Amelanocytic Anhidrotic Alopecia Areata-Like Phenotype After Allogeneic Hematopoietic Cell Transplant

OBSERVATION Amelanocytic Anhidrotic Alopecia Areata-like Phenotype After Allogeneic Hematopoietic Cell Transplant

Edidong Celestine Ntuen Kamin´ska, MD; Richard A. Larson, MD; Vesna Petronic-Rosic, MD, MSc

Background: Diffuse alopecia areata or canities subita plant. Results of a histopathologic examination, which is a rare variant of alopecia in which hair loss is associ- has previously not been reported in this disease, dem- ated with regrowth of white hairs and possible lighten- onstrated a complete lack of epidermal and follicular ing of the skin. Preferential loss of pigmented hair in this melanocytes and a dense perifollicular and periadnexal disorder may be related to the melanin pigment system lymphocytic infiltrate. and/or melanocytes. Acquired generalized anhidrosis can be associated with autoimmune disease, cancer, graft- Conclusions: The hair- and skin-lightening phenom- vs-host disease, or medications or can be idiopathic. ena in diffuse alopecia areata may be the result of an over- Extensive anhidrosis may cause hyperpyrexia on exposure stimulated immune system that targets epidermal and fol- to heat, and protection from overheating is essential. licular melanocytes. Destruction results in irreversible pigmentary loss of the skin. In a patient with multiple Observations: A 38-year-old man with idiopathic au- risk factors for anhidrosis, a specific cause may be diffi- toimmune aplastic anemia developed permanent dif- cult to determine. fuse skin and hair whitening and generalized anhidrosis after a successful allogeneic hematopoietic stem cell trans- Arch Dermatol. 2012;148(8):931-934

LOPECIA AREATA IS AN AU- refractory to multiple immunomodula- toimmune disease charac- tory medications (antithymocyte globu- terized by patchy hair loss. lin, cyclosporine, methylprednisolone Diffuse alopecia areata or sodium succinate, and mycophenolate canities subita is a rare mofetil hydrochloride) and required fre- variantA in which hair loss is associated with quent blood transfusions underwent an regrowth of white hairs and possible light- allogeneic hematopoietic stem cell trans- ening of the skin. The pathophysiology of plant 18 months before presenting for alopecia areata is not completely under- evaluation of diffuse hair whitening and stood; however, preferential loss of pig- generalized anhidrosis. Eighteen months mented hair in this disorder has led some earlier, he had received chemotherapy experts to hypothesize that the autoim- with fludarabine phosphate, alemtu- mune target in alopecia areata may be re- zumab, and melphalan hydrochloride as lated to the melanin pigment system and/or preparation for a matched unrelated- melanocytes. Acquired generalized anhi- donor stem cell transplant. During and drosis can be associated with autoim- immediately after chemotherapy he had mune disease, cancer, graft vs host dis- his normal brown hair; 2 weeks later, he ease (GVHD), or medications or can be experienced hair loss all over his body idiopathic. Regardless of the cause, exten- consistent with anagen effluvium, fol- sive anhidrosis may cause hyperpyrexia on lowed by regrowth of brown hair. Six exposure to heat, and protection from months later, a bout of patchy loss of overheating is essential. We herein re- pigmented hair occurred on the face, port a case of alopecia areata with diffuse scalp, and body within 24 hours. This skin and hair whitening and generalized shedding was followed by a decreased anhidrosis. density and uneven regrowth of completely white hair. Eighteen months after Author Affiliations: Sections of the transplant, the white hairs persisted Dermatology (Drs Kamin´ ska REPORT OF A CASE Figure 1 and Petronic-Rosic) and ( ); he had complete anhidrosis Hematology/Oncology and excessively dry skin. He denied (Dr Larson), Department of A 38-year-old man with a history of decreased tear or saliva production. His Medicine, The University of hypothyroidism and idiopathic autoim- therapeutic course had been previously Chicago, Chicago, Illinois. mune aplastic anemia that became complicated by mild chronic GVHD with

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Figure 1. Diffuse alopecia sequence of events. A, Photograph of the patient immediately after completing chemotherapy for preparation of stem cell transplant; 2 weeks later the patient experienced anagen effluvium, followed by regrowth of brown hair. B, Active shedding of brown hair 6 months after chemotherapy that occurred within 24 hours, followed by regrowth of all white hair (the patient shaved to minimize hair loss). C, Eighteen months after chemotherapy, white hairs persisted and patchy hair loss (insets) continued.

