Yutaka Shimomura

Delayed-onset heat intolerance in a Japanese patient with X-linked hypohidrotic ectodermal dysplasia associated with a large deletion involving four genes

tumor with multinodular and infiltrative growth pattern. The tumor was mainly composed of polygonal clear myoepithelial type cells with various degree of cytological atypia and surrounded by abundant homogenous eosinophilic stroma (Fig. 1e,f). Immunohistochemistry revealed positivity for high molecular weight cytokeratin and calponin, a-smooth muscle actin, vimentin and p63 (Fig. 1g–k). The histopathological features were consistent with clear cell type myoepithelial carcinoma. Following the biopsy, positron emission tomography was performed to look for the primary tumor site or possible metastasis (Fig. 1b). No abnormally hypermetabolic lesion was observed in the parotid glands or any other area, except for the right vertex area. The diagnosis of primary cutaneous myoepithelial carcinoma (PCMC) on the scalp was given. She received multiple stages of Mohs surgery and the tumor mass was measured as 35 mm 9 80 mm (Fig. 1c). Interestingly, seemingly normal perilesional scalp had also been proved to be myoepithelial carcinoma on frozen biopsy. During 10 months of follow up, no local recurrence was observed (Fig. 1d). Myoepithelial carcinoma is a very rare tumor which accounts for 0.45% of the salivary gland tumors. Frost et al. reported that myoepithelial carcinoma occurred with a female predominance and the mean age at diagnosis was 43 years. It usually manifested as a painless mass on the parotid glands, but it has also been reported to occur in the breast, soft tissue, skin and lung. Histopathological features exhibit both epithelial and myoid phenotypes with various morphological and cytological diversity. Based on the multinodular and infiltrative growth pattern, mixed groups of spindle, plasmacytoid, epithelioid and clear cells with myxoid stroma are observed. The histological appearance of myoepithelial carcinoma may be similar to that of epithelial myoepithelial carcinoma, adenoid cystic carcinoma, proximal type epithelioid sarcoma. Immunohistochemical study would be helpful for the diagnosis. Myoepithelial carcinoma shows an immunoreactivity for both epithelial (pancytokeratin, epithelial membrane antigen) and myogenic (calponin, p63) markers. Myoepithelial carcinoma behaves aggressively with reported rates of local recurrence and metastasis ranging 11–80%. To our knowledge, 11 cases of PCMC have been reported around the world and a few cases have presented on the scalp. In practice, scalp nodules are often regarded as adnexal benign tumors. Considering the poor prognosis of myoepithelial carcinoma, it is essential to establish an early diagnosis. Yet, the possible manifestation of PCMC on the scalp urges clinicians to suspect and further examine scalp nodules. In addition, considering its atypical cutaneous manifestations, a highly meticulous multistage Mohs surgery is necessary to properly manage myoepithelial carcinoma. The resulting large postsurgical defect often causes a challenge for physicians.

Guidelines for the diagnosis and treatment of male‐pattern and female‐pattern hair loss, 2017 version

Male‐pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence‐based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and womens perception of MPHL has undergone change and the term “female‐pattern hair loss (FPHL)” is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first‐line treatments. Self‐hair transplantation, irradiation by light‐emitting diodes and low‐level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t‐flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan.

Hypohidrotic ectodermal dysplasia with strabismus

Dear Editor, We encountered a patient with hypohidrotic ectodermal dysplasia (HED) with strabismus. A 26-year-old man with a history of bronchial asthma and atopic dermatitis was admitted for the evaluation of congenital heat retention. His brother manifested the same symptoms and died at the age of 4 months; his two sisters had no such history. His scalp hair and eyebrows were sparse (Fig. 1a), and axillary and pubic hair were absent. Frontal bossing, saddlenose, thick lips, strabismus, hypodontia, dry skin, but no nail deformities were observed (Figs. 1a–c). Abdominal skin biopsy showed sweat gland hypoplasia. A 15-min sweat test (41°C, 22% humidity) elicited no sweating except on his palms; his body temperature rose by 1°C. Topical injection of 5% acetylcholine chloride at the anhidrotic area elicited no sweating. Genetic analysis using peripheral blood cells revealed the deletion of 36 bases in exon 4 of the ectodysplasin A (EDA) gene (c.646_681del), resulting in the loss of 12 amino acids from the 216th proline to the 227th glycine (Fig. 1d). Because the mutation is an in-frame deletion, it can be predicted that the mutant transcript is stably expressed in the patient’s skin. Ectodermal dysplasias (ED), characterized by disorders of various organs including the skin, is attributable to the abnormal development of the primordial external germ layer. It is roughly divided into HED and hidrotic ED depending on the presence or absence of sweat gland hypoplasia. Typical clinical manifestations of HED include hypotrichosis with fine and slow-growing scalp and body hair, sparse eyebrows, hypohidrosis, nail anomalies, hypodontia, frontal bossing, saddle-nose and thick lips. In some patients, the body temperature is as high as 42°C. Atopic dermatitis and bronchial asthma are frequent complications of HED. Besides typical findings, our patient manifested strabismus which is often seen in hidrotic ED. We found no HED patient with strabismus in the published work. Approximately 200 ED subtypes have been reported; the implicated gene has been studied in 30. X-linked HED, its most common form, accounted for approximately 70% of HED. It is due to mutations in the ED1 gene encoding EDA. EDA plays

