Are You Confident of the Diagnosis?
Pernio may be primary/idiopathic or may occur secondarily in the setting of systemic diseases including Raynaud phenomenon, acrocyanosis, complex regional pain syndrome, livedoid vasculopathy, peripheral arterial occlusive disease, erythromelalgia, leukemia, systemic lupus erythematosus, cryoproteinemia, or anorexia nervosa. It has also been reported to occur as an adverse reaction to sulindac.
What you should be alert for in the history
The diagnosis of pernio can often be made on clinical grounds. Patients typically report the development of tender, pruritic, and/or painful digits following exposure to nonfreezing cold, damp conditions. The dorsal surfaces of the toes and fingers are the most common sites, but the ear, nose, thighs, or buttocks may also be affected.
Characteristic findings on phystical examination
Physical examination reveals red to violet or bluish macules, papules or nodules (Figure 1). Affected digits may be mildly edematous or scaly. Rarely, erosions, ulcers, vesicles or scarring occur. Most acute episodes begin within 12-24 hours of cold exposure and resolve spontaneously within 2 weeks; however, some patients may develop more chronic lesions that last 3-4 months.
Expected results of diagnostic studies
When episodic or seasonal patterns are not described or when lesions are ulcerated or scarred, establishing the diagnosis is more difficult. Diagnostic studies such as a skin biopsy and laboratory tests are helpful. Skin biopsies of pernio demonstrate dermal edema and a lymphocytic perivascular and perieccrine inflammatory infiltrate. Occasional necrotic keratinocytes and focal areas of basal vacuolization may be seen in the epidermis.
Pernio-like lesions may occur in patients with lupus erythematosus (chilblain lupus erythematosus of Hutchinson). In this setting, skin biopsies often demonstrate interface histology in addition to the lymphocytic vasculitis. Nonetheless, histopathologic differentiation of idiopathic and lupus associated perniosis is unreliable and clinicopathologic correlation is necessary.
Familial chilblain lupus erythemtosus has been reported in two families, occurring in an autosomal dominant fashion. Mutations in the TREX1 gene that encodes the 3’-5’ repair exonuclease1 have been demonstrated in these families. Interestingly, mutations in the TREX1 gene have also been described in patients with systemic lupus erythematosus,
Sjõgren’s syndrome, and Aicardi-Goutieres syndrome, is an inherited encephalopathy characterized by progressive neurologic dysfunction in which pernio-like skin findings are the most common extra-neurologic finding. In the appropriate clinical context, genetic testing for mutations in the TREX1 gene is available, and may be useful in diagnosing familial chilblain lupus erythematosus and Aicardi-Goutieres syndome.
In otherwise healthy adults, laboratory testing is not necessary; however if history and biopsy findings suggest the possibility of secondary pernio, laboratory testing including complete blood count, antinuclear antibody titer, rheumatoid factor, comprehensive metabolic panel, cryoglobulin, cryofibrinogen, cold agglutinin, and serum viscosity measurements to rule out cryopathy or connective tissue disease are worthwhile. In children, pernio may be associated with cryoproteins in up to 50% of patients, whereas in adults, cryoglobulins have been reported in only 2.5% of patients.
The differential diagnosis of pernio includes Raynaud phenomenon (patterned white/ischemic then blue/cyanotic then and red/reperfusion discoloration of the digits following cold exposure; episodes last hours rather than weeks as in pernio), frostbite (characterized by tissue necrosis induced by freezing), nodular vasculitis (distinguished histologically, not related to temperature), and embolic or thrombotic phenomena (distinct histology, no relation to cold temperature).
Who is at Risk for Developing this Disease?
Pernio is more common in females and most often occurs in those aged 15-30 years, although it has also been reported in children and the elderly. Low body mass index (<25 percentile) is often reported. Exposure to cold but not freezing, humid conditions triggers flares.
What is the Cause of the Disease?
The exact etiology of pernio is not known.
It is theorized that abnormal neurovascular responses to dermal temperature changes, vasospasm, abnormal vasoconstricion, hyperviscosity, and/or autoimmunity lead to cold-induced vascular damage, hypoxemia, and secondary inflammation.
Systemic Implications and Complications
Pernio is a benign cutaneous condition that is typically self-limited and does not result in any systemic complications. In case reports and small series, pernio has been reported in association with anorexia nervosa, parental neglect, systemic lupus erythematosus, lupus anticoagulant positivity, antiphospholipid antibody positivity, cryoproteinemia (especially in children), atopy, and celiac disease (in children). If the history, physical examination, or skin biopsy suggest the possibilty of lupus erythematosus or hypercoagulabilty, appropriate screening laboratory tests should be ordered.
Medical: nifedipine, amlodipine, hydroxychloroquine
Surgical: not applicable
Physical: Maintenance of warm, nonmoist skin
Optimal Therapeutic Approach for this Disease
Pernio is generally a self-limited condition with episodes lasting days to weeks. For the vast majority of patients, conservative, preventative measures aimed at keeping the acral skin warm and dry are all that is necessary for both prevention and treatment. Smoking cessation should be encouraged, as nicotine enhances cold-induced vasospasm. For patients with secondary pernio, treatment of the underlying condition should be optimized.
If conservative measures are insufficient, oral nifedipine is the most effective therapy in both children and adults. Nifedipine has been shown to reduce the duration, severity and frequency of pernio flares. Side effects include hypotension, headaches, and facial flushing. In adults, dosing may be started at 10mg three times daily and increased to 20mg three times daily if needed. Amlopdipine may be used if nifedipine is not tolerated.
Hydroxychloroquine therapy is the treatment of choice for chilblain lupus erythematosus, and it has also been reported to benefit some patients with primary/idiopathic chilblains. Dosing should not exceed 6.5mg/kg/day, and typical adult dosing is 200mg twice daily. Patients must be monitored for ocular toxicity annually, and periodically for hematologic or hepatic toxicity (rare).
For patients requiring pharmacotherapy, medication can often be discontinued during warm seasons and restarted just prior to cold weather months.
There have been a number of medical, surgical, and physical modalities attempted in the treatment of pernio, including: vitamin B and D derivatives, alpha blockers (prazosin), topical and oral corticosteroids, pentoxyfylline, phototherapy, and sympathectomy. None of these have been demonstrated to be widely effective and they are generally not recommended.
Patients should be educated regarding the environmental triggers of pernio (cool, moist conditions) and that medical therapy is generally not needed if conservative measures to maintain normal skin/body temperature are utilized. It is also important to reassure patients that pernio is a self-limited condition that is not typically associated with serious cutaneous or systemic complications.
A thorough history and skin examination should be performed to identify patients who may have secondary pernio related to an autoimmune connective tissue disease, or vascular disease; these patients should undergo laboratory evaluation based upon the history and/or examination findings. If pharmacotherapy is required, medication can often be discontinued during warm months and restarted just prior to colder months.
Unusual Clinical Scenarios to Consider in Patient Management
Pernio episodes are typically of short duration (days to weeks) and are related to exposure to cold damp climate. In the rare instances when episodes are chronic or do not appear to have a seasonal/environmental trigger, it is important to rule out mimickers. Skin biopsy should be performed in such instances. Laboratory studies to rule out hypercoagulability are recommended if vascular occlusion is demonstrated histologically. Leukemia (due to hyperviscosity) and metastatic breast cancer have been reported to cause pernio-like lesions.
What is the Evidence?
Prakash, S, Weisman, MH. “Idiopathic Chilblains”. Am J Med. vol. 122. 2009. pp. 1152-55. (This is an excellent recent review highlighting the clinical diagnostic features and management of pernio.)
Boada, A, Bielsa, I, Fernandez-Figueras, M, Ferrandiz, C. “Perniosis: clinical and histopathological analysis”. Am J Dermatopathol. vol. 32. 2010. pp. 19-23. (This retrospective analysis of biopsies from 20 patients with idiopathic perniosis and autoimmune-associated pernio (chilblain lupus) suggests that despite generally similar histopathology, perieccrine inflammation and dermal edema are features more typical of idiopathic pernio while findings including basal vacuolar change, and the presence of necrotic keratinocytes are most common in autoimmune-associated pernio. The authors review the similar findings of previous histopathologic analyses of idiopathic and autoimmune-associated pernio.)
Gardinal-Galera, I, Pajot, C, Paul, C, Mazereeuw-Hautier, J. “Childhood chilblains is an uncommon and invalidant disease”. Arch Dis Child. vol. 95. 2010. pp. 567-8. (This is a retrospective study of nine children with pernio that demonstrated that laboratory abnormalities are more common among pediatric patients with pernio than in adults. Cryoglobulinemia and antinuclear antibodies were the most common findings occuring in four of nine and 2 of nine patients, respectively.)
Weston, WL, Morelli, JG. “Childhood pernio and cryoproteins”. Pediatr Dermatol. vol. 17. 2000. pp. 97-99. (This retrospective case series evaluated eight patients with childhood pernio and demonstrated that 50% of the children had cryoproteins (three with cryoglobulins and one with cold agglutinins). Possible pathomechanisms are suggested.)
Crowson, AN, Magro, CM. “Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases”. Hum Pathol. vol. 28. 1997. pp. 478-84. (Chart data and biopsy specimens of 38 patients for whom perniosis was considered in the clinical or pathologic differential diagnosis were analyzed. The authors describe features typical of idiopathic perniosis and contrast these with pernio-like eruptions arising in the setting of systemic diseases [most often connective tissue diseases].)
Rustin, MH, Newton, JA, Smith, NP, Dowd, PM. “The treatment of chilblains with nifedipine: the results of a pilot study, a double-blind placebo-controlled randomized study and a long-term open trial”. Br J Dermatol. vol. 120. 1989. pp. 267-75. (This article reports findings from 3 prospective studies of nifedipine treatment for pernio. The reduction in pernio severity, duration, and episode frequency following nifedipine treatment is reported.)
AlMahameed, A, Pinto, D. “Pernio (chilblains)”. Curr Treat Options Cardiovasc Med. vol. 10. 2008. pp. 128-35. (This is an excellent and thorough clinical review that includes evidence-based and expert opinion regarding treatment of pernio.)
Yang, X, Perez, OA, English, JC. “Successful treatment of perniosis with hydroxychloroquine”. J Drugs Dermatol. vol. 9. 2010. pp. 1242-6. (This case series describes the authors' experience utilizing hydroxychloroquine for pernio, but also reviews the literature with regard to pernio treatment.)
Hedrich, CM, Fiebig, B, Hauck, FH, Sallman, GH, Pfeiffer, C, Heubner, G. “Chilblain lupus erythematosus – a review of the literature”. Clin Rheumatol. vol. 27. 2008. pp. 949-54. (This article reviews the presentation, pathogenesis, diagnosis, and treatment of chilblain lupus erythematosus. The role of TREX1 gene mutations in some patients with pernio-like skin changes is reviewed.)
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