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Cutis is a peer-reviewed clinical journal for the dermatologist, allergist, and general practitioner published monthly since 1965. Concise clinical articles present the practical side of dermatology, helping physicians to improve patient care. Cutis is referenced in Index Medicus/MEDLINE and is written and edited by industry leaders.
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A peer-reviewed, indexed journal for dermatologists with original research, image quizzes, cases and reviews, and columns.
What's Eating You? The South African Fattail Scorpion (Parabuthus transvaalicus)
Demodex Mites as a Cause of Human Disease [editorial]
The Taylor Hyperpigmentation Scale: A New Visual Assessment Tool for the Evaluation of Skin Color and Pigmentation
Eruptive Syringomas: An Unusual Presentation on the Buttocks
Scurvy Masquerading as Leukocytoclastic Vasculitis: A Case Report and Review of the Literature
Scurvy is prominent in world history. The disease was rampant among sailing crews from the Renaissance to the 18th century, when advances in shipbuilding and navigation facilitated sea voyages of long duration. From 1497 to 1499, half of the Vasco da Gama crew died from scurvy while sailing around the Cape of Good Hope to the east coast of Africa. In 1747, Scottish naval surgeon Sir James Lind was the first to conduct a clinical trial demonstrating improvement in scorbutic patients who ingested fresh lemons and oranges. It was not until the end of the 18th century, when Sir Gilbert Blane required British sailors to ingest lime juice routinely, that citrus fruits were used to prevent scurvy.1 Outbreaks of scurvy have occurred throughout history, including during the 1845 potato famine in Ireland, the 1848 California Gold Rush, the US Civil War (1861–1865), and the 1915 Gallipoli campaign of World War I.1,2
Case Report
A 59-year-old white man with a medical history of chronic obstructive pulmonary disease presented to the emergency department with a petechial rash on his lower extremities. He denied having fever or arthralgias at that time. The rash was dismissed as leukocytoclastic vasculitis, and the patient was sent home. He failed to follow-up in the outpatient clinic for workup and returned to the emergency department 4 months later with severe right thigh pain. Results of a computed tomographic scan of the lower extremity revealed right thigh and right gluteal hematomas. Hemoglobin and hematocrit levels were 11.6 g/dL and 35.0%, respectively. The dermatology department was consulted to evaluate the petechiae of the thighs and arms. On more careful examination, discrete perifollicular hemorrhages were noted (Figure 1), a large ecchymosis was found on the right leg and foot (Figure 2), and the patient was found to be emaciated. This combination of signs prompted a search for other stigmata of scurvy. Corkscrew hairs were noted (Figure 3), though no obvious gingivitis was present; however, the patient confirmed he had a history of bleeding gums, especially after brushing. An unprompted diet history revealed ingestion of canned tuna (which contains 0% vitamin C), pasta without tomato sauce, oatmeal, and water. The patient could not afford fruit, vegetables, or orange juice.
Although the patient's serum ascorbic acid level was not confirmed by testing, his symptoms promptly resolved within a week of oral administration of 1 g of vitamin C taken twice daily. Of note, the patient's platelet count; clotting factor level; international normalized ratio value; activated partial thromboplastin time; bleeding time; and concentrations of serum albumin (4.3 g/dL), total protein (7.3 g/dL), serum calcium (9.6 mg/dL), and serum phosphorus (3.7 mg/dL) were all within reference range. However, his erythrocyte sedimentation rate was elevated at 60 mm/h. Results of a skin biopsy revealed only interstitial perivascular hemorrhage without significant infiltrate. Results of a bone scan revealed 4 small foci of uptake—2 in the sacrum and 1 in each sacroiliac joint. Results of a computed tomographic scan revealed diffuse sacral osteopenia, which is a characteristic finding in adult scurvy.
Comment
Scurvy is a clinical condition resulting from inadequate intake of vitamin C. Although scurvy is well documented historically, it is relatively uncommon in industrialized countries and, therefore, may be underdiagnosed.3 Most animals are able to synthesize ascorbic acid from glucose4; however, humans harbor only a nonfunctional partial copy of the L-gulono-γ-lactone oxidase (GULO) gene, the product of which catalyzes the last step in ascorbic acid synthesis—specifically, the conversion of glucuronic acid to glucuronolactone and ascorbate.5 Therefore, vitamin C, a water-soluble vitamin, is essential for humans and must be acquired from diet. Scurvy most commonly is seen in individuals with a diet lacking in vitamin C. Citrus fruits, green vegetables, tomatoes, and potatoes are especially rich sources of vitamin C; additionally, the vitamin can be found in milk, liver, fish, multivitamins, and artificially fortified foods.6-7 The people most at risk for scurvy due to poor diet are the elderly,8 especially those who are institutionalized9; men who live alone8; alcoholics8,10; people following fad diets8; and the mentally ill.11,12 Scurvy also has been reported in patients with cancer. In this setting, the condition is thought to be a consequence of increased vitamin C requirements (as is true of smokers and diabetic patients) and poor dietary intake secondary to depression, impaired taste, dysphagia, and abdominal pain, as well as the mucositis, nausea, vomiting, and diarrhea that can accompany chemotherapy.8,13 In addition, scurvy has been reported as a complication of total parenteral nutrition,8 enteral feeds,14 and malabsorption secondary to either radiotherapy8 or intestinal processes such as Whipple disease.15 Peritoneal dialysis and hemodialysis also have been implicated in cases where water-soluble vitamin C is removed from the body during the dialysis process.16 Patients with scurvy can present with fatigue and malaise early on and with myalgia as the vitamin C deficiency progresses. The clinical signs of scurvy include hair follicle abnormalities, complications from bleeding diathesis, and osteopenia. Cachexia may be an associated finding. Follicle findings include perifollicular palpable purpura, follicular hyperkeratosis, and bent or coiled body hairs, which are often termed entrapped corkscrew hairs.4 Other findings can include xerosis, leg edema, and poor wound healing. Bleeding diathesis often results in hemarthroses and soft tissue hematomas that are produced by mild or inapparent trauma and tend to involve the legs.4,17 Interestingly, gingival findings occur only in patients with teeth and include gingival swelling, petechial lesions, purplish discoloration, bleeding with little provocation, and secondary bacterial periodontal infections.4,7,18 Bleeding complications in children can be more dramatic than in adults and include possible subperiosteal hematomas and retrobulbar, subarachnoid, and intracerebral hemorrhages.18 In rare extreme cases, the bleeding complications of scurvy can involve the peritoneum, pericardium, and adrenal glands.6 Anemia frequently accompanies scurvy secondary both to bleeding and to a decrease in iron absorption that is precipitated by ascorbic acid deficiency.4,7 Scurvy that is left untreated is fatal as a result of either sudden death or infection. The late stages of scurvy are characterized by neuropathy, edema, oliguria, syncope, leukopenia, and intracerebral hemorrhage.4,19,20 Severe hypertension was