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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.

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Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood.

Extramammary Paget’s disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase–AKT–mTOR signaling. ABCC11, which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves FOXA1 mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.

DEAR EDITOR, Mutations in LIPH are one cause of autosomal recessive woolly hair/hypotrichosis (ARWH). 1 LIPH mutations are not uncommon and are found all over the world. In this report, we present four patients with ARWH with LIPH muta-

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