Kana Tanahashi

Lamellar ichthyosis in a collodion baby caused by CYP4F22 mutations in a non-consanguineous family outside the Mediterranean.

[3] Negi M, Tsuboi R, Matsui T, Ogawa H. Isolation and characterization from Candida albicans: substrate specificity. J Invest Dermatol 1984;83:32–6. [4] Tsuboi R, Kurita Y, Negi M, Ogawa H. A specific inhibitor of keratinolytic proteinase from Candida albicans could inhibit the cell growth of C. albicans. J Invest Dermatol 1985;85:438–40. [5] Aoki W, Kitahara N, Miura N, Morisaka H, Yamamoto Y, Kuroda K, et al. Comprehensive characterization of secreted aspartic proteases encoded by a virulence gene family in Candida albicans. J Biochem 2011;150:431–8. [6] Hornbach A, Heyken A, Schild L, Hube B, Löffler J, Kurzai O. The glycosylphosphatidylinositol-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils. Infect Immun 2009;77:5216–24. [7] Hube B, Monod M, Schofield DA, Brown AJ, Gow NA. Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol 1994;14:87–99. Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China Laboratory for Biochemistry, Juntendo University School of Health Care and Nursing, Urayasu, Japan; Department of Dermatology, Tokyo Medical University, Tokyo, Japan; Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan

Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood.

Background  Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis.

Highly Prevalent LIPH Founder Mutations Causing Autosomal Recessive Woolly Hair/Hypotrichosis in Japan and the Genotype/Phenotype Correlations

Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH), and the 2 missense mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn) are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016), and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024). In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

TRPS1 Haploinsufficiency Results in Increased STAT3 and SOX9 mRNA Expression in Hair Follicles in Trichorhinophalangeal Syndrome.

Trichorhinophalangeal syndrome types I and III (TRPS1, OMIM 190350; TRPS3, OMIM 190351) are rare hereditary diseases with autosomal dominant inheritance (1, 2). The first case was reported in 1966 (3). In 2000 the TRPS1 gene was identified as one of its causative genes and mapped to chromosomal region 8q24.1 (1). These syndromes have characteristic sparse and slow-growing hair, craniofacial abnormalities, such as bulbous pear-shaped nose, and skeletal abnormalities (3–5). We report here the effects of TRPS1 protein deficiency in a case of TRPS1.

Novel TGM1 missense mutation p.Arg727Gln in a case of self-healing collodion baby.

Collodion babies are newborns encased in a glistening membrane that cracks in a characteristic manner within 48 h and desquamates in large lamellae after a few days. Most collodion babies later develop one of the several types of autosomal recessive congenital ichthyoses (ARCI), such as lamellar ichthyosis (LI) or congenital ichthyosiform erythroderma; however, about 10% heal spontaneously (1). This healing condition is known as “self-healing collodion baby” or “self-improving collodion baby” (SHCB/SICB). Raghunath et al. (1) showed that this phenotype is possibly a hydrostatic pressuresensitive phenotype of TGM1 mutations. The SHCB/ SICB phenotype was subsequently reported in patients with ALOX12B and ALOXE3 mutations (2). To date, few reports on SHCB/SICB cases with TGM1 mutations have been published (1–4). TGM1 is the most commonly involved gene in ARCI, and encodes transglutaminase-1 (TGase-1) (1, 5–8). Here, we describe an ARCI patient with a novel TGM1 mutation who presented at birth with a collodion membrane but spontaneously healed within 2 months without any skin manifestations.

Topical minoxidil improves congenital hypotrichosis caused by LIPH mutations.

DEAR EDITOR, Mutations in LIPH are one cause of autosomal recessive woolly hair/hypotrichosis (ARWH). LIPH mutations are not uncommon and are found all over the world. In this report, we present four patients with ARWH with LIPH mutations who showed hair growth after application of topical minoxidil. Four nonconsanguineous Japanese patients with ARWH who used 1% or 5% topical minoxidil were observed and followed up. Topical minoxidil is used for androgenic alopecia and is available over the counter in Japan. The present patients used it on their own initiative. Direct sequencing of exon 6 of the LIPH gene revealed homozygous c.736T>A (p.Cys246Ser) mutations in patients A and B. The homozygous c.742C>A (p.His248Asn) mutation was found in patient C, and compound heterozygous c.736T>A and c.742C>A mutations were

A new EDA gene mutation in a family of X-linked hypohidrotic ectodermal dysplasia

Hypohidrotic ectodermal dysplasia (HED) is a rare congenital genodermatosis characterized by abnormal development of sweat glands, teeth, nails and hair. Other clinical symptoms include saddle nose, low-set ears, immunodeficiency, and atopic dermatitis (AD). HED mainly originates from loss-of-function development via a signaling center called ‘‘the enamel not’’ where the expression of EDAR is confined; EDA also regulates hair follicle cycling, especially the length of the growth phase/ onset of regression which is proportional to the length of the hair shaft [2]. The role of EDA in the development of sweat glands is still unclear. EDA is a member of the tumor necrosis factor (TNF) family and is a type-a transmembrane protein, having 2 common isoforms: EDA-A1 and EDA-A2. Most EDA mutations of 4 genes: EDA (ectodysplasin A) on chromosome Xq12-q13.1 accounting for X-linked forms, ectodysplasin A receptor (EDAR) on chromosome 2q11-q13 and ectodysplasin A receptor-associated death domain (EDARADD) on chromosome 1q42-q43 causing both autosomal dominant and recessive forms, and WNT10A on chromosome 2q35 resulting in autosomal recessive forms [1]. The EDA-EDAR-EDARADD axis is a unique example of naturally occurring mutations in ligand, receptor, and adaptor protein giving rise to the same phenotypic disease [2]. This pathway is highly conserved in various vertebrate species and regulates the development of ectodermal organs [3]. The function of EDA is being elucidated through analysis of lossand gain-of-function mouse models for HED. EDA is essential for the formation of primary hair placodes, although the mechanism is not yet clear [2]. EDA is also involved in the initiation of tooth

Noteworthy clinical findings of harlequin ichthyosis: digital autoamputation caused by cutaneous constriction bands in a case with novel ABCA12 mutations.

1 Farrell AM, Dean D, Millard PR et al. Cytokine alterations in lichen sclerosus: an immunohistochemical study. Br J Dermatol 2006; 155:931–40. 2 Lowenstein EB, Zeichner JA. Intralesional adalimumab for the treatment of refractory balanitis xerotica obliterans. JAMA Dermatol 2013; 149:23–4. 3 Bunker CB. Atopy, the barrier, urine and genital lichen sclerosus. Br J Dermatol 2013; 169:953. 4 Farrell AM, Marren P, Dean D, Wojnarowska F. Lichen sclerosus: evidence that immunological changes occur at all levels of the skin. Br J Dermatol 1999; 140:1087–92. 5 Meyrick Thomas RH, Ridley CM, Black MM. The association of lichen sclerosus et atrophicus and autoimmune-related disease in males. Br J Dermatol 1983; 109:661–4. 6 Edmonds EV, Oyama N, Chan I et al. Extracellular matrix protein 1 autoantibodies in male genital lichen sclerosus. Br J Dermatol 2011; 165:218–19. 7 Azurdia RM, Luzzi GA, Byren I et al. Lichen sclerosus in adult men: a study of HLA associations and susceptibility to autoimmune disease. Br J Dermatol 1999; 140:79–83. 8 Terlou A, Santegoets LA, van der Meijden WI et al. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol 2012; 132:658–66. 9 Limpers A, van Royen-Kerkhof A, van Roon JA et al. Overlapping gene expression profiles indicative of antigen processing and the interferon pathway characterize inflammatory fibrotic skin diseases. Expert Rev Clin Immunol 2014; 10:231–41. 10 Diab M, Coloe JR, Magro C, Bechtel MA. Treatment of recalcitrant generalized morphea with infliximab. Arch Dermatol 2010; 146:601–4.

Disappearance of circulating autoantibodies to RNA polymerase III in a patient with systemic sclerosis successfully treated with corticosteroid and methotrexate

Editor Although the titres of anti-RNAP III often change in association with total thickness skin score (TSS), it is extremely rare for anti-RNAP III to become negative after treatment in patients with SSc. A 66-year-old man exhibited Raynaud’s phenomenon in the fingers. Four months later, oedema of the bilateral hands and feet and polyarthralgia occurred. A half-year after the initial episode of Raynaud’s phenomenon, the patient was admitted to our hospital with severe joint pain and the inability to walk unaided. He had no particular past history. Echocardiography, chest computer tomography, upper gastrointestinal endoscopy and colonoscopy revealed no remarkable finding for heart, lungs and abdomen. His fingers, hands and forearms were swollen with redness, and sclerodermatous skin change was present in the fingers (Fig. 1a). Pitting oedema was observed in the feet (Fig. 1b). The modified Rodnan TSS was 16. The laboratory data were as follows: ESR of 37 mm/h, WBC count of 3740/lL, platelets of 37 300/mm, total protein of 7.1 g/dL, albumin of 2.9 g/dL, blood urea nitrogen of 10 mg/dL, creatinine of 0.59 mg/dL and UA of 3.6 mg/dL, CRP of 5.07 mg/dL, MMP-3 of 39.2 ng/mL (normal range: 36.9–121.0 ng/mL) and plasma renin activity of 3.1 ng/mL/h (normal range: 0.2–3.9 ng/mL/h). Antinuclear antibody (ANA) was positive (1:80; nuclear speckled staining), and anti-RNAP III was detected by enzyme-linked immunosorbent assay (ELISA) with a high index of 104 and 77 at two points (normal range: < 28). Rheumatoid factor, anticyclic citrullinated peptide, anti-SSA/Ro, anti-U1-RNP, anti-Scl-70 and anticentromere antibodies were negative. A skin biopsy sample obtained from the extensor surface of the forearm showed oedema of the upper and mid dermis (data not shown). Neither bone erosion/destruction nor calcification was seen in the bilateral wrists (Fig. 1c), and there was bone marrow oedema in the carpal bones (Fig. 1d). In light of the above-mentioned findings, the patient was diagnosed as having SSc with anti-RNAP III associated with synovitis. We administrated systemic prednisolone (PSL) at 30 mg/day, while carefully watching for signs of scleroderma kidney. This achieved almost complete remission of all symptoms, except discomfort of the metacarpophalangeal joints. After tapering the PSL dose by 2.5 mg every 2–3 weeks, the TSS fell to 0 and CRP and ESR levels normalized. When the PSL tapering reached 20 mg/day, the oedema and arthralgia relapsed and the CRP rebounded. After 3 months of PSL treatment, methotrexate (MTX) at 6 mg/week and later at 8 mg/week was added, and the joint symptoms were relieved and the CRP level decreased again. PSL has been tapered to 9 mg, and MTX at 8 mg/week has been continued; however, no recurrence of skin sclerosis or arthralgia, or even of Raynaud’s phenomenon has occurred for 2 years. Surprisingly, anti-RNAP III became negative (index value: 10) with ELISA about 1 year after PSL was started (Fig. 2). ANA also became negative. We do not know the exact mechanism of how the antibodies disappeared in this case, although we assume that the extremely positive response to the treatments for SSc, to the extent of completely resolving the Raynaud’s phenomenon, might be related to the disappearance of anti-RNAP III. The disappearance of anti-MDA-5 autoantibodies in clinically amyopathic dermatomyositis/interstitial lung disease during disease remission is (a)

Autosomal dominant progressive hyperpigmentation and lentigines in a Japanese pedigree due to a missense mutation near the C-terminus of KIT

The transmembrane receptor tyrosine kinase (KIT), encoded by KIT, and the KIT ligand, encoded by KITLG, play crucial roles in the control of physiological and pathological skin pigmentation. The binding of KITLG to KIT regulates the migration, proliferation, differentiation and survival of melanocytes, and regulates melanogenesis and melanosome transfer.1 KITLG⁄KIT, which triggers the Ras⁄MAPK signaling pathway, plays crucial roles in melanin synthesis. Loss-of-function mutations in KIT cause piebaldism, and gain-of-function mutations in KIT induce mastocytosis and gastrointestinal stromal tumors (GISTs).1 In addition, somatic mutations in KIT cause GIST or mastocytosis. Ten cases of hyperpigmentation and 2 cases of lentigines were reported in familial mastocytosis or GIST associated with germline KIT mutations. This article is protected by copyright. All rights reserved.