomas in Proteus syndrome can be well-demarcated subcutaneous lesions or locally invasive when located in the intra-abdominal or intrathoracic cavity. Vascular lesions tend to be vascular malformations rather than infantile hemangiomas and can be composed of capillaries, venules, lymphatics, or a combination of these vascular channels. These lesions slowly grow with time in proportion with the patient. Although connective tissue nevi can occur anywhere on the body, they are almost pathognomonic for Proteus syndrome when they appear on the plantar foot or palmar hand and have a cerebriform appearance. Histologic evaluation of the lesion shows a compact collection of collagen in the dermis that has different staining characteristics from the native collagen. The epidermal nevi in Proteus syndrome are flat and soft rather than verrucous type,6 and histologically they are characterized by hyperkeratosis, acanthosis, and papillomatosis, without adnexal hyperplasia. Proteus syndrome has unique findings that help define the condition, but other syndromes can have similar clinical findings. Therefore, it is important to distinguish Proteus syndrome from other overgrowth syndromes (Table).

When confronted with a patient suspected of having Proteus syndrome, the initial evaluation should include baseline skeletal and vertebral radiographs and clinical photographs. In addition, a high-resolution chest computed tomographic scan should be performed to evaluate pulmonary cysts and magnetic resonance imaging to evaluate intracranial malformation and to rule out the presence of intra-abdominal or intrathoracic lipomas.3,6 Surgical management should be directed toward functional improvement. Patients with leg-length discrepancy, joint immobility, and macrodactyly are best managed by a team consisting of an experienced orthopedic surgeon, pediatrician, and physical and occupational therapists. The patient also may require consultation with a craniofacial or oral maxillofacial surgeon if airway obstruction or feeding difficulties occur because of hemifacial macrosomia. In addition, surgical consultation may be required for resection of internal lipomas or cystic lung malformations. Because of the high incidence of deep vein thrombosis, it is recommended that antithrombotic prophylaxis is considered prior to all surgical procedures.3

Conclusion
Proteus syndrome is a complex disorder with a variable clinical presentation, yet an appropriate diagnosis can be established if the diagnostic guidelines are followed. Despite the rarity of Proteus syndrome, support networks exist to help patients and their families manage the disease.

Proteus syndrome is characterized by asymmetric disproportionate enlargement of the limbs, skull, or vertebrae, associated with a number of cutaneous lesions. The variability in clinical presentation often results in misdiagnosis, and currently no diagnostic test exists. Although not seen in every patient, cerebriform connective tissue nevi, most commonly located on the plantar foot, are almost pathognomonic for the condition. While on a US Navy humanitarian mission in Southeast Asia, 2 patients with Proteus syndrome were identified. Herein, the clinical findings of 2 patients are presented and the current clinical diagnostic criteria are reviewed. 

Case Reports
Patient 1—A 19-year-old man from Nias Island, Indonesia, presented for evaluation of a progressively enlarging left foot. The patient's father noted that his son had a small vascular lesion on his left calf at birth, but the father was unaware of a discrepancy in foot size until his son was a year old. Over the years, the vascular malformation increased proportionately to the son's growth; the foot, however, enlarged in a disproportionate fashion. At approximately 7 years of age, the plantar foot began to progressively thicken, resulting in pain and difficulty walking. On examination, the patient had a substantially enlarged and distorted left foot with a large cerebriform connective tissue nevus on the plantar foot (Figure 1). A plain lateral radiograph of the foot confirmed enlargement of the bones and soft tissues (Figure 2). In addition, the patient's left calf was larger than the right calf and had an underlying vascular malformation (Figure 3). The patient did not have any café au lait spots, port-wine stains, varicosities, lipomas, or epidermal nevi. It was not possible to obtain a computed tomographic scan or magnetic resonance image to evaluate if there was involvement of other organ systems.

Patient 2—A 10-year-old boy presented for evaluation of a vascular lesion on his right chest. His mother noted that the lesion was present at birth and gradually had increased in size. On examination, the patient had asymmetric enlargement of his right chest associated with a poorly delineated vascular malformation that extended from his right chest and involved his upper abdomen and flank (Figure 4). The lower aspect of the lesion consisted of verrucous papules that intermittently bled and/or drained serosanguineous fluid. In addition, the patient had substantial cervical scoliosis and multiple large lipomas on his back and flank (Figure 5). No epidermal or connective tissue nevi were identified.

Comment
In 1979, Cohen and Hayden1 described 2 patients with overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. Subsequently, Wiedemann et al2 named the condition Proteus syndrome after the Greek god Proteus to denote its polymorphous clinical presentation. Awareness of the syndrome was heightened when Joseph Merrick, known as "The Elephant Man," was diagnosed with Proteus syndrome rather than neurofibromatosis type 1, which previously was believed to be the cause of his deformity. It has been suggested that Proteus syndrome is caused by a phosphatase and tensin homolog (PTEN) mutation; however, the patients cited did not fulfill the current diagnostic criteria that have been established for Proteus syndrome. Subsequently, 34 cases of bona fide Proteus syndrome were studied and none were shown to have a PTEN defect.3 Although the etiology of the condition remains unknown, Happle4 postulated that Proteus syndrome most likely arises from a post-zygotic mutation caused by a dominant lethal gene that survived by mosaicism. Proteus syndrome is relatively rare, and although there are approximately 250 cases reported in the literature, the actual number of confirmed cases of Proteus syndrome is less than 100 if the current diagnostic criteria are applied. The syndrome can occur in individuals of any race and shows a male predominance, with a male to female ratio of 1.9:1.5 Because of the variability in clinical presentation, Proteus syndrome has a high rate of misdiagnosis. Therefore, at the First National Conference on Proteus Syndrome for Parents and Families held at the National Institutes of Health in March 1998, specific diagnostic criteria were established.6 Regardless of the presence of other clinical findings, the following 3 criteria were believed to be mandatory to make the diagnosis: the lesions must have a mosaic distribution, follow a progressive course, and be inherited in a sporadic fashion.5,6 In addition to the aforementioned criteria, a patient may have either a connective tissue nevus, with the cerebriform variant being almost pathognomonic (category A); 2 of 3 lesions in category B (epidermal nevus; asymmetric disproportionate tissue overgrowth; or specific tumors before the end of the second decade, namely ovarian cystadenoma, meningioma, testicular tumor, or parotid monomorphic adenoma); or all 3 criteria in category C (dysregulated adipose tissue growth, vascular malformations, or specific facial phenotype).6 Currently, it is not recommended to combine partial criteria from categories B and C to diagnose Proteus syndrome.5,6 Other common findings include ophthalmologic abnormalities (42% of patients), central nervous system manifestations inclusive of mental retardation (40% of patients), cystic lung malformations (12%–13% of patients), and urologic abnormalities (9% of patients).3,5,6 It also is important to be cognizant of the fact that approximately 20% of patients will have premature deaths because of pneumonia, surgical complications, or pulmonary embolism from deep vein thrombosis.3 When the lesions of Proteus syndrome are fully developed, the diagnosis is not difficult; however, early in childhood, the tissue overgrowth and cutaneous lesions may not be present. One review5 showed that only 43% (42/97) of patients with Proteus syndrome had vascular malformations or epidermal nevi at birth, but even if present, these findings also can be seen in other syndromes or occur in isolation; consequently, the clinical findings may not be immediately associated with a diagnosis of Proteus syndrome. Furthermore, the characteristic asymmetric disproportionate tissue overgrowth is only seen in 17.5% (17/97) of patients at birth; therefore, diagnosis often is delayed until the lesions are fully expressed later in childhood or adolescence.3,5 The most striking feature of Proteus syndrome is asymmetric disproportionate tissue overgrowth with involvement of bones and soft tissues. The overgrowth most often affects an extremity but also commonly involves the skull or vertebrae. The asymmetric bony hyperplasia can result in scoliosis or may be so substantial that bone invades a joint space, resulting in reduced mobility. Characteristically, the overgrowth is progressive, but after adolescence, it tends to plateau.3 Overgrowth of various organs also can occur, particularly the thymus or spleen; however, it is an uncommon finding. The most common cutaneous lesions in Proteus syndrome are lipomas, vascular malformations, connective tissue nevi, epidermal nevi, hyperostoses, and focal areas of dermal and/or lipohypoplasia.3,6,7 The unique combination of tissue overgrowth with focal atrophy results in a body habitus characterized by wasting of the upper body with an elongated thorax and neck and muscular hypertrophy of the lower extremities. The lipomas in Proteus syndrome can be well-demarcated subcutaneous lesions or locally invasive when located in the intra-abdominal or intrathoracic cavity. Vascular lesions tend to be vascular malformations rather than infantile hemangiomas and can be composed of capillaries, venules, lymphatics, or a combination of these vascular channels. These lesions slowly grow with time in proportion with the patient. Although connective tissue nevi can occur anywhere on the body, they are almost pathognomonic for Proteus syndrome when they appear on the plantar foot or palmar hand and have a cerebriform appearance. Histologic evaluation of the lesion shows a compact collection of collagen in the dermis that has different staining characteristics from the native collagen. The epidermal nevi in Proteus syndrome are flat and soft rather than verrucous type,6 and histologically they are characterized by hyperkeratosis, acanthosis, and papillomatosis, without adnexal hyperplasia. Proteus syndrome has unique findings that help define the condition, but other syndromes can have similar clinical findings. Therefore, it is important to distinguish Proteus syndrome from other overgrowth syndromes (Table).

When confronted with a patient suspected of having Proteus syndrome, the initial evaluation should include baseline skeletal and vertebral radiographs and clinical photographs. In addition, a high-resolution chest computed tomographic scan should be performed to evaluate pulmonary cysts and magnetic resonance imaging to evaluate intracranial malformation and to rule out the presence of intra-abdominal or intrathoracic lipomas.3,6 Surgical management should be directed toward functional improvement. Patients with leg-length discrepancy, joint immobility, and macrodactyly are best managed by a team consisting of an experienced orthopedic surgeon, pediatrician, and physical and occupational therapists. The patient also may require consultation with a craniofacial or oral maxillofacial surgeon if airway obstruction or feeding difficulties occur because of hemifacial macrosomia. In addition, surgical consultation may be required for resection of internal lipomas or cystic lung malformations. Because of the high incidence of deep vein thrombosis, it is recommended that antithrombotic prophylaxis is considered prior to all surgical procedures.3

Conclusion
Proteus syndrome is a complex disorder with a variable clinical presentation, yet an appropriate diagnosis can be established if the diagnostic guidelines are followed. Despite the rarity of Proteus syndrome, support networks exist to help patients and their families manage the disease.

Proteus syndrome is characterized by asymmetric disproportionate enlargement of the limbs, skull, or vertebrae, associated with a number of cutaneous lesions. The variability in clinical presentation often results in misdiagnosis, and currently no diagnostic test exists. Although not seen in every patient, cerebriform connective tissue nevi, most commonly located on the plantar foot, are almost pathognomonic for the condition. While on a US Navy humanitarian mission in Southeast Asia, 2 patients with Proteus syndrome were identified. Herein, the clinical findings of 2 patients are presented and the current clinical diagnostic criteria are reviewed. 

