CASE LETTER An Unusual Presentation of Calciphylaxis Jessica Garelik, DO; Vitaly Terushkin, MD; Arielle Nagler, MD; Chris Hale, MD; Hideko Kamino, MD; Beth McLellan, MD calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen PRACTICE POINTS in our patient.1,5,6 We report this uncommon presentation • Calciphylaxis is a rare microvascular occlusion syn- to highlight the variety in clinical appearance of calciphy- drome characterized by cutaneous ischemia and laxis and the importancecopy of early diagnosis. necrosis secondary to calcification. A 43-year-old woman presented to the emergency • Clinically, lesions present with severely painful, department for evaluation of chest and abdominal violaceous, retiform patches and plaques, and less commonly bullae that progress to necrotic ulcers pain that began 1 day prior to presentation. She had on the buttocks, legs, or abdomen, which is most a history of systemic lupus erythematosus and ESRD often associated with end-stage renal disease secondarynot to poststreptococcal glomerulonephritis and and hyperparathyroidism. was currently on peritoneal dialysis. The patient was • The diagnosis is made through deep wedge or exci- admitted for peritonitis and treated with broad-spectrum sional biopsy and shows calcification of medium-sized antibiotics. At the time of admission, the patient also vessels in the deep dermis and subcutaneous fat. was noted to have several painful bullae on the legs. Treatment requires a multidisciplinary approach, butDo Her medical history also was remarkable for cerebral morbidity and mortality remain high. infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathy- To the Editor: roidectomy, and cholecystectomy. The patient’s medica- Calciphylaxis (also known as calcific uremic arteriolopathy tions included sevelamer carbonate, prednisone, epogen, and calcifying panniculitis) is a rare vasculopathy affect- calcium carbonate, esomeprazole, ondansetron, topical ing the small vessels.1 It is characterized by cutaneous gentamicin, and atorvastatin. ischemia and necrosisCUTIS secondary to calcification. It is most Skin examination was performed by the inpatient der- commonly seen in patients with end-stage renal disease matology service and revealed several tense, 1- to 5-cm, (ESRD) and hyperparathyroidism.1-3 Histopathologic fea- nonhemorrhagic bullae on the thighs and lower legs, tures that are consistent with the diagnosis of calciphy- some that had ruptured. The lesions were notably tender laxis include calcification of medium-sized vessels in the to palpation. No surrounding erythema, ecchymosis, or deep dermis or subcutaneous fat as well as smaller distal warmth was appreciated. The Nikolsky sign was negative. vessels that supply the papillary dermis and epidermis.4,5 The patient also was noted to have at least grade 2 to 3+ Although it commonly presents as well-demarcated, pitting edema of the bilateral legs. The oral and conjunc- painful, purplish lesions that evolve into necrotic eschars, tival mucosae were unremarkable. Drs. Garelik and McLellan are from the Department of Dermatology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York. Drs. Terushkin, Nagler, Hale, and Kamino are from The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York. The authors report no conflict of interest. Correspondence: Jessica Garelik, DO, Albert Einstein College of Medicine, Montefiore Medical Center, Department of Dermatology, 111 E 210th St, Bronx, NY 10467 ([email protected]). E24 I CUTIS® WWW.MDEDGE.COM/DERMATOLOGY Copyright Cutis 2020. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. CALCIPHYLAXIS Antinuclear antibody, double-stranded DNA, and 4% in those receiving dialysis.2-5 The average age at pre- anti-Smith antibody levels were negative. A punch biopsy sentation is 48 years.6,7 Although calciphylaxis has been of the left lateral thigh revealed intraepidermal vesicular noted to affect males and females equally, some studies dermatitis with dermal edema suggestive of edema bullae have suggested a female predominance.5-8 and direct immunofluorescence was negative for immune The etiology of calciphylaxis is unknown, but ESRD complex and complement deposition. requiring dialysis, primary or secondary hyperparathy- Conservative therapy with wound care was recom- roidism, obesity, diabetes mellitus, skin trauma, and/or a mended. The patient continued to report persistent severe hypercoagulable state may put patients at increased risk