A B COMMENT

Diffuse alopecia areata followed by white, depigmented hair regrowth has been reported as early as 83 CE during the Babylonian Talmud era.1 Other names for this disease include Marie Antoinette syndrome, named after the queen whose hair reputedly turned white the night before her guillotine execution during the French revolu- tion; canities subita; and sudden or rapid whitening of the hair. Several case reports of sudden hair whitening from Figure 2. Results of a punch biopsy from the right arm. as early as 30 minutes to several weeks after a stressful A, Hematoxylin-eosin–dense lymphocytic infiltrates surround a hair follicle and eccrine glands (original magnification ϫ100). B, Immunohistochemical event or nonautoimmune disease have been de- 2-6 microphthalmia-associated transcription factor (MITF) staining reveals internal scribed. The pathophysiology is not completely un- control of mast cells highlighted with brown (original magnification ϫ200); derstood, but a 2-step mechanism has been proposed.1 no melanocytes were noted with MITF and melan-A stain (not shown). First, the pilar unit is transformed from one that produces pigmented hair to one that produces nonpig- mented hair; the pigmented telogen hairs are rapidly shed, an erythematous and pruritic rash, eosinophilia, and and the new anagen hairs are depigmented. Next, the sud- loose stools. den whitening may be attributed to the retention of pre- On physical examination, depigmented hairs were existing white hairs and abrupt selective shedding of the found on the entire body surface with irregular thin- pigmented hairs. Synchronous lengthening of the white ning of the scalp and facial hairs, including eyelashes. hairs during regrowth provides the final appearance. Exclamation point hairs were visible on the scalp. Wiry Therefore, unlike classic alopecia areata, diffuse alope- hairs were observed on the extremities and trunk. The cia areata may not be associated with the typical circu- skin appeared mildly erythematous, xerotic, and devoid lar patches of alopecia areata or progression to alopecia of pigment. Results of a punch biopsy on the right arm totalis or alopecia universalis. However, a rapid loss of showed vacuolization of the basal layer and satellite cell pigmented hairs and a general thinning of the scalp and necrosis in the epidermis, which was consistent with a body hairs followed by regrowth of white hairs are diagnosis of GVHD. Eccrine glands with thick basement observed. membranes and hair follicles surrounded by lympho- Alopecia areata might be a disease of differentiating cytes were also noted (Figure 2A). Immunohisto- cortical keratinocytes, the failure of pigmentation in the chemical staining with melan A and microphthalmia- regrowing white hair may be a postinflammatory reac- associated transcription factor demonstrated a specimen tion, and the pigmentary mechanisms in the hair bulb completely devoid of melanocytes (Figure 2B). might contribute to the pathogenesis.7 Cases of alopecia The patient was treated for cutaneous GVHD with topi- areata can demonstrate abnormal melanoblasts and me- cal triamcinolone acetonide ointment, 0.1%, twice a day lanogenesis,8 and pigmented hairs are preferentially tar- as needed; he was informed that the white hairs and de- geted, whereas depigmented hairs are preserved within pigmented skin were likely permanent. In addition, he evolving patches.9 Depigmented hairs may persist.10 These was advised that he must prevent himself from overheat- findings and others suggest that the autoimmune target ing because of the anhidrosis and that he must wear sun in alopecia areata may be related to the melanin pig- protection regularly. ment system and/or the melanocytes.11,12 Observations