Case Reports
Patient 1—A 19-year-old man from Nias Island, Indonesia, presented for evaluation of a progressively enlarging left foot. The patient's father noted that his son had a small vascular lesion on his left calf at birth, but the father was unaware of a discrepancy in foot size until his son was a year old. Over the years, the vascular malformation increased proportionately to the son's growth; the foot, however, enlarged in a disproportionate fashion. At approximately 7 years of age, the plantar foot began to progressively thicken, resulting in pain and difficulty walking. On examination, the patient had a substantially enlarged and distorted left foot with a large cerebriform connective tissue nevus on the plantar foot (Figure 1). A plain lateral radiograph of the foot confirmed enlargement of the bones and soft tissues (Figure 2). In addition, the patient's left calf was larger than the right calf and had an underlying vascular malformation (Figure 3). The patient did not have any café au lait spots, port-wine stains, varicosities, lipomas, or epidermal nevi. It was not possible to obtain a computed tomographic scan or magnetic resonance image to evaluate if there was involvement of other organ systems.

Patient 2—A 10-year-old boy presented for evaluation of a vascular lesion on his right chest. His mother noted that the lesion was present at birth and gradually had increased in size. On examination, the patient had asymmetric enlargement of his right chest associated with a poorly delineated vascular malformation that extended from his right chest and involved his upper abdomen and flank (Figure 4). The lower aspect of the lesion consisted of verrucous papules that intermittently bled and/or drained serosanguineous fluid. In addition, the patient had substantial cervical scoliosis and multiple large lipomas on his back and flank (Figure 5). No epidermal or connective tissue nevi were identified.