Waardenburg syndrome type IIE in a Japanese patient caused by a novel non-frame-shift duplication mutation in the SOX10 gene

Dear Editor, SOX10 plays an essential role in the development of cells in the neural crest lineage, including melanocytes and enteric ganglia neurons. Mutations in SOX10 have been found in patients with Waardenburg syndrome (WS) type 2 (WS2E, Online Mendelian Inheritance in Man [OMIM] no. 611584), WS4 (WS4C, OMIM no. 613266; this subtype is associated with Hirchsprung disease [HD]), peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS and HD (PCWH, OMIM no. 609136), and Kallman syndrome. However, the reason for phenotypic heterogeneity in patients with nontruncating mutations in SOX10 remains unknown; the rs2435357 polymorphism in RET, which is statistically associated with the development of HD, has been investigated in several WS patients searching for the genetic modifier. We also recently reported a patient with WS2 (without HD) harboring a heterozygous p.N131D mutation in SOX10 who had no risk allele in rs2435357. Here, we additionally report a familial case of WS2E with a novel non-truncating mutation in SOX10. The patient was 8-month-old girl presenting bilateral blue irides and sensorineural hearing impairment. Piebald leukoderma, white forelock, dystopia canthorum, limb anomaly, motor impairment or HD were absent, suggesting that she was clinically divided into WS2 (Fig. 1a). Her symptoms were similar to her father (Fig. 1b) and her paternal grandmother, indicating autosomal dominant inheritance. The patient and her parents provided written informed consent for participation in this study, which was conducted according to a protocol approved by the ethics committee of the Yamagata University Faculty of Medicine. Mutational screening for MITF and SOX10 showed a novel heterozygous duplication mutation, c.381_386dupGCACCT (p.L129_H130dup), in SOX10 (Fig. 1c). Genotyping for rs2435357 revealed that both the patient and her father were homozygous for the C allele (risk allele for the HD is T allele). While the major gene playing a role for HD susceptibility is RET, SOX10 has been demonstrated to directly activate RET transcription in synergy with PAX3 at the RET enhancer region. In addition, the T allele (frequency in Asia, 0.45) in rs2435357 alters a functional SOX10 binding site and results in a lower level of expression of RET in vitro. So, it is reasonable to genotype rs2435357 (a common RET intronic polymorphism located in an enhancer) as a strong candidate genetic modifier for the WS patients with SOX10 mutation. However, the impact of the T allele to the development of HD in patients with SOX10 mutations has not been proved yet, awaiting further study. The phenotypes of our patient and our previously reported patient were very similar; both of them only revealed bilateral blue irides and sensorineural hearing impairment but no other specific manifestations of WS. One may speculate that this can be partially explained by the close position of amino acid alteration (p.L129_H130dup and p.N131D). One may also speculate that the absence of the risk allele in rs2435357, which was common among them, may affect their mild phenotypes. Our sequential reports accentuated the importance of

Two cases of hypohidrotic ectodermal dysplasia caused by novel deletion mutations in the EDA gene

Dear Editor, Hypohidrotic ectodermal dysplasia (HED) is one of 200 different genetic conditions of ectodermal dysplasia (ED) characterized by hypotrichosis, hypodontia and hypohidrosis. Most cases of HED show X-linked recessive inheritance and are caused by mutations in the ectodysplasin (EDA) gene (Online Mendelian Inheritance in Man #305100). We herein report two Japanese patients with X-linked HED caused by novel deletion mutations. Patient 1 was a 12-year-old Japanese boy admitted to hospital because of decreased sweating with idiopathic fever since birth. His scalp hair was sparse and he had a saddle nose and hypodontia (Fig. 1a–c). Patient 2 was a 3-month-old boy admitted to a hospital because of dry skin and hypotrichosis. He also showed low-set ears and a saddle nose (Fig. 1e,f). Patient 1 had typical symptoms of HED. In patient 2, facial abnormalities, including low-set ears and saddle nose, were suspected as ED. We were unable to clearly determine

Identification of a novel splice site mutation in the LIPH gene in a Japanese family with autosomal recessive woolly hair

Dear Editor, Among all hereditary hair disorders, a non-syndromic form of autosomal recessive woolly hair (ARWH; Online Mendelian Inheritance in Man #604379) resulting from mutations in the lipase H (LIPH) gene is known to be highly prevalent in the Japanese population. The LIPH gene is abundantly expressed in hair follicles and encodes an enzyme that produces 2-acyllysophosphatidic acid. Therefore, a lipid mediator is believed to play crucial roles in the hair follicle development. Although most Japanese patients with ARWH are caused by two founder mutations in the LIPH gene, p.C246S and p.H248N, other LIPH mutations can occasionally be found. We recently identified a Japanese family with two affected girls showing typical clinical features as non-syndromic woolly hair (Fig. 1a,b). Neither of their parents was affected. After obtaining written informed consent, we collected blood samples from the patients to extract genomic DNA. We were unable to obtain samples from either parent. We searched for mutations in the LIPH gene of the patients using primer pairs described previously. We initially identified a heterozygous mutation c.736T>A (p.C246S) in exon 6 of the LIPH gene in both patients (Fig. 1c). In addition, they carried heterozygous sequences in intron 7 of LIPH (Fig. 1d). Polymerase chain reaction (PCR) for this region amplified two distinct products from the patients’ DNA (Fig. 1e), while only a single fragment was amplified from 100 healthy control individuals (Fig. 1e; data not shown). We cloned the PCR products from the patients into a vector and sequenced each product separately, which showed that the shorter product not only had a nucleotide substitution T>A at position c.982+2, but also a 15-bp nucleotide deletion at position c.982+7_+21, and thus, the mutation was designated as c.982+2T>A; +7_+21del (Fig. 1f). To our knowledge, it has not previously been reported. As the next step, we PCR-amplified the sequences containing exons 6–8 of LIPH from the patients’ DNA and subcloned the products into the pCXN2.1 vector. Direct sequencing analysis revealed that each mutation was on a different allele. Then, we transfected the vectors into HEK293T cells, extracted total RNA after 24 h and performed reverse transcription PCR following the methods reported previously. This in vitro transcription assays demonstrated a shorter LIPH cDNA from the p.246C (c.982+2T>A; +7_+21del) allele, as compared with the p.246S allele (Fig. 1g). Sequencing of the shorter product revealed that it lacked the entire sequences of exon 7; that is, skipping of exon 7 was induced during the splicing event from the p.246C allele (Fig. 1h). In this study, we analyzed a Japanese family with ARWH and identified a novel splice site mutation c.982+2T>A; +7_+21del in the LIPH gene (Fig. 1d–f), which caused skipping of exon 7 in cultured cells (Fig. 1g,h). As exon 7 consists of 96-bp nucleotide sequences, the protein product from this aberrant transcript was predicted to have an amino acid substitution at codon 296 and an in-frame amino acid deletion from codons 297–328, thus designated p.G296V; p.Y297_M328del (Fig. 1h). Functional consequences resulting from the mutant protein need to be analyzed in the future.

Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review

Autosomal recessive woolly hair is a relatively rare hereditary hair disorder characterized by sparse, short, curly hair. This condition is known to be caused by mutations in the LIPH gene, LPAR6 gene or KRT25 gene. In the Japanese population, most patients with autosomal recessive woolly hair carry one of two founder mutations in the LIPH gene, c.736T>A (p.Cys246Ser) or c.742C>A (p.His248Asn). However, occasionally, individuals with this condition carry compound heterozygous mutations, typically one founder mutation and another mutation. In this study, we describe a patient with a compound heterozygous mutation in the LIPH gene at c.736T>A and c.1095‐3C>G. The latter mutation created a novel splice site. This was the fourth splice site mutation to be described in the LIPH gene. Furthermore, we performed an in vitro transcription assay in cultured cells, and demonstrated that the c.1095‐3C>G mutation led to a frame‐shift, which created a premature termination codon at the protein level (p.Glu366Ilefs*7). Finally, we summarized the mutations previously reported for the LIPH gene. Our findings provide further clues as to the molecular basis of autosomal recessive woolly hair.

A novel missense mutation in exon 3 of the TRPS1 gene in a patient with a mild phenotype of tricho-rhino-phalangeal syndrome type 1

271 In the present case, the exceptional histopathological findings of a marked hyperplastic epidermis overlying a stroma containing large lakes of mucin (similar to that of the mucinous adenocarcinoma of anal canal) reinforce previous observations concerning the mechanism of pagetoid phenomenon: mucinous neoplastic cells have the capability of metastatic spread into the epidermis; conversely, the mucin produced by tumour cells may act as a carcinogenic stimulus on apocrine structures [2]. In conclusion, these histopathological findings should raise the suspicion of a perianal EMPD due to a pagetoid spread of mucinous adenocarcinoma. Histopathological and immunohistochemical studies are crucial for the clinical approach for EMPD.