reported in one case.11 Because vitamin C is intimately involved in collagen synthesis, the pathophysiology of bleeding in scurvy originates in the decreased tensile strength of the connective tissue collagen that supports blood vessels and that is found within vessel walls. Biochemically, vitamin C regenerates the prosthetic metal ions in prolyl and lysyl hydroxylase.21 This enzyme hydroxylates proline and lysine residues in the procollagen polypeptide chain. The hydroxylated residues serve to crosslink and stabilize the ensuing collagen triple helix. Impaired cross-linking destabilizes collagen fibrils, decreases collagen secretion from fibroblasts, and increases collagen solubility, which makes the protein more vulnerable to enzymatic degradation.7 Scurvy-related bleeding tendencies revolve around the collagen content of dermal structures: the dermis and blood vessel tunica adventitia primarily contain type I collagen, blood vessel tunica media contains type III collagen, and the blood vessel basement membrane contains type IV collagen.22 Vitamin C deficiency also has been shown to suppress the rate of synthesis of procollagen peptides independent of proline and lysine hydroxylation,23 with additional evidence demonstrating lower expression of type IV collagen and elastin messenger RNA in scorbutic states.24 Apart from its role in structural integrity, vitamin C is essential for the conversion of histamine to aspartic acid. Exponential increases in blood histamine with corresponding decreases in aspartic acid as a consequence of vitamin C deficiency causes vascular endothelial cells to separate, which also may contribute to the bleeding tendency in scurvy.25 Of note, vitamin C has not been reported to affect bleeding time or clotting factor production or function. Examples of decreased structural integrity of the microcirculation and supporting tissue other than scurvy include senile purpura, in which long-term sun damage and decreased structural components secondary to aging results in purpuric patches; potent topical corticosteroid excess, in which cutaneous atrophy can lead to purpura; Ehlers-Danlos syndromes, which have various collagen defects; and amyloid infiltration of blood vessel walls in a primary systemic amyloidosis that is associated with, for example, multiple myeloma.18 The impairment of connective tissue components that occurs in patients with scurvy also can manifest in bone and produce radiographic findings such as osteopenia, as in the case presented here. Epidemiologic studies have reported a positive association between vitamin C intake and bone density,26 and guinea pig models of scurvy have demonstrated lower bone density in scorbutic animals.27 Impaired collagen leads to a primary disturbance in the formation of the osteoid matrix, with no effect on mineralization. Decreased osteoblast function with unimpaired osteoclast function also contributes to the osteopenia. Osteoporosis related to vitamin C deficiency is seen primarily in the axial skeleton.28 Other radiographic findings in patients with scurvy are typically related to growing children7 and include metaphyseal spurs and marginal fractures known as Pelkan sign; a ring of increased density surrounding the epiphysis, or Wimberger sign; widening of the zone of provisional calcification, or the white line of Frankl; and a transverse band of radiolucency in the metaphysis, known as the scurvy line or Trummerfeld zone.28 Other bony deformities may be observed, such as a bowing of the long bones, an abnormally depressed sternum, and an outward projection of the ends of the ribs.7 Infantile scurvy, also known as Barlow disease, is characterized by ecchymoses, bone fractures, and nonhealing ulcers29 and can be mistaken for child abuse. A vitamin C dose of 60 to 100 mg/d is sufficient to prevent scurvy; the consumption of 5 daily servings of fruits or vegetables provides more than 60 mg of vitamin C.6,8 Good dietary sources of vitamin C include citrus fruits, broccoli, tomatoes, and potatoes6 (eg, a 100-g orange contains 50 mg of vitamin C).8 Despite the inconclusive role of the antioxidant function of ascorbic acid in preventing disease, the higher US recommended daily allowance of vitamin C established in 2002 (75 mg for women, 90 mg for men) is based on the vitamin's antioxidant function and not just on the amount required to protect against deficiency30; the requirement for smokers may be up to 140 mg/d. The rationale for a higher recommended daily allowance of vitamin C may be due to the fact that higher daily intakes of the vitamin (150–200 mg) possibly may augment the role of ascorbic acid in immune response, pulmonary function, and iron absorption.31 Weeks to months of deficient vitamin C intake, defined as consuming as little as 10 mg/d,6 is usually necessary to drop the body's normal vitamin C reserves (1500 mg) down to 300 mg; below this level, symptoms may appear.8 Diagnosis of scurvy is based on clinical findings and results of laboratory tests to assess vitamin C levels. Low serum vitamin C, typically defined as less than 0.1 mg/dL,20 reflects inadequate recent dietary intake. The level of ascorbate in leukocytes more accurately reflects the body's stores, though is not a routinely available test.8 Fortunately, however, all cases of scurvy, even those with advanced involvement, respond to administration of vitamin C. Recommended and reported treatment regimens vary from 200 mg/d, with symptoms improving over several days, to 1 g/d for 2 weeks, with symptom resolution within 2 weeks.6,9,12 Complete absorption of vitamin C occurs if less than 100 mg is administered in a single dose, whereas only 50% or less is absorbed at doses greater than 1 g. Side effects of oxalate-related nephrolithiasis, abdominal pain, nausea, and diarrhea may be observed with greater than 2 g/d; increased alanine aminotransferase, lactate dehydrogenase, and serum uric acid levels may occur with greater than 3 g/d.6 High-dose vitamin C can induce hemolysis in patients with glucose 6-phosphate dehydrogenase deficiency, and doses of more than 1 g/d can cause false-negative guaiac reactions.6
Conclusion
Given its rarity in the modern day, scurvy might easily be mistaken for child abuse29 or misdiagnosed as a connective tissue disease, systemic vasculitis,32 or malignancy. Despite its rarity and because of its simple treatment, scurvy must not be overlooked as a possible diagnosis in a patient presenting with suggestive findings in the appropriate context.
- French RK. Scurvy. In: Kiple KF, ed. The Cambridge World History of Human Disease. Cambridge, England: Cambridge University Press; 1993:1000-1005.
- McGrew RE. Encyclopedia of Medical History. New York, NY: McGraw Hill; 1985:312.
- Oeffinger KC. Scurvy: more than historical relevance. Am Fam Physician. 1993;48:609-613.
- Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol. 1999;41:895-906.
- Goldman L, Ausiello D, Bennet JC, et al, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: WB Saunders Company; 2003:190.
- Russel RM. Vitamin and trace mineral deficiency and excess. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Online. Chapter 61. Available at: http://www.accessmedicine.com. Accessed January 15, 2005.
- Kumar V, Abbas AK, Fausto N. Robbins and Cotran's Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: WB Saunders Co; 2004:458-459.
- Fain O, Mathieu E, Thomas M. Scurvy in patients with cancer. BMJ. 1998;316:1661-1662.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Vasudevan AR, Kumar S, Lim A, et al. Purple skin and a swollen thigh in an alcoholic. Postgrad Med J. 2002;78:430-434.
- Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108:E55.
