Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma

Punctate palmoplantar keratoderma type 1 (PPPK1) is a rare autosomal dominant inherited skin disease, characterized by multiple hyperkeratotic lesions on the palms and soles. The causative gene for PPPK1 has been identified as AAGAB, which encodes α‐ and γ‐adaptin‐binding protein p34. We describe the clinical features in three unrelated families with PPPK1, and report three recurrent causative mutations in AAGAB.     

Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma

Focal palmoplantar keratoderma (PPK) with severe pain is a hallmark of pachyonychia congenita, a rare autosomal dominant disorder involving PPK and hypertrophic nail dystrophy. Some families present focal PPK with either minimal or no nail changes. Dominant‐negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16 or KRT17, lead to pachyonychia congenita. However, the majority of families with focal PPK showing minimal or no nail changes do not harbor mutations in these genes. Recently, mutations of KRT6C were identified in families with focal PPK alone. Here, we report a 26‐year‐old Japanese man with focal plantar hyperkeratosis that developed at approximately 10 years of age with no palmar involvement and no nail alterations. We identified a missense KRT6C mutation c.1414G>A resulting in an p.Glu472Lys substitution, as reported in other Japanese patients. When the mutant keratin 6c protein is exogenously expressed in human HaCaT cells, a collapse of the keratin filament network is observed in a dose‐dependent manner, suggesting the mutation has a dominant‐negative effect on keratin filament network formation. The mutated residue is located at the helix termination motif of keratin 6c. The peptide sequence around this residue is highly conserved among type II, III and IV intermediate filament proteins. Glu to Lys mutations of the equivalent residue have been reported in a variety of inherited diseases, including neurodegenerative diseases, corneal dystrophy and skin disorders, suggesting that this residue is vital to keratin function.     

Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis

Generalized pustular psoriasis is a distinct type of psoriasis characterized by recurrent febrile attacks with disseminated subcorneal pustules on generalized skin rashes. Recently, homozygous and compound heterozygous mutations of the IL36RN gene, which encodes the anti‐inflammatory cytokine interleukin (IL)‐36 receptor antagonist, were identified in familial and sporadic cases of various ethnicities with generalized pustular psoriasis. Here we report a 39‐year‐old Japanese male patient who had suffered from repeated attacks of generalized pustular psoriasis since infancy with intervals of several years. At presentation, erythematous lesions with a few pustules were found only on some parts of the body and controlled with topical corticosteroids. An analysis of the IL36RN gene revealed compound heterozygous mutations of c.28C>T and c.368C>T. While the former mutation causing the premature termination p.Arg10X is recurrent in Japanese cases, the latter missense mutation causing p.Thr123Met substitution is novel, but another mutation in the same position has been reported in one Japanese case. Our report further supports the presence of the Japanese‐specific hot spots in the IL36RN gene, 28C and 368C, and suggests the functional significance of Thr123. This special type of generalized pustular psoriasis caused by IL36RN mutations has been designated as deficiency for IL‐36 receptor antagonist, a new hereditary autoinflammatory disease, and its phenotypes have emerged to include other related pustular disorders, palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis. The genetic analysis of the cases with these diseases would be important for establishment and application of the specific treatments targeting the IL‐36 signaling.     

Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid

Palmoplantar keratodermas (PPK) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK (PPPK), one of the subtypes of hereditary PPK, is a rare punctate keratoderma characterized by tiny “raindrop” keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I (PPKP1), also called Buschke–Fisher–Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose‐related adverse effects are common. Therefore, combination of low‐dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK. Herein, we report a case of PPKP1 treated with combination of low‐dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low‐dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity.     

Review of 52 cases with Hailey–Hailey disease identified 25 novel mutations in Chinese Han population

Hailey–Hailey disease (HHD) is a rare autosomal dominant inherited keratosis caused by mutations in ATP2C1. The aim of our study was to identify and analyze the features of the mutations in HHD. We examined 52 Chinese Han cases which were diagnosed as HHD based on their clinical and histological findings. Genomic DNA polymerase chain reaction and direct sequencing of ATP2C1 were performed from peripheral blood samples of the patients and 100 unrelated healthy controls. Twenty‐five novel mutations and 14 recurrent mutations were identified, including 11 (28.2%) missense mutations, nine (23.1%) frame‐shift deletion mutations, eight (20.5%) nonsense mutations, seven (17.9%) splicing mutations and four (10.3%) frame‐shift insertion mutations. Together with ours, all 209 mutations showed a uniform distribution without hotspots or clusters. In addition, there is no specific genotype–phenotype correlation in HHD. Our findings update the spectrum of mutations in ATP2C1.     

CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis

Some familial cases of pityriasis rubra pilaris (PRP) have the CARD14 gene mutations that are also detected in familial psoriasis vulgaris. However, genotype–phenotype correlation in these two entities is poorly understood. Here, we report a case of PRP with a new mutation in CARD14. Genomic analysis of a 40‐year‐old female patient with sporadic PRP type V identified a heterozygous dominant c.412G>A mutation (p.Glu138Lys) in CARD14. Two types of CARD14 mutations causing Glu138 substitutions have been reported in cases of familial PRP and pustular psoriasis. All three types, including the present case, are predicted to cause similar loss of the negative charges at this site. This suggests that the difference in molecular charge and the resulting change in molecular interaction around the N‐terminal end of the coiled‐coil region of CARD14 molecule do not determine the phenotypic differences between psoriasis and PRP.     

Genetic alterations in RAS‐regulated pathway in acral lentiginous melanoma

Studies integrating clinicopathological and genetic features have revealed distinct patterns of genomic aberrations in Melanoma. Distributions of BRAF or NRAS mutations and gains of several oncogenes differ among melanoma subgroups, while 9p21 deletions are found in all melanoma subtypes. In the study, status of genes involved in cell cycle progression and apoptosis was evaluated in a panel of 17 frozen primary acral melanomas. NRAS mutations were found in 17% of the tumors. In contrast, BRAF mutations were not found. Gains of AURKA gene (20q13.3) were detected in 37.5% of samples, gains of CCND1 gene (11q13) or TERT gene (5p15.33) in 31.2% and gains of NRAS gene (1p13.2) in 25%. Alterations in 9p21 were identified in 69% of tumors. Gains of 11q13 and 20q13 were mutually exclusive, and 1p13.2 gain was associated with 5p15.33. Our findings showed that alterations in RAS‐related pathways are present in 87.5% of acral lentiginous melanomas.     

Loss of desmoglein 1 associated with palmoplantar keratoderma,dermatitis and multiple allergies

Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss‐of‐function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.     

Case report of Schöpf–Schulz–Passarge syndrome resulting from a missense mutation,p.Arg104Cys,in WNT10A

Schöpf–Schulz–Passarge syndrome (SSPS) is a rare ectodermal dysplasia characterized by cysts of the eyelids, hypodontia, hypotrichosis, palmoplantar keratosis and onychodystrophy, and it is not common in Asia according to the published work. This autosomal recessive disorder was believed to result from mutations in the WNT10A gene. We report a 54‐year‐old Taiwanese man with SSPS resulted from a homozygous mutation (p.Arg104Cys) in WNT10A. This mutation has not been reported in odonto‐onycho‐dermal dysplasia but was demonstrated to link with dental abnormalities. This report implies the significance of WNT10A gene mutation in ectodermal dysplasia and highlights the clinical features of SSPS.     

Evaluation of 308-nm monochromatic excimer light in the treatment of psoriasis vulgaris and palmoplantar psoriasis

Background: The purpose of this study is to evaluate the efficacy and safety of 308‐nm monochromatic excimer light (MEL) in the treatment of psoriasis vulgaris and palmoplantar psoriasis. Methods: Thirty‐five patients with psoriasis vulgaris and 15 patients with palