Masae Takeda

Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima‐type palmoplantar keratosis

Nagashima‐type palmoplantar keratosis (NPPK) is a distinct autosomal recessive genodermatosis characterized by diffuse transgressive palmoplantar keratoderma (PPK). Very recently, putative loss‐of‐function mutations in SERPINB7, which encodes a member of the serine protease inhibitor superfamily and is abundantly expressed in the epidermis, have been identified as a cause of NPPK.

A novel NCSTN mutation alone may be insufficient for the development of familial hidradenitis suppurativa.

Familial hidradenitis suppurativa (familial HS; OMIM #142690) an autosomal dominant chronic inflammatory follicular occlue disease. The clinical features include comedones, recurrent aining sinuses, painful nodules, skin abscesses, dermal contracinvasive squamous cell carcinoma, based on the pathological findings. Genomic DNA of two affected and four unaffected members of the family with HS were obtained from peripheral blood or saliva using QIAamp DNA Blood Maxi Kit (Qiagen, Germantown, MD) or Oragene DNA Self-Collection Kit (DNA Genotek, Kanata, ON), respectively (Fig. 1C). The participants or their legal guardians gave written informed consent for mutation analysis in compliance w ap Un en Pr (N ph po 31 de p. id br Fi NC w et w (d w m en 16 pr res and disfiguring scars, mainly on the scalp, neck, axilla, groin d/or perianal and perineal regions. Familial cases showing tosomal dominant inheritance have been reported in one third HS patients. Recent studies have demonstrated that mutations the genes encoding g-secretase underlie some familial cases ith HS with complete penetrance, while significant interdividual variability of the disease severity was reported [1]. re we describe the first family with HS in which a g-secretase ne mutation does not completely segregate with the disease. A 62-year-old Japanese man presented with the chief complaint 7-cm-diameter ulcerative reddish-colored skin tumor on e anterior neck (Fig. 1A). Physical examination also revealed idespread sinuses, comedones, pustules, inflamed cysts, skin scesses, disfiguring scars and post-inflammatory hyperpigmention on the face, neck, trunk and buttocks (Fig. 1A and B), where had had recurrent episodes of bacterial skin infection since the e of 15. The patient has no significant past medical history cluding diabetes mellitus. He has a positive family history, as his der brother (II-1) and his son (III-1) had similar infectious skin sions on the neck and back (Fig. 1C). A diagnosis of familial HS as made, as the patient and two other individuals in his family lfilled the diagnostic criteria of HS [2], the other individuals in e family did not meet the criteria (Fig. 1C). The skin tumor on the ck was completely excised and subsequently diagnosed as

A severe case of X-linked ichthyosis showing palmar hyperlinearity without FLG mutations.

Editor A 57-year-old Japanese man was referred to us with generalised dry skin and dark brown, adherent scales on the trunk and extremities (Fig. 1a). Plate-like scales were also noted on the shins (Fig. 1b). His cutaneous manifestations had been present since soon after birth. He had a past medical history of squamous cell carcinoma of the gingiva, but was otherwise healthy. His unrelated parents and four sisters were all unaffected. Moreover, none of the male members in the maternal family were affected. A skin biopsy showed compact hyperkeratosis and basal melanosis without parakeratosis and/or acanthosis. Stratum granulosum was neither thickened nor diminished. From these findings, he was suspected of having X-linked ichthyosis (XLI). After obtaining approval for genetic study from the institutional review board and written informed consent from the patient, we performed fluorescence in situ hybridization using his white blood cells, which detected a genomic deletion at the STS locus on Xp22.3 (data not shown); this confirmed the diagnosis of XLI. Notably, he also manifested palmar and plantar hyperlinearity, with the former much more pronounced (Fig. 1c). Taken together with his severe skin conditions for XLI, this led us to suspect an additional mutation in the gene encoding filaggrin (FLG). We performed mutation analysis of the entire coding regions of FLG using the genomic DNA extracted from his peripheral blood as described previously; however, it identified no loss-of-function mutations. Our patient showed severe skin phenotypes for XLI. Liao et al. reported an association between FLG mutations and exacerbation of XLI phenotypes. In their study, two affected brothers showed different phenotypic severity, despite having a same STS genomic deletion. Notably, the more severely affected brother was found to be a heterozygous carrier of the nonsense mutation p.Arg501Ter in FLG, whereas the other was wild-type for the mutation. These findings, together with the fact that about 10% of the Japanese and British populations have loss-offunction mutations in FLG, indicate that FLG mutations can modify or exacerbate phenotypes of genodermatoses including XLI. However, our patient with XLI presented severe phenotypes without FLG mutations. Interestingly, Gruber et al. reported an XLI family in which two affected brothers carrying pathogenic mutations both in STS and FLG presented strikingly variable phenotypic severity, which indicates that hitherto unrecognised genes might contribute to phenotypic severity in XLI. This study provides further evidence for genetic and/or environmental modifiers exacerbating XLI other than FLG mutations. Palmar hyperlinearity is widely accepted as a useful clinical finding for the differential diagnosis of XLI and ichthyosis vulgaris (IV) because it has been reported to be specific to IV and/ or atopic dermatitis (AD). Nevertheless, our XLI patient showed palmar hyperlinearity without FLG mutations. CuevasCovarrubias et al. also reported a case of XLI presenting with palmar hyperlinearity with clinical signs of neither IV nor AD, although mutation analysis of FLG was not performed in their patient. These findings suggest that patients with XLI might exhibit palmar hyperlinearity even without FLG mutationrelated disorders, although a larger case study is warranted to validate this hypothesis.

Genetic analysis of a novel splice‐site mutation in TMC8 reveals the in vivo importance of the transmembrane channel‐like domain of TMC8

DEAR EDITOR, Epidermodysplasia verruciformis (EV, MIM 226400) is a rare autosomal recessive genodermatosis characterized by abnormal susceptibility to b-human papillomaviruses (b-HPVs). However, patients with EV are not vulnerable to other pathogens. Loss-of-function mutations in TMC6 and TMC8 have been identified as causes of EV. Seven mutations have been reported in each of TMC6 and TMC8. The transmembrane channel-like (TMC) family of proteins comprises eight members in mammals (TMC1–8), all of which possess a functionally important, conserved 120-aminoacid domain, known as the TMC domain. For TMC8, amino acids 418–537 correspond to this domain. Earlier in vitro studies demonstrated that the TMC domain of TMC8 binds to at least two proteins: zinc transporter-1 (ZnT-1) and tumour necrosis factor (TNF) receptor type 1-associated death domain protein (TRADD). The TMC8–ZnT-1 complex regulates intracellular distribution of free zinc and inhibits free zinc influx to nucleoli in keratinocytes, which eventually downregulates transcription factors including activator protein-1 (AP-1), a protein that plays a key role in the life cycle of HPVs. Moreover, the TMC8–TRADD complex promotes TNF-a-induced

Low-dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work

Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss‐of‐function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis‐based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame‐shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low‐dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1.

Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis

TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22‐year‐old Japanese man presented with large, dark brown, plate‐like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype–phenotype correlations and pathogenesis in lamellar ichthyosis.

Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes

Heterozygous chromosomal inversions suppress recombination. Therefore, they may potentially influence recombination-associated phenotypes of human diseases, but no studies have verified this hypothesis. Here, we describe a 35-year-old man with severe congenital ichthyosis. Mutation analysis revealed a heterozygous splice-site mutation, c.1374-2A>G (p.Ser458Argfs*120), in KRT10 on 17q21.2. This mutation was previously reported in patients with ichthyosis with confetti type I (IWC-I), a prominent skin disease characterized by the frequent occurrence of recombination-induced reversion of pathogenic mutations. Intriguingly, the number of revertant skin areas in this patient is considerably reduced compared with typical IWC-I cases. G-banded karyotyping revealed that the patient harbors a heterozygous nonpathogenic inversion, inv(17)(p13q12), whose long-arm breakpoint was subsequently refined to chromosomal positions (chr17: 36,544,407-36,639,830) via FISH. Collectively, the only chance of revertant mosaicism through somatic recombination appears to involve recombination between the KRT10 mutation and the inversion breakpoint. Indeed, in the examined revertant spot, the KRT10 mutation was diminished by somatic recombination starting from chromosomal positions (chr17: 36,915,505-37,060,285) on 17q12. This study provides the first evidence to our knowledge implicating chromosomal inversions as a potential modifier of clinical phenotypes. Furthermore, the reduced occurrence of revertant spots in the recombination-suppressed patient suggests that somatic recombination is the main mechanism of revertant mosaicism in IWC-I.

Association of filaggrin gene mutations and childhood eczema and wheeze with phthalates and phosphorus flame retardants in house dust: The Hokkaido study on Environment and Children's Health

BACKGROUND AND AIM Exposure to phthalates and phosphorus flame retardants (PFRs) is considered to be a risk factor for asthma and allergies. However, little is known about the contribution of loss-of-function mutations in the gene encoding filaggrin (FLG) gene, which are considered to be predisposing factors for eczema and asthma, to these associations. We investigated the associations between exposure to phthalates and PFRs in dust and eczema/wheeze among Japanese children, taking into consideration loss-of-function mutations in FLG. METHODS This study was part of the Hokkaido study on Environment and Childrens Health. Seven phthalates and 11 PFRs in household dust were measured by gas chromatography-mass spectrometry. Eczema and wheeze were assessed in children aged 7 years using the International Study of Asthma and Allergies in Childhood questionnaire. Eight FLG mutations previously identified in the Japanese population were extracted from cord blood samples. Children with one or more FLG mutations were considered to be positive for FLG mutations. The study included 296 children who had complete data (birth records, FLG mutations, first trimester and 7 years questionnaires, and phthalate/PFR levels). Odds ratios (ORs) and 95% confidential intervals (CIs) of eczema and wheeze were calculated for log-transformed phthalate/PFR levels by logistic regression. We also performed stratified analyses based on FLG mutations. RESULTS The prevalence rates of eczema and wheeze were 20.6% and 13.9%, respectively. Among children without any FLG mutations, tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP) increased the OR of wheeze, (OR: 1.22, CI: 1.00-1.48). Significant p values for trends were found between tris (2-butoxyethyl) phosphate (TBOEP) and eczema and di-iso-nonyl phthalate (DiNP) and eczema among children without any FLG mutations, respectively. CONCLUSIONS Despite our limited sample size and cross-sectional study design, the effects of indoor environmental factors on childhood eczema and wheeze were clearer in children without loss-of-function mutations in FLG than in children with mutations. Children with FLG mutations might already be cared for differently in terms of medication or parental lifestyle. Further studies in larger populations are warranted so that severity of symptoms and combinations of FLG mutations can be investigated.