skin pain and developed a subcutaneous nodule on the for developing this disease.2,3 Other risk factors include right inner thigh 1 week later, prompting a second biopsy. systemic corticosteroids, liver disease, increased serum Results of the excisional biopsy were nondiagnostic but aluminum, and increased erythrocyte sedimentation rate. were suggestive of calciphylaxis, revealing subepider- Although high calcium-phosphate product has been mal bullae with epidermal necrosis, a scant perivascular noted as a risk factor in prior studies, one retrospective lymphocytic infiltrate, and extravasated erythrocytes. No study found that it does not reliably confirm or exclude a evidence of calcification was seen within the vessels. diagnosis of calciphylaxis.8 The patient was then started on sodium thiosulfate with The pathogenesis of calciphylaxis is not well under- hemodialysis for treatment of presumed calciphylaxis. stood; however, some researchers suggest that an imbal- Despite meticulous wound care and treatment with ance in calcium-phosphate homeostasis may lead to sodium thiosulfate, the patient developed ulcerations calciphylaxis; that is, elevated calcium and phosphate with necrotic eschars on the bilateral buttocks, hips, and levels exceed their solubility and deposit in the walls of thighs 1 month later (Figure 1). She subsequently wors- small- and medium-sized arteries, which consequently ened over the next few weeks. She developed sepsis and leads to ischemic necrosiscopy and gangrene of the surround- was transferred to the intensive care unit. A third biopsy ing tissue.9 was performed, finally confirming the diagnosis of cal- Clinically, calciphylaxis has an indolent onset and ciphylaxis. Histopathology revealed small blood vessels usually presents as well-demarcated, painful, purplish, with basophilic granular deposits in the walls consistent mottled lesions that evolve into necrotic gray-black with calcium in the subcutaneous tissue (highlighted with eschars and gangrene in adjacent tissues.1,5,6 The ischemic not 5 the von Kossa stain), as well as thrombi in the lumens of process may even extend to the muscle layer. Other com- some vessels; early fat necrosis; focal epidermal necrosis mon presentations include mild erythematous patches; with underlying congested blood vessels with deposits in livedo reticularis; painful nodules; necrotic ulcerating their walls; a perivascular infiltrate predominately of lym- lesions; and more rarely flaccid, hemorrhagic, or serous phocytes and neutrophils with scattered nuclear dust;Do and bullous lesions followed by ulceration, as was seen in thick, hyalinized, closely crowded collagen bundles in the our patient.6,9,10 Lesions usually begin at sites of trauma reticular dermis and in a widened subcutaneous septum and seem to be distributed symmetrically.5,6 The most (Figures 2 and 3). commonly affected locations are the legs, specifically Supportive care and pain control were continued, but the medial thighs, as well as the abdomen and buttocks, the overall prognosis was determined to be very poor, and but lesions also can be found at more distal sites such as the patient eventually was discharged to hospice and died. the breasts, tongue, vulva, penis, fingers, and toes.5,6,10 Although calciphylaxis is commonly seen in patients The head and neck region rarely is affected. Although with ESRD and hyperparathyroidism, patients with- uncommon, calciphylaxis may affect other organs, includ- out renal disease also may develop the condition.2,3 ing the lungs, stomach, kidneys, and adrenal glands.5 Prior epidemiologic studiesCUTIS have shown a prevalence of The accompanying systemic symptoms and findings may 1% in patients with chronic kidney disease and up to include muscle weakness, tenderness, or myositis with A B FIGURE 1. A and B, Rupture of nonhemorrhagic bullae on the left leg that evolved into ulcerations and necrotic eschars with surrounding purpura. WWW.MDEDGE.COM/DERMATOLOGY VOL. 105 NO. 3 I MARCH 2020 E25 Copyright Cutis 2020. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. CALCIPHYLAXIS A FIGURE 3. Calcium deposits were highlighted in the vessel walls (von Kossa, original magnification ×40). rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the centralcopy nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcifica- tion of the cardiac conduction system.6 Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deepnot to the areas of necrosis.5,6 A careful