Comment
In 1979, Cohen and Hayden1 described 2 patients with overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. Subsequently, Wiedemann et al2 named the condition Proteus syndrome after the Greek god Proteus to denote its polymorphous clinical presentation. Awareness of the syndrome was heightened when Joseph Merrick, known as "The Elephant Man," was diagnosed with Proteus syndrome rather than neurofibromatosis type 1, which previously was believed to be the cause of his deformity. It has been suggested that Proteus syndrome is caused by a phosphatase and tensin homolog (PTEN) mutation; however, the patients cited did not fulfill the current diagnostic criteria that have been established for Proteus syndrome. Subsequently, 34 cases of bona fide Proteus syndrome were studied and none were shown to have a PTEN defect.3 Although the etiology of the condition remains unknown, Happle4 postulated that Proteus syndrome most likely arises from a post-zygotic mutation caused by a dominant lethal gene that survived by mosaicism. Proteus syndrome is relatively rare, and although there are approximately 250 cases reported in the literature, the actual number of confirmed cases of Proteus syndrome is less than 100 if the current diagnostic criteria are applied. The syndrome can occur in individuals of any race and shows a male predominance, with a male to female ratio of 1.9:1.5 Because of the variability in clinical presentation, Proteus syndrome has a high rate of misdiagnosis. Therefore, at the First National Conference on Proteus Syndrome for Parents and Families held at the National Institutes of Health in March 1998, specific diagnostic criteria were established.6 Regardless of the presence of other clinical findings, the following 3 criteria were believed to be mandatory to make the diagnosis: the lesions must have a mosaic distribution, follow a progressive course, and be inherited in a sporadic fashion.5,6 In addition to the aforementioned criteria, a patient may have either a connective tissue nevus, with the cerebriform variant being almost pathognomonic (category A); 2 of 3 lesions in category B (epidermal nevus; asymmetric disproportionate tissue overgrowth; or specific tumors before the end of the second decade, namely ovarian cystadenoma, meningioma, testicular tumor, or parotid monomorphic adenoma); or all 3 criteria in category C (dysregulated adipose tissue growth, vascular malformations, or specific facial phenotype).6 Currently, it is not recommended to combine partial criteria from categories B and C to diagnose Proteus syndrome.5,6 Other common findings include ophthalmologic abnormalities (42% of patients), central nervous system manifestations inclusive of mental retardation (40% of patients), cystic lung malformations (12%–13% of patients), and urologic abnormalities (9% of patients).3,5,6 It also is important to be cognizant of the fact that approximately 20% of patients will have premature deaths because of pneumonia, surgical complications, or pulmonary embolism from deep vein thrombosis.3 When the lesions of Proteus syndrome are fully developed, the diagnosis is not difficult; however, early in childhood, the tissue overgrowth and cutaneous lesions may not be present. One review5 showed that only 43% (42/97) of patients with Proteus syndrome had vascular malformations or epidermal nevi at birth, but even if present, these findings also can be seen in other syndromes or occur in isolation; consequently, the clinical findings may not be immediately associated with a diagnosis of Proteus syndrome. Furthermore, the characteristic asymmetric disproportionate tissue overgrowth is only seen in 17.5% (17/97) of patients at birth; therefore, diagnosis often is delayed until the lesions are fully expressed later in childhood or adolescence.3,5 The most striking feature of Proteus syndrome is asymmetric disproportionate tissue overgrowth with involvement of bones and soft tissues. The overgrowth most often affects an extremity but also commonly involves the skull or vertebrae. The asymmetric bony hyperplasia can result in scoliosis or may be so substantial that bone invades a joint space, resulting in reduced mobility. Characteristically, the overgrowth is progressive, but after adolescence, it tends to plateau.3 Overgrowth of various organs also can occur, particularly the thymus or spleen; however, it is an uncommon finding. The most common cutaneous lesions in Proteus syndrome are lipomas, vascular malformations, connective tissue nevi, epidermal nevi, hyperostoses, and focal areas of dermal and/or lipohypoplasia.3,6,7 The unique combination of tissue overgrowth with focal atrophy results in a body habitus characterized by wasting of the upper body with an elongated thorax and neck and muscular hypertrophy of the lower extremities. The lipomas in Proteus syndrome can be well-demarcated subcutaneous lesions or locally invasive when located in the intra-abdominal or intrathoracic cavity. Vascular lesions tend to be vascular malformations rather than infantile hemangiomas and can be composed of capillaries, venules, lymphatics, or a combination of these vascular channels. These lesions slowly grow with time in proportion with the patient. Although connective tissue nevi can occur anywhere on the body, they are almost pathognomonic for Proteus syndrome when they appear on the plantar foot or palmar hand and have a cerebriform appearance. Histologic evaluation of the lesion shows a compact collection of collagen in the dermis that has different staining characteristics from the native collagen. The epidermal nevi in Proteus syndrome are flat and soft rather than verrucous type,6 and histologically they are characterized by hyperkeratosis, acanthosis, and papillomatosis, without adnexal hyperplasia. Proteus syndrome has unique findings that help define the condition, but other syndromes can have similar clinical findings. Therefore, it is important to distinguish Proteus syndrome from other overgrowth syndromes (Table).

When confronted with a patient suspected of having Proteus syndrome, the initial evaluation should include baseline skeletal and vertebral radiographs and clinical photographs. In addition, a high-resolution chest computed tomographic scan should be performed to evaluate pulmonary cysts and magnetic resonance imaging to evaluate intracranial malformation and to rule out the presence of intra-abdominal or intrathoracic lipomas.3,6 Surgical management should be directed toward functional improvement. Patients with leg-length discrepancy, joint immobility, and macrodactyly are best managed by a team consisting of an experienced orthopedic surgeon, pediatrician, and physical and occupational therapists. The patient also may require consultation with a craniofacial or oral maxillofacial surgeon if airway obstruction or feeding difficulties occur because of hemifacial macrosomia. In addition, surgical consultation may be required for resection of internal lipomas or cystic lung malformations. Because of the high incidence of deep vein thrombosis, it is recommended that antithrombotic prophylaxis is considered prior to all surgical procedures.3

Conclusion
Proteus syndrome is a complex disorder with a variable clinical presentation, yet an appropriate diagnosis can be established if the diagnostic guidelines are followed. Despite the rarity of Proteus syndrome, support networks exist to help patients and their families manage the disease.

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.