- Chatproedprais S, Wananukul S. Scurvy: a case report. J Med Assoc Thai. 2001;84(suppl 1):S106-S110.
- Nguyen RT, Cowley DM, Muir JB. Scurvy: a cutaneous clinical diagnosis. Australas J Dermatol. 2003;44:48-51.
- Gorman SR, Armstrong G, Allen KR, et al. Scarcity in the midst of plenty: enteral tube feeding complicated by scurvy. J Pediatr Gastroenterol Nutr. 2002;35:93-95.
- Berger ML, Siegel DM, Lee EL. Scurvy as an initial manifestation of Whipple's disease. Ann Intern Med. 1984;101:58-59.
- Ihle BU, Gillies M. Scurvy and thrombocytopathy in a chronic hemodialysis patient. Aust N Z J Med. 1983;13:523.
- Leone J, Delhinger V, Maes D, et al. Rheumatic manifestations of scurvy. a report of two cases. Rev Rhum Engl Ed. 1997;64:428-431.
- Hoffman R, Benj EJ, Shattil SJ, et al. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1831.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Baron RB. Nutrition. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment, 2004. New York, NY: McGraw-Hill Medical; 2004:1203-1234.
- Padh H. Vitamin C: newer insights into its biochemical functions. Nutr Rev. 1991;49:65-70.
- Junqueira LC, Carneiro J, Kelley RO. Basic Histology. 8th ed. East Norwalk, Conn: Appleton & Lange; 1995:202.
- Peterkovsky B. Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis
Scurvy is prominent in world history. The disease was rampant among sailing crews from the Renaissance to the 18th century, when advances in shipbuilding and navigation facilitated sea voyages of long duration. From 1497 to 1499, half of the Vasco da Gama crew died from scurvy while sailing around the Cape of Good Hope to the east coast of Africa. In 1747, Scottish naval surgeon Sir James Lind was the first to conduct a clinical trial demonstrating improvement in scorbutic patients who ingested fresh lemons and oranges. It was not until the end of the 18th century, when Sir Gilbert Blane required British sailors to ingest lime juice routinely, that citrus fruits were used to prevent scurvy.1 Outbreaks of scurvy have occurred throughout history, including during the 1845 potato famine in Ireland, the 1848 California Gold Rush, the US Civil War (1861–1865), and the 1915 Gallipoli campaign of World War I.1,2
Case Report
A 59-year-old white man with a medical history of chronic obstructive pulmonary disease presented to the emergency department with a petechial rash on his lower extremities. He denied having fever or arthralgias at that time. The rash was dismissed as leukocytoclastic vasculitis, and the patient was sent home. He failed to follow-up in the outpatient clinic for workup and returned to the emergency department 4 months later with severe right thigh pain. Results of a computed tomographic scan of the lower extremity revealed right thigh and right gluteal hematomas. Hemoglobin and hematocrit levels were 11.6 g/dL and 35.0%, respectively. The dermatology department was consulted to evaluate the petechiae of the thighs and arms. On more careful examination, discrete perifollicular hemorrhages were noted (Figure 1), a large ecchymosis was found on the right leg and foot (Figure 2), and the patient was found to be emaciated. This combination of signs prompted a search for other stigmata of scurvy. Corkscrew hairs were noted (Figure 3), though no obvious gingivitis was present; however, the patient confirmed he had a history of bleeding gums, especially after brushing. An unprompted diet history revealed ingestion of canned tuna (which contains 0% vitamin C), pasta without tomato sauce, oatmeal, and water. The patient could not afford fruit, vegetables, or orange juice.
Although the patient's serum ascorbic acid level was not confirmed by testing, his symptoms promptly resolved within a week of oral administration of 1 g of vitamin C taken twice daily. Of note, the patient's platelet count; clotting factor level; international normalized ratio value; activated partial thromboplastin time; bleeding time; and concentrations of serum albumin (4.3 g/dL), total protein (7.3 g/dL), serum calcium (9.6 mg/dL), and serum phosphorus (3.7 mg/dL) were all within reference range. However, his erythrocyte sedimentation rate was elevated at 60 mm/h. Results of a skin biopsy revealed only interstitial perivascular hemorrhage without significant infiltrate. Results of a bone scan revealed 4 small foci of uptake—2 in the sacrum and 1 in each sacroiliac joint. Results of a computed tomographic scan revealed diffuse sacral osteopenia, which is a characteristic finding in adult scurvy.
Comment
Scurvy is a clinical condition resulting from inadequate intake of vitamin C. Although scurvy is well documented historically, it is relatively uncommon in industrialized countries and, therefore, may be underdiagnosed.3 Most animals are able to synthesize ascorbic acid from glucose4; however, humans harbor only a nonfunctional partial copy of the L-gulono-γ-lactone oxidase (GULO) gene, the product of which catalyzes the last step in ascorbic acid synthesis—specifically, the conversion of glucuronic acid to glucuronolactone and ascorbate.5 Therefore, vitamin C, a water-soluble vitamin, is essential for humans and must be acquired from diet. Scurvy most commonly is seen in individuals with a diet lacking in vitamin C. Citrus fruits, green vegetables, tomatoes, and potatoes are especially rich sources of vitamin C; additionally, the vitamin can be found in milk, liver, fish, multivitamins, and artificially fortified foods.6-7 The people most at risk for scurvy due to poor diet are the elderly,8 especially those who are institutionalized9; men who live alone8; alcoholics8,10; people following fad diets8; and the mentally ill.11,12 Scurvy also has been reported in patients with cancer. In this setting, the condition is thought to be a consequence of increased vitamin C requirements (as is true of smokers and diabetic patients) and poor dietary intake secondary to depression, impaired taste, dysphagia, and abdominal pain, as well as the mucositis, nausea, vomiting, and diarrhea that can accompany chemotherapy.8,13 In addition, scurvy has been reported as a complication of total parenteral nutrition,8 enteral feeds,14 and malabsorption secondary to either radiotherapy8 or intestinal processes such as Whipple disease.15 Peritoneal dialysis and hemodialysis also have been implicated in cases where water-soluble vitamin C is removed from the body during the dialysis process.16 Patients with scurvy can present with fatigue and malaise early on and with myalgia as the vitamin C deficiency progresses. The clinical signs of scurvy include hair follicle abnormalities, complications from bleeding diathesis, and osteopenia. Cachexia may be an associated finding. Follicle findings include perifollicular palpable purpura, follicular hyperkeratosis, and bent or coiled body hairs, which are often termed entrapped corkscrew hairs.4 Other findings can include xerosis, leg edema, and poor wound healing. Bleeding diathesis often results in hemarthroses and soft tissue hematomas that are produced by mild or inapparent trauma and tend to involve the legs.4,17 Interestingly, gingival findings occur only in patients with teeth and include gingival swelling, petechial lesions, purplish discoloration, bleeding with little provocation, and