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 in mouse models indicate that the induction of T-cell– lymphocytic infiltrate surrounding the eccrine glands mediated immunity against hair follicle melanocytes could be consistent with an autoimmune anhidrosis, a causes alopecia areata and may be accompanied by viti- definitive cause of the anhidrosis could not be con- ligolike coat color change.13 In addition, decreased num- firmed in this patient. Patients with anhidrosis should bers of follicular melanocytes are documented in pa- avoid factors that produce thermal stress; if a primary tients with alopecia areata.12 The skin-lightening cause is determined, it should be treated. phenomenon may also be a result of the proposed de- Finally, adnexal involvement in chronic GVHD, in- fect or destruction of the melanin pigment system and cluding different types of scarring and nonscarring alo- melanocytes; therefore, diffuse alopecia areata may over- pecia and impairment of sweating, is a constant finding lap with or encompass vitiligo in its disease course. in up to 80% of patients with chronic GVHD.25 There- Generalized vitiligo and leukotrichia have been fore, in a patient with a known genetic predisposition, described in patients with GVHD and those undergo- chronic GVHD may act as a triggering factor for the ap- ing hematopoietic stem cell transplant or donor lym- pearance of autoantibodies and autoimmune diseases. Dif- phocyte infusion.14-16 Alopecia areata in the ophiasis fuse alopecia areata is an uncommon type of alopecia pattern was observed in a single patient with vitiligo areata that dermatologists should be able to recognize and and GVHD.16 In contrast to the present case, these diagnose. Although the pathophysiology of alopecia areata reports describe a gradual progression of vitiligo with and its variants has not been completely elucidated, au- patches of normal pigmentation visible on examina- toimmune targets such as follicular melanocytes likely tion. Consistent with previous reports of diffuse alope- play a role. Further studies are necessary to confirm these cia, our patient’s hair turned white overnight (no pro- findings. gression to leukoderma), with no evidence of normal pigmentation. Total leukoderma has also been Accepted for Publication: January 21, 2012. described as a rare complication of GVHD and hema- Correspondence: Vesna Petronic-Rosic, MD, MSc, Sec- topoietic stem cell transplant15; however, associated tions of Dermatology and Hematology/Oncology, De- hair loss was not observed. Our patient had an acute partment of Medicine, The University of Chicago, 5841 (24-hour) patchy hair loss of pigmented hairs all over S Maryland Ave, Mail Code 5067, Chicago, IL 60637 his body. Unlike diffuse alopecia areata, vitiligo causes ([email protected]). destruction of melanocytes resulting in depigmented Author Contributions: All authors had full access to all patches of skin and leukotrichia, but it is not associ- the data in the study and take responsibility for the in- ated with hair loss. Melanocyte destruction caused by tegrity of the data and the accuracy of the data analysis. autoimmune reactions triggered by chronic GVHD Study concept and design: Petronic-Rosic. Acquisition of may have contributed to a diffuse alopecia areata–like data: Larson and Petronic-Rosic. Analysis and interpre- phenotype in this patient. A similar pathophysiologic tation of data: Kamin´ ska, Larson, and Petronic-Rosic. process has been suggested for vitiligo in patients with Drafting of the manuscript: Kamin´ ska. Critical revision of chronic GVHD and a history of hematopoietic stem the manuscript for important intellectual content: Kamin´ ska, cell transplant.16 Larson, and Petronic-Rosic. Administrative, technical, and Chemotherapy has also been associated with alope- material support: Larson. Study supervision: Kamin´ ska, Lar- cia areata or skin and hair depigmentation. Recurring son, and Petronic-Rosic. alopecia areata in a patient receiving paclitaxel and Financial Disclosure: None reported. carboplatin was presumed to be related to the autoimmune changes instigated by rather than a direct effect REFERENCES of the chemotherapy.17 Inhibitors of c-kit tyrosine kinase are known to cause hair and skin depigmenta- 1. Goldenhersh MA. Rapid whitening of the hair first reported in the Talmud: pos- tion that is usually reversible on cessation of the sible mechanisms of this intriguing phenomenon. Am J Dermatopathol. 1992; therapy.18-21 In the present case, irreversible skin and 14(4):367-368. hair whitening began after 6 months and occurred 2. Ephraim AJ. On sudden or rapid whitening of the hair. Arch Derm. 1959;79(2): 228-236. within 24 hours; the patient had a history of autoim- 3. Dinh QQ, Chong AH. A case of widespread non-pigmented hair regrowth in dif- mune disease and did not have exposure to paclitaxel, fuse alopecia areata. 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Top-Accessed Article: Skin Markers of Occult Spinal Dysraphism in Children

Guggisberg D, Hadj-Rabia S, Viney C, et al. Skin markers of occult spinal dysraphism in children: a review of 54 cases. Arch Dermatol. 2004;140(9):1109-1115.

“Marker” skin lesions on the posterior midline are evident in approximately 80% of individuals with occult spinal dysraphism.1 In a retrospective study of 54 children with congenital midline lumbosacral skin lesions, Guggisberg and colleagues found that 61% (11 of 18) of patients with 2 or more types of cutaneous findings in this location had occult spinal dysraphism compared with 8% (3 of 36) of those with a single skin finding (PϽ.001). Although small numbers of patients precluded risk assessment for specific types of isolated lumbosacral skin lesions, the authors concluded that certain solitary lesions (eg, a lipoma or a dermal sinus) were “high risk.” More recently, a prospective study showed an approximately 35% risk of spinal anomalies in patients with an isolated lumbosacral infantile hemangioma larger than 2.5 cm in diameter,2 adding this to the high-risk category. Both Guggisberg and coauthors and Drolet et al2 emphasized the need for spinal magnetic resonance imaging in individuals with multiple or high-risk isolated lumbosacral skin lesions, noting only approximately 50% sensitivity for spinal ultrasonography (even if performed at Ͻ4-6 months of age). From October 2010 to August 2011, this article was viewed 2916 times on the Archives of Dermatology Web site. Julie V. Schaffer, MD Contact Dr Schaffer at the Department of Dermatology, New York University School of Medicine, 560 First Ave, Rm H-100, New York, NY 10016 (julie.schaffer@nyumc .org).

1. Schropp C, So¨rensen N, Collmann H, Krauss J. Cutaneous lesions in occult spinal dysraphism—correlation with intraspinal findings. Childs Nerv Syst. 2006;22(2):125-131. 2. Drolet BA, Chamlin SL, Garzon MC, et al. Prospective study of spinal anomalies in children with infantile hem- angiomas of the lumbosacral skin. J Pediatr. 2010;157(5):789-794.

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