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Skin Fragility, Woolly Hair Syndrome with a Desmoplakin Mutation

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Skin Fragility, Woolly Hair Syndrome with a Desmoplakin Mutation Correspondence e73 recovery of CD4+ T-cells by highly active antiretroviral therapy 4 Shiohara T, Kurata M, Mizukawa Y, et al. Recognition of immune (HAART) in human immunodeficiency virus (HIV) patients. reconstitution syndrome necessary for better management of patients with severe drug eruptions and those under Recently, a similar concept, which implies that discontinuation immunosuppressive therapy. Allergol Int 2010; 59: 333–343. or abrupt tapering of systemic steroids and/or immunosuppres- 5 Sueki H, Mizukawa Y, Aoyama Y. Immune reconstitution sants increases the risk of opportunistic infection in non-HIV inflammatory syndrome in non-HIV immunosuppressed patients. patients, has been proposed.4,5 DIHS is suggested to be a J Dermatol 2018; 45:3–9. manifestation of the newly reported IRS.4 Kano et al. reported 6 Kano Y, Horie C, Inaoka M, et al. Herpes zoster in patients with drug-induced hypersensitivity syndrome/DRESS. Acta Derm that three out of 28 patients with DIHS in their institute devel- – 6 Venereol 2012; 92: 206 207. oped herpes zoster within 6 months after resolution. They 7 Kano Y, Inaoka M, Shiohara T. Association between speculate that the administration of systemic corticosteroids anticonvulsant hypersensitivity syndrome and human herpes 6 may alter the pathomechanisms of DIHS and lead to the later reactivation and hypogammaglobulinemia. Arch Dermatol 2004; occurrence of herpes zoster. Herpes zoster usually occurs 140: 183–188. 8 Takahashi R, Kano Y, Yamazaki Y, et al. Defective regulatory T 2–3 months after the resolution of DIHS and is often associated cells in patients with severe drug eruptions: timing of the with the reduction of corticosteroids. In contrast, it is unlikely dysfunction is associated with the pathological phenotype and that treatment with systemic corticosteroids was associated with outcome. J Immunol 2009; 182: 8071–8079. the reactivation of VZV, because such treatment was not per- formed in the present case. The causative drugs of DIHS have immunosuppressive properties,4 and it was reported that a Skin fragility, woolly hair syndrome with a desmoplakin decrease in immunoglobulin levels and B-cell counts was mutation – a case from India induced by such drugs,7 which may primarily contribute to the + reactivation of VZV. In contrast, CD4 T-cell numbers initially We report a case of skin fragility woolly hair syndrome (SFWH; increase, which subsequently decrease coincident with clinical OMIM 607655), an autosomal recessive disorder caused by 4 improvement of DIHS. Those alterations of lymphocyte subsets mutations in desmoplakin (DSP). during the course may be related to subsequent occurrence of A 23-year-old woman born of third degree consanguineous various viral reactivation. Unfortunately, we could not examine marriage from south India presented with short curly hair and CD4 T-cell counts during the course. Moreover, dysfunction of thickening of nails since birth. She complained of recurrent blis- regulatory T cells at the resolution phase contributes to oppor- ters with secondary infection from infancy. The skin blistering 8 tunistic infection, which also may have played an important occurred more during the summer season and frequently over role in VZV reactivation in the present case. the feet. She had observed that the degree of blistering had reduced with age. There were no symptoms suggestive of car- Takako Miura, MD diac involvement. There was a family history of a similar skin Nobuyuki Kikuchi, MD condition in her 12-year-old nephew (own sister’s son). No other Mikio Ohtsuka, MD, PhD family members were affected. At presentation, she had coarse Toshiyuki Yamamoto*, MD, PhD woolly hair with few erosions on the scalp, crusted erosions over the infranasal region, blisters on the dorsa of toes, and hyperker- Department of Dermatology, Fukushima Medical University, atotic papules all over the body (Figs. 1 and 2a). There was dif- Fukushima, Japan fuse thickening of the palms with focal hyperkeratosis over the *E-mail: [email protected] thenar and volar aspects of metacarpophalangeal joints and dif- fuse thickening of the soles with a bulla over the dorsum of the Conflicts of interest: None. first toe. There was thickening of nail plates of the left first, sec- doi: 10.1111/ijd.14091 ond, and third fingernails and all the toenails (Figs. 2a and b). Clinical differential diagnoses considered were Naxos disease References (due to plakoglobin mutations) and Carvajal syndrome (due to 1 Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a desmoplakin mutations), both having woolly hair, palmoplantar DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol keratoderma, and cardiomyopathy. Pachyonychia congenita, a 2007; 156: 1083–1084. keratin disorder, was also considered in view of thickened nail 2 Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of the lymphocyte plate, keratoderma, and hyperkeratotic papules. transformation test in the diagnosis of drug sensitivity: Her routine blood investigations were within normal limits. dependence on its timing and the type of drug eruption. Allergy Her cardiac evaluation with electrocardiogram and echocardio- 2007; 62: 1439–1444. 