secondary bacterial periodontal infections.4,7,18 Bleeding complications in children can be more dramatic than in adults and include possible subperiosteal hematomas and retrobulbar, subarachnoid, and intracerebral hemorrhages.18 In rare extreme cases, the bleeding complications of scurvy can involve the peritoneum, pericardium, and adrenal glands.6 Anemia frequently accompanies scurvy secondary both to bleeding and to a decrease in iron absorption that is precipitated by ascorbic acid deficiency.4,7 Scurvy that is left untreated is fatal as a result of either sudden death or infection. The late stages of scurvy are characterized by neuropathy, edema, oliguria, syncope, leukopenia, and intracerebral hemorrhage.4,19,20 Severe hypertension was reported in one case.11 Because vitamin C is intimately involved in collagen synthesis, the pathophysiology of bleeding in scurvy originates in the decreased tensile strength of the connective tissue collagen that supports blood vessels and that is found within vessel walls. Biochemically, vitamin C regenerates the prosthetic metal ions in prolyl and lysyl hydroxylase.21 This enzyme hydroxylates proline and lysine residues in the procollagen polypeptide chain. The hydroxylated residues serve to crosslink and stabilize the ensuing collagen triple helix. Impaired cross-linking destabilizes collagen fibrils, decreases collagen secretion from fibroblasts, and increases collagen solubility, which makes the protein more vulnerable to enzymatic degradation.7 Scurvy-related bleeding tendencies revolve around the collagen content of dermal structures: the dermis and blood vessel tunica adventitia primarily contain type I collagen, blood vessel tunica media contains type III collagen, and the blood vessel basement membrane contains type IV collagen.22 Vitamin C deficiency also has been shown to suppress the rate of synthesis of procollagen peptides independent of proline and lysine hydroxylation,23 with additional evidence demonstrating lower expression of type IV collagen and elastin messenger RNA in scorbutic states.24 Apart from its role in structural integrity, vitamin C is essential for the conversion of histamine to aspartic acid. Exponential increases in blood histamine with corresponding decreases in aspartic acid as a consequence of vitamin C deficiency causes vascular endothelial cells to separate, which also may contribute to the bleeding tendency in scurvy.25 Of note, vitamin C has not been reported to affect bleeding time or clotting factor production or function. Examples of decreased structural integrity of the microcirculation and supporting tissue other than scurvy include senile purpura, in which long-term sun damage and decreased structural components secondary to aging results in purpuric patches; potent topical corticosteroid excess, in which cutaneous atrophy can lead to purpura; Ehlers-Danlos syndromes, which have various collagen defects; and amyloid infiltration of blood vessel walls in a primary systemic amyloidosis that is associated with, for example, multiple myeloma.18 The impairment of connective tissue components that occurs in patients with scurvy also can manifest in bone and produce radiographic findings such as osteopenia, as in the case presented here. Epidemiologic studies have reported a positive association between vitamin C intake and bone density,26 and guinea pig models of scurvy have demonstrated lower bone density in scorbutic animals.27 Impaired collagen leads to a primary disturbance in the formation of the osteoid matrix, with no effect on mineralization. Decreased osteoblast function with unimpaired osteoclast function also contributes to the osteopenia. Osteoporosis related to vitamin C deficiency is seen primarily in the axial skeleton.28 Other radiographic findings in patients with scurvy are typically related to growing children7 and include metaphyseal spurs and marginal fractures known as Pelkan sign; a ring of increased density surrounding the epiphysis, or Wimberger sign; widening of the zone of provisional calcification, or the white line of Frankl; and a transverse band of radiolucency in the metaphysis, known as the scurvy line or Trummerfeld zone.28 Other bony deformities may be observed, such as a bowing of the long bones, an abnormally depressed sternum, and an outward projection of the ends of the ribs.7 Infantile scurvy, also known as Barlow disease, is characterized by ecchymoses, bone fractures, and nonhealing ulcers29 and can be mistaken for child abuse. A vitamin C dose of 60 to 100 mg/d is sufficient to prevent scurvy; the consumption of 5 daily servings of fruits or vegetables provides more than 60 mg of vitamin C.6,8 Good dietary sources of vitamin C include citrus fruits, broccoli, tomatoes, and potatoes6 (eg, a 100-g orange contains 50 mg of vitamin C).8 Despite the inconclusive role of the antioxidant function of ascorbic acid in preventing disease, the higher US recommended daily allowance of vitamin C established in 2002 (75 mg for women, 90 mg for men) is based on the vitamin's antioxidant function and not just on the amount required to protect against deficiency30; the requirement for smokers may be up to 140 mg/d. The rationale for a higher recommended daily allowance of vitamin C may be due to the fact that higher daily intakes of the vitamin (150–200 mg) possibly may augment the role of ascorbic acid in immune response, pulmonary function, and iron absorption.31 Weeks to months of deficient vitamin C intake, defined as consuming as little as 10 mg/d,6 is usually necessary to drop the body's normal vitamin C reserves (1500 mg) down to 300 mg; below this level, symptoms may appear.8 Diagnosis of scurvy is based on clinical findings and results of laboratory tests to assess vitamin C levels. Low serum vitamin C, typically defined as less than 0.1 mg/dL,20 reflects inadequate recent dietary intake. The level of ascorbate in leukocytes more accurately reflects the body's stores, though is not a routinely available test.8 Fortunately, however, all cases of scurvy, even those with advanced involvement, respond to administration of vitamin C. Recommended and reported treatment regimens vary from 200 mg/d, with symptoms improving over several days, to 1 g/d for 2 weeks, with symptom resolution within 2 weeks.6,9,12 Complete absorption of vitamin C occurs if less than 100 mg is administered in a single dose, whereas only 50% or less is absorbed at doses greater than 1 g. Side effects of oxalate-related nephrolithiasis, abdominal pain, nausea, and diarrhea may be observed with greater than 2 g/d; increased alanine aminotransferase, lactate dehydrogenase, and serum uric acid levels may occur with greater than 3 g/d.6 High-dose vitamin C can induce hemolysis in patients with glucose 6-phosphate dehydrogenase deficiency, and doses of more than 1 g/d can cause false-negative guaiac reactions.6
Conclusion
Given its rarity in the modern day, scurvy might easily be mistaken for child abuse29 or misdiagnosed as a connective tissue disease, systemic vasculitis,32 or malignancy. Despite its rarity and because of its simple treatment, scurvy must not be overlooked as a possible diagnosis in a patient presenting with suggestive findings in the appropriate context.
Scurvy is prominent in world history. The disease was rampant among sailing crews from the Renaissance to the 18th century, when advances in shipbuilding and navigation facilitated sea voyages of long duration. From 1497 to 1499, half of the Vasco da Gama crew died from scurvy while sailing around the Cape of Good Hope to the east coast of Africa. In 1747, Scottish naval surgeon Sir James Lind was the first to conduct a clinical trial demonstrating improvement in scorbutic patients who ingested fresh lemons and oranges. It was not until the end of the 18th century, when Sir Gilbert Blane required British sailors to ingest lime juice routinely, that citrus fruits were used to prevent scurvy.1 Outbreaks of scurvy have occurred throughout history, including during the 1845 potato famine in Ireland, the 1848 California Gold Rush, the US Civil War (1861–1865), and the 1915 Gallipoli campaign of World War I.1,2
Case Report
A 59-year-old white man with a medical history of chronic obstructive pulmonary disease presented to the emergency department with a petechial rash on his lower extremities. He denied having fever or arthralgias at that time. The rash was dismissed as leukocytoclastic vasculitis, and the patient was sent home. He failed to follow-up in the outpatient clinic for workup and returned to the emergency department 4 months later with severe right thigh pain. Results of a computed tomographic scan of the lower extremity revealed right thigh and right gluteal hematomas. Hemoglobin and hematocrit levels were 11.6 g/dL and 35.0%, respectively. The dermatology department was consulted to evaluate the petechiae of the thighs and arms. On more careful examination, discrete perifollicular hemorrhages were noted (Figure 1), a large ecchymosis was found on the right leg and foot (Figure 2), and the patient was found to be emaciated. This combination of signs prompted a search for other stigmata of scurvy. Corkscrew hairs were noted (Figure 3), though no obvious gingivitis was present; however, the patient confirmed he had a history of bleeding gums, especially after brushing. An unprompted diet history revealed ingestion of canned tuna (which contains 0% vitamin C), pasta without tomato sauce, oatmeal, and water. The patient could not afford fruit, vegetables, or orange juice.
Although the patient's serum ascorbic acid level was not confirmed by testing, his symptoms promptly resolved within a week of oral administration of 1 g of vitamin C taken twice daily. Of note, the patient's platelet count; clotting factor level; international normalized ratio value; activated partial thromboplastin time; bleeding time; and concentrations of serum albumin (4.3 g/dL), total protein (7.3 g/dL), serum calcium (9.6 mg/dL), and serum phosphorus (3.7 mg/dL) were all within reference range. However, his erythrocyte sedimentation rate was elevated at 60 mm/h. Results of a skin biopsy revealed only interstitial perivascular hemorrhage without significant infiltrate. Results of a bone scan revealed 4 small foci of uptake—2 in the sacrum and 1 in each sacroiliac joint. Results of a computed tomographic scan revealed diffuse sacral osteopenia, which is a characteristic finding in adult scurvy.
Comment
Scurvy is a clinical condition resulting from inadequate intake of vitamin C. Although scurvy is well documented historically, it is relatively uncommon in industrialized countries and, therefore, may be underdiagnosed.3 Most animals are able to synthesize ascorbic acid from glucose4; however, humans harbor only a nonfunctional partial copy of the L-gulono-γ-lactone oxidase (GULO) gene, the product of which catalyzes the last step in ascorbic acid synthesis—specifically, the conversion of glucuronic acid to glucuronolactone and ascorbate.5 Therefore, vitamin C, a water-soluble vitamin, is essential for humans and must be acquired from diet. Scurvy most commonly is seen in individuals with a diet lacking in vitamin C. Citrus fruits, green vegetables, tomatoes, and potatoes are especially rich sources of vitamin C; additionally, the vitamin can be found in milk, liver, fish, multivitamins, and artificially fortified foods.6-7 The people most at risk for scurvy due to poor diet are the elderly,8 especially those who are institutionalized9; men who live alone8; alcoholics8,10; people following fad diets8; and the mentally ill.11,12 Scurvy also has been reported in patients with cancer. In this setting, the condition is thought to be a consequence of increased vitamin C requirements (as is true of smokers and diabetic patients) and poor dietary intake secondary to depression, impaired taste, dysphagia, and abdominal pain, as well as the mucositis, nausea, vomiting, and diarrhea that can accompany chemotherapy.8,13 In addition, scurvy has been reported as a complication of total parenteral nutrition,8 enteral feeds,14 and malabsorption secondary to either radiotherapy8 or intestinal processes such as Whipple disease.15 Peritoneal dialysis and hemodialysis also have been implicated in cases where water-soluble vitamin C is removed from the body during the dialysis process.16 Patients with scurvy can present with fatigue and malaise early on and with myalgia as the vitamin C deficiency progresses. The clinical signs of scurvy include hair follicle abnormalities, complications from bleeding diathesis, and osteopenia. Cachexia may be an associated finding. Follicle findings include perifollicular palpable purpura, follicular hyperkeratosis, and bent or coiled body hairs, which are often termed entrapped corkscrew hairs.4 Other findings can include xerosis, leg edema, and poor wound healing. Bleeding diathesis often results in hemarthroses and soft tissue hematomas that are produced by mild or inapparent trauma and tend to involve the legs.4,17 Interestingly, gingival findings occur only in patients with teeth and include gingival swelling, petechial lesions, purplish discoloration, bleeding with little provocation, and secondary bacterial periodontal infections.4,7,18 Bleeding complications in children can be more dramatic than in adults and include possible subperiosteal hematomas and retrobulbar, subarachnoid, and intracerebral hemorrhages.18 In rare extreme cases, the bleeding complications of scurvy can involve the peritoneum, pericardium, and adrenal glands.6 Anemia frequently accompanies scurvy secondary both to bleeding and to a decrease in iron absorption that is precipitated by ascorbic acid deficiency.4,7 Scurvy that is left untreated is fatal as a result of either sudden death or infection. The late stages of scurvy are characterized by neuropathy, edema, oliguria, syncope, leukopenia, and intracerebral hemorrhage.4,19,20 Severe hypertension was reported in one case.11 Because vitamin C is intimately involved in collagen synthesis, the pathophysiology of bleeding in scurvy originates in the decreased tensile strength of the connective tissue collagen that supports blood vessels and that is found within vessel walls. Biochemically, vitamin C regenerates the prosthetic metal ions in prolyl and lysyl hydroxylase.21 This enzyme hydroxylates proline and lysine residues in the procollagen polypeptide chain. The hydroxylated residues serve to crosslink and stabilize the ensuing collagen triple helix. Impaired cross-linking destabilizes collagen fibrils, decreases collagen secretion from fibroblasts, and increases collagen solubility, which makes the protein more vulnerable to enzymatic degradation.7 Scurvy-related bleeding tendencies revolve around the collagen content of dermal structures: the dermis and blood vessel tunica adventitia primarily contain type I collagen, blood vessel tunica media contains type III collagen, and the blood vessel basement membrane contains type IV collagen.22 Vitamin C deficiency also has been shown to suppress the rate of synthesis of procollagen peptides independent of proline and lysine hydroxylation,23 with additional evidence demonstrating lower expression of type IV collagen and elastin messenger RNA in scorbutic states.24 Apart from its role in structural integrity, vitamin C is essential for the conversion of histamine to aspartic acid. Exponential increases in blood histamine with corresponding decreases in aspartic acid as a consequence of vitamin C deficiency causes vascular endothelial cells to separate, which also may contribute to the bleeding tendency in scurvy.25 Of note, vitamin C has not been reported to affect bleeding time or clotting factor production or function. Examples of decreased structural integrity of the microcirculation and supporting tissue other than scurvy include senile purpura, in which long-term sun damage and decreased structural components secondary to aging results in purpuric patches; potent topical corticosteroid excess, in which cutaneous atrophy can lead to purpura; Ehlers-Danlos syndromes, which have various collagen defects; and amyloid infiltration of blood vessel walls in a primary systemic amyloidosis that is associated with, for example, multiple myeloma.18 The impairment of connective tissue components that occurs in patients with scurvy also can manifest in bone and produce radiographic findings such as osteopenia, as in the case presented here. Epidemiologic studies have reported a positive association between vitamin C intake and bone density,26 and guinea pig models of scurvy have demonstrated lower bone density in scorbutic animals.27 Impaired collagen leads to a primary disturbance in the formation of the osteoid matrix, with no effect on mineralization. Decreased osteoblast function with unimpaired osteoclast function also contributes to the osteopenia. Osteoporosis related to vitamin C deficiency is seen primarily in the axial skeleton.28 Other radiographic findings in patients with scurvy are typically related to growing children7 and include metaphyseal spurs and marginal fractures known as Pelkan sign; a ring of increased density surrounding the epiphysis, or Wimberger sign; widening of the zone of provisional calcification, or the white line of Frankl; and a transverse band of radiolucency in the metaphysis, known as the scurvy line or Trummerfeld zone.28 Other bony deformities may be observed, such as a bowing of the long bones, an abnormally depressed sternum, and an outward projection of the ends of the ribs.7 Infantile scurvy, also known as Barlow disease, is characterized by ecchymoses, bone fractures, and nonhealing ulcers29 and can be mistaken for child abuse. A vitamin C dose of 60 to 100 mg/d is sufficient to prevent scurvy; the consumption of 5 daily servings of fruits or vegetables provides more than 60 mg of vitamin C.6,8 Good dietary sources of vitamin C include citrus fruits, broccoli, tomatoes, and potatoes6 (eg, a 100-g orange contains 50 mg of vitamin C).8 Despite the inconclusive role of the antioxidant function of ascorbic acid in preventing disease, the higher US recommended daily allowance of vitamin C established in 2002 (75 mg for women, 90 mg for men) is based on the vitamin's antioxidant function and not just on the amount required to protect against deficiency30; the requirement for smokers may be up to 140 mg/d. The rationale for a higher recommended daily allowance of vitamin C may be due to the fact that higher daily intakes of the vitamin (150–200 mg) possibly may augment the role of ascorbic acid in immune response, pulmonary function, and iron absorption.31 Weeks to months of deficient vitamin C intake, defined as consuming as little as 10 mg/d,6 is usually necessary to drop the body's normal vitamin C reserves (1500 mg) down to 300 mg; below this level, symptoms may appear.8 Diagnosis of scurvy is based on clinical findings and results of laboratory tests to assess vitamin C levels. Low serum vitamin C, typically defined as less than 0.1 mg/dL,20 reflects inadequate recent dietary intake. The level of ascorbate in leukocytes more accurately reflects the body's stores, though is not a routinely available test.8 Fortunately, however, all cases of scurvy, even those with advanced involvement, respond to administration of vitamin C. Recommended and reported treatment regimens vary from 200 mg/d, with symptoms improving over several days, to 1 g/d for 2 weeks, with symptom resolution within 2 weeks.6,9,12 Complete absorption of vitamin C occurs if less than 100 mg is administered in a single dose, whereas only 50% or less is absorbed at doses greater than 1 g. Side effects of oxalate-related nephrolithiasis, abdominal pain, nausea, and diarrhea may be observed with greater than 2 g/d; increased alanine aminotransferase, lactate dehydrogenase, and serum uric acid levels may occur with greater than 3 g/d.6 High-dose vitamin C can induce hemolysis in patients with glucose 6-phosphate dehydrogenase deficiency, and doses of more than 1 g/d can cause false-negative guaiac reactions.6
Conclusion
Given its rarity in the modern day, scurvy might easily be mistaken for child abuse29 or misdiagnosed as a connective tissue disease, systemic vasculitis,32 or malignancy. Despite its rarity and because of its simple treatment, scurvy must not be overlooked as a possible diagnosis in a patient presenting with suggestive findings in the appropriate context.
- French RK. Scurvy. In: Kiple KF, ed. The Cambridge World History of Human Disease. Cambridge, England: Cambridge University Press; 1993:1000-1005.
- McGrew RE. Encyclopedia of Medical History. New York, NY: McGraw Hill; 1985:312.
- Oeffinger KC. Scurvy: more than historical relevance. Am Fam Physician. 1993;48:609-613.
- Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol. 1999;41:895-906.
- Goldman L, Ausiello D, Bennet JC, et al, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: WB Saunders Company; 2003:190.
- Russel RM. Vitamin and trace mineral deficiency and excess. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Online. Chapter 61. Available at: http://www.accessmedicine.com. Accessed January 15, 2005.
- Kumar V, Abbas AK, Fausto N. Robbins and Cotran's Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: WB Saunders Co; 2004:458-459.
- Fain O, Mathieu E, Thomas M. Scurvy in patients with cancer. BMJ. 1998;316:1661-1662.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Vasudevan AR, Kumar S, Lim A, et al. Purple skin and a swollen thigh in an alcoholic. Postgrad Med J. 2002;78:430-434.
- Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108:E55.
- Chatproedprais S, Wananukul S. Scurvy: a case report. J Med Assoc Thai. 2001;84(suppl 1):S106-S110.
- Nguyen RT, Cowley DM, Muir JB. Scurvy: a cutaneous clinical diagnosis. Australas J Dermatol. 2003;44:48-51.
- Gorman SR, Armstrong G, Allen KR, et al. Scarcity in the midst of plenty: enteral tube feeding complicated by scurvy. J Pediatr Gastroenterol Nutr. 2002;35:93-95.
- Berger ML, Siegel DM, Lee EL. Scurvy as an initial manifestation of Whipple's disease. Ann Intern Med. 1984;101:58-59.
- Ihle BU, Gillies M. Scurvy and thrombocytopathy in a chronic hemodialysis patient. Aust N Z J Med. 1983;13:523.
- Leone J, Delhinger V, Maes D, et al. Rheumatic manifestations of scurvy. a report of two cases. Rev Rhum Engl Ed. 1997;64:428-431.
- Hoffman R, Benj EJ, Shattil SJ, et al. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1831.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Baron RB. Nutrition. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment, 2004. New York, NY: McGraw-Hill Medical; 2004:1203-1234.
- Padh H. Vitamin C: newer insights into its biochemical functions. Nutr Rev. 1991;49:65-70.