3 Tsutsumi R, Adachi K, Yoshida Y, et al. Drug-induced gram were normal. Histopathological examination of the skin hypersensitivity syndrome in association with varicella. Acta Derm from the dorsa of feet adjacent to an erosion showed a promi- Venereol 2015; 95: 503–504. nent granular layer with intraepidermal clefting (Fig. 2c). Direct ª 2018 The International Society of Dermatology International Journal of Dermatology 2018, 57, e59–e81 e74 Correspondence (a) (b) Figure 1 (a) Woolly hair over the scalp and erosions over the right infranasal region. (b) Follicular hyperkeratosis over the legs (a) (c) (b) Figure 2 (a) Thickening of the nail plates of the toe with bulla over the dorsa of left toe. (b) Diffuse keratoderma of the soles. (c) Prominent granular layer with intraepidermal clefting. (H&E, x40) DNA sequencing revealed a homozygous mutation, DSP SFWHS caused by DSP mutations is a rare autosomal reces- p.Arg2366Cys; c.7096C>T, in exon 24. Her affected nephew sive disorder.1 The complexity of the structure of desmosomes was also homozygous for p.Arg2366Cys. His parents (whose and the large number of proteins involved partly explain the mother is her unaffected sister) were both heterozygous carriers genetic and clinical heterogeneity of desmosomal disorders.2 of the mutation. Desmoplakin is a large desmosomal plaque protein that Thus, a diagnosis of skin fragility woolly hair syndrome belongs to the plakin family of cytoskeletal linker proteins that is (SFWHS) was made based on the clinical features of recurrent expressed in many tissues including skin. There are three alter- blisters, woolly hair, palmoplantar keratoderma, and nail native splice variants, DSP-I, DSP-II, and DSPIa; DSP-II and changes in the absence of cardiomyopathy, and genetic analy- DSPIa both have a shorter central rod domain than DSP-I due sis identifying a homozygous mutation in desmoplakin. to differing sizes of exon 23.1,3,4 Desmoplakin-I is the major International Journal of Dermatology 2018, 57, e59–e81 ª 2018 The International Society of Dermatology Correspondence e75 isoform expressed in heart tissue. DSP-II is reportedly absent/ Project (to F.J.D.S, www.pachyonychia.org). The Centre for present at very low levels in the heart and simple epithelia but Dermatology and Genetic Medicine at the University of plays a more significant role than DSP-I in maintaining robust Dundee is supported by a Wellcome Trust Strategic Award adhesion in keratinocytes. Desmoplakin-Ia is evident in both (098439/Z/12/Z to W.H.I.McLean). We would also like to heart and skin but at considerably lower levels than DSP-I and thank Mary E. Schwartz and Holly A. Evans of Pachyony- DSP-II.4 chia Congenita Project (www.pachyonychia.org) for their The p.Arg2366Cys mutation in exon 24 is present in all iso- assistance. forms of DSP. It is within the carboxy B domain of the inner 1, desmosomal plaque region at the C-terminal of DSP. The Dincy C. V. Peter *, MD 2 C-terminal region of DSP is involved in interactions with inter- Meera Thomas , MD 3 mediate filament proteins, and it is predicted this missense Neil J. Wilson , MSc 4 mutation will alter the tertiary structure of the carboxy domain Frances J. D. Smith , PhD and interfere with binding of DSP to keratin filaments.3 1 The clinical heterogeneity demonstrated by DSP mutations is Department of Dermatology, Venereology and Leprosy, due to the position and type of mutation together with different Christian Medical College, Vellore, Tamil Nadu, India 2 expression and functional properties of the DSP isoforms, partic- Department of Pathology, Christian Medical College, Vellore, ularly in the heart.5 Mutations in DSP are associated with sev- Tamil Nadu, India 3 eral distinct clinical phenotypes affecting skin, nails, hair, and⁄or Centre for Dermatology and Genetic Medicine, Division of heart which are inherited as either autosomal recessive or domi- Biological Chemistry and Drug Discovery, School of Life nant traits. Autosomal recessive forms include SFWHS, Carvajal Sciences, University of Dundee, Dundee, UK 4 syndrome, and lethal acantholytic epidermolysis bullosa. Autoso- Pachyonychia Congenita Project, Holladay, mal dominant disorders include arrhythmogenic right ventricular UT, USA dysplasia and keratosis palmoplantaris striata II.1 *E-mail: [email protected] SFWHS caused by mutations in DSP presents with woolly hair with varying degree of alopecia, recurrent blisters especially during Conflict of interest : none. 1,3,5 summertime, palmoplantar keratoderma, and nail dystrophy. doi: 10.1111/ijd.14096 Reportedly there is absence of cardiomyopathy, but with only a small number of cases reported, it is wise to monitor patients regu- References larly. Genetic testing confirms both the clinical diagnosis and mode 1 Al-Owain M, Wakil S, Shareef F, et al.
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