- Junqueira LC, Carneiro J, Kelley RO. Basic Histology. 8th ed. East Norwalk, Conn: Appleton & Lange; 1995:202.
- Peterkovsky B. Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis
- French RK. Scurvy. In: Kiple KF, ed. The Cambridge World History of Human Disease. Cambridge, England: Cambridge University Press; 1993:1000-1005.
- McGrew RE. Encyclopedia of Medical History. New York, NY: McGraw Hill; 1985:312.
- Oeffinger KC. Scurvy: more than historical relevance. Am Fam Physician. 1993;48:609-613.
- Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol. 1999;41:895-906.
- Goldman L, Ausiello D, Bennet JC, et al, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: WB Saunders Company; 2003:190.
- Russel RM. Vitamin and trace mineral deficiency and excess. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Online. Chapter 61. Available at: http://www.accessmedicine.com. Accessed January 15, 2005.
- Kumar V, Abbas AK, Fausto N. Robbins and Cotran's Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: WB Saunders Co; 2004:458-459.
- Fain O, Mathieu E, Thomas M. Scurvy in patients with cancer. BMJ. 1998;316:1661-1662.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Vasudevan AR, Kumar S, Lim A, et al. Purple skin and a swollen thigh in an alcoholic. Postgrad Med J. 2002;78:430-434.
- Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108:E55.
- Chatproedprais S, Wananukul S. Scurvy: a case report. J Med Assoc Thai. 2001;84(suppl 1):S106-S110.
- Nguyen RT, Cowley DM, Muir JB. Scurvy: a cutaneous clinical diagnosis. Australas J Dermatol. 2003;44:48-51.
- Gorman SR, Armstrong G, Allen KR, et al. Scarcity in the midst of plenty: enteral tube feeding complicated by scurvy. J Pediatr Gastroenterol Nutr. 2002;35:93-95.
- Berger ML, Siegel DM, Lee EL. Scurvy as an initial manifestation of Whipple's disease. Ann Intern Med. 1984;101:58-59.
- Ihle BU, Gillies M. Scurvy and thrombocytopathy in a chronic hemodialysis patient. Aust N Z J Med. 1983;13:523.
- Leone J, Delhinger V, Maes D, et al. Rheumatic manifestations of scurvy. a report of two cases. Rev Rhum Engl Ed. 1997;64:428-431.
- Hoffman R, Benj EJ, Shattil SJ, et al. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1831.
- Pimental L. Scurvy: historical review and current diagnostic approach. Am J Emerg Med. 2003;21:328-332.
- Baron RB. Nutrition. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment, 2004. New York, NY: McGraw-Hill Medical; 2004:1203-1234.
- Padh H. Vitamin C: newer insights into its biochemical functions. Nutr Rev. 1991;49:65-70.
- Junqueira LC, Carneiro J, Kelley RO. Basic Histology. 8th ed. East Norwalk, Conn: Appleton & Lange; 1995:202.
- Peterkovsky B. Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis
Cold Urticaria: A Case Report and Review of the Literature
Case Report
An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.
On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.
Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).
PLEASE REFER TO THE PDF TO VIEW THE FIGURE
A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative.
Comment
Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.1 Cold urticaria syndromes were first described in the 19th century2 and are uncommon. However, it has been observed that approximately one third of adult3 and pediatric4 patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.
The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.3 Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.8 Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.12
PLEASE REFER TO THE PDF TO VIEW THE TABLE
Although most forms of cold urticaria are considered to be acquired, familial forms have been described,7,13 some of which have been classified within the hereditary periodic fever syndromes.12 Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al14 observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.
Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water3 or placing the patient in a cold room15; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.9,15
Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.12 Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.16
Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.17 Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.5 Bonadonna et al6 demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.12
Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria.
- Wanderer AA, Grandel KE, Wasserman SI, et al. Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria. J Allergy Clin Immunol. 1986;78:417-423.
- Bourdon H. Note Sur L'uticaire intermittente. Bull Mem Soc Med Hop Paris. 1866;3:259-262.
- Neittaanmaki H. Cold urticaria. clinical findings in 220 patients. J Am Acad Dermatol. 1985;13:636-644.
- Alangari AA, Twarog FJ, Shih MC, et al. Clinical features and anaphylaxis in children with cold urticaria. Pediatrics. 2004;113:e313-e317.
- Hani N, Hartmann K, Casper C, et al. Improvement of cold urticaria by treatment with the leukotriene receptor antagonist montelukast [letter]. Acta Derm Venereol. 2000;80:229.
- Bonadonna P, Lombardi C, Gianenrico S, et al. Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination. J Am Acad Dermatol. 2003;49:714-716.
- Soter NA, Joshi NP, Twarog FJ, et al. Delayed cold-induced urticaria: a dominantly inherited disorder. J Allergy Clin Immunol. 1977;59:294-297.
- Wanderer A. Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol. 1990;85:965-981.
- Costanzi JJ, Coltman CA. Kappa chain cold precipitable immunoglobulin G (IgG) associated with cold urticaria, I: clinical observations. Clin Exp Immunol. 1967;2:167-178.
- Rawnsley HM, Shelley WB. Cold urticaria with cryoglobulinemia in a patient with chronic lymphocytic leukemia. Arch Dermatol. 1968;98:12-17.
- Hauptmann G, Lang JM, North ML, et al. Lymphosarcoma, cold urticaria, IgG1 monoclonal cryoglobulin, and compliment abnormalities. Scand J Haematol. 1975;15:22-26.
- Wanderer AA, Hoffman HM. The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am. 2004;24:259-286.
- Hoffman HM, Wright FA, Broide DH, et al. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693-1698.
- Visitsuntorn N, Tuchinda M, Arunyanark N, et al. Ice cube test in children with cold urticaria. Asian Pac J Allergy Immunol. 1992;10:111-115.
- Kaplan AP. Unusual cold-induced disorders: cold-dependant dermatographism and systemic cold urticaria. J Allergy Clin Immunol. 1984;73:453-456.
- Koeppel MC, Bertrand S, Abitan R, et al. Urticaria caused by cold. 104 cases [in French]. Ann Dermatol Venereol. 1996;123:627-632.
- Wanderer AA, St Pierre JP, Ellis EF. Primary acquired cold urticaria. double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo. Arch Dermatol. 1977;113:1375-1377.
- Villas Martinez F, Contreras FJ, Lopez Cazana JM, et al. A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria (ACU). J Investig Allergol Clin Immunol. 1992;2:258-262.
- Juhlin L. Inhibition of cold urticaria by desloratidine. J Dermatolog Treat. 2004;15:51-59.
Case Report
An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.
On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.
Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).
PLEASE REFER TO THE PDF TO VIEW THE FIGURE
A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative.
Comment
Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.1 Cold urticaria syndromes were first described in the 19th century2 and are uncommon. However, it has been observed that approximately one third of adult3 and pediatric4 patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.
The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.3 Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.8 Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.12
PLEASE REFER TO THE PDF TO VIEW THE TABLE
Although most forms of cold urticaria are considered to be acquired, familial forms have been described,7,13 some of which have been classified within the hereditary periodic fever syndromes.12 Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al14 observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.
Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water3 or placing the patient in a cold room15; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.9,15
Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.12 Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.16
Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.17 Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.5 Bonadonna et al6 demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.12
Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria.
Case Report
An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.
On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.
Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).
PLEASE REFER TO THE PDF TO VIEW THE FIGURE
A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative.
Comment
Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.1 Cold urticaria syndromes were first described in the 19th century2 and are uncommon. However, it has been observed that approximately one third of adult3 and pediatric4 patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.
The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.3 Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.8 Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.12
PLEASE REFER TO THE PDF TO VIEW THE TABLE
Although most forms of cold urticaria are considered to be acquired, familial forms have been described,7,13 some of which have been classified within the hereditary periodic fever syndromes.12 Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al14 observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.
Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water3 or placing the patient in a cold room15; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.9,15
Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.12 Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.16
Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.17 Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.5 Bonadonna et al6 demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.12
Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria.
- Wanderer AA, Grandel KE, Wasserman SI, et al. Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria. J Allergy Clin Immunol. 1986;78:417-423.
- Bourdon H. Note Sur L'uticaire intermittente. Bull Mem Soc Med Hop Paris. 1866;3:259-262.
- Neittaanmaki H. Cold urticaria. clinical findings in 220 patients. J Am Acad Dermatol. 1985;13:636-644.
- Alangari AA, Twarog FJ, Shih MC, et al. Clinical features and anaphylaxis in children with cold urticaria. Pediatrics. 2004;113:e313-e317.
- Hani N, Hartmann K, Casper C, et al. Improvement of cold urticaria by treatment with the leukotriene receptor antagonist montelukast [letter]. Acta Derm Venereol. 2000;80:229.
- Bonadonna P, Lombardi C, Gianenrico S, et al. Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination. J Am Acad Dermatol. 2003;49:714-716.
- Soter NA, Joshi NP, Twarog FJ, et al. Delayed cold-induced urticaria: a dominantly inherited disorder. J Allergy Clin Immunol. 1977;59:294-297.
- Wanderer A. Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol. 1990;85:965-981.
- Costanzi JJ, Coltman CA. Kappa chain cold precipitable immunoglobulin G (IgG) associated with cold urticaria, I: clinical observations. Clin Exp Immunol. 1967;2:167-178.
- Rawnsley HM, Shelley WB. Cold urticaria with cryoglobulinemia in a patient with chronic lymphocytic leukemia. Arch Dermatol. 1968;98:12-17.
- Hauptmann G, Lang JM, North ML, et al. Lymphosarcoma, cold urticaria, IgG1 monoclonal cryoglobulin, and compliment abnormalities. Scand J Haematol. 1975;15:22-26.
- Wanderer AA, Hoffman HM. The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am. 2004;24:259-286.
- Hoffman HM, Wright FA, Broide DH, et al. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693-1698.
- Visitsuntorn N, Tuchinda M, Arunyanark N, et al. Ice cube test in children with cold urticaria. Asian Pac J Allergy Immunol. 1992;10:111-115.
- Kaplan AP. Unusual cold-induced disorders: cold-dependant dermatographism and systemic cold urticaria. J Allergy Clin Immunol. 1984;73:453-456.
- Koeppel MC, Bertrand S, Abitan R, et al. Urticaria caused by cold. 104 cases [in French]. Ann Dermatol Venereol. 1996;123:627-632.
- Wanderer AA, St Pierre JP, Ellis EF. Primary acquired cold urticaria. double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo. Arch Dermatol. 1977;113:1375-1377.
- Villas Martinez F, Contreras FJ, Lopez Cazana JM, et al. A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria (ACU). J Investig Allergol Clin Immunol. 1992;2:258-262.
- Juhlin L. Inhibition of cold urticaria by desloratidine. J Dermatolog Treat. 2004;15:51-59.
- Wanderer AA, Grandel KE, Wasserman SI, et al. Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria. J Allergy Clin Immunol. 1986;78:417-423.
- Bourdon H. Note Sur L'uticaire intermittente. Bull Mem Soc Med Hop Paris. 1866;3:259-262.
- Neittaanmaki H. Cold urticaria. clinical findings in 220 patients. J Am Acad Dermatol. 1985;13:636-644.
- Alangari AA, Twarog FJ, Shih MC, et al. Clinical features and anaphylaxis in children with cold urticaria. Pediatrics. 2004;113:e313-e317.
- Hani N, Hartmann K, Casper C, et al. Improvement of cold urticaria by treatment with the leukotriene receptor antagonist montelukast [letter]. Acta Derm Venereol. 2000;80:229.
- Bonadonna P, Lombardi C, Gianenrico S, et al. Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination. J Am Acad Dermatol. 2003;49:714-716.
- Soter NA, Joshi NP, Twarog FJ, et al. Delayed cold-induced urticaria: a dominantly inherited disorder. J Allergy Clin Immunol. 1977;59:294-297.
- Wanderer A. Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol. 1990;85:965-981.
- Costanzi JJ, Coltman CA. Kappa chain cold precipitable immunoglobulin G (IgG) associated with cold urticaria, I: clinical observations. Clin Exp Immunol. 1967;2:167-178.
- Rawnsley HM, Shelley WB. Cold urticaria with cryoglobulinemia in a patient with chronic lymphocytic leukemia. Arch Dermatol. 1968;98:12-17.
- Hauptmann G, Lang JM, North ML, et al. Lymphosarcoma, cold urticaria, IgG1 monoclonal cryoglobulin, and compliment abnormalities. Scand J Haematol. 1975;15:22-26.
- Wanderer AA, Hoffman HM. The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am. 2004;24:259-286.
- Hoffman HM, Wright FA, Broide DH, et al. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693-1698.
- Visitsuntorn N, Tuchinda M, Arunyanark N, et al. Ice cube test in children with cold urticaria. Asian Pac J Allergy Immunol. 1992;10:111-115.
- Kaplan AP. Unusual cold-induced disorders: cold-dependant dermatographism and systemic cold urticaria. J Allergy Clin Immunol. 1984;73:453-456.
- Koeppel MC, Bertrand S, Abitan R, et al. Urticaria caused by cold. 104 cases [in French]. Ann Dermatol Venereol. 1996;123:627-632.
- Wanderer AA, St Pierre JP, Ellis EF. Primary acquired cold urticaria. double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo. Arch Dermatol. 1977;113:1375-1377.
- Villas Martinez F, Contreras FJ, Lopez Cazana JM, et al. A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria (ACU). J Investig Allergol Clin Immunol. 1992;2:258-262.
- Juhlin L. Inhibition of cold urticaria by desloratidine. J Dermatolog Treat. 2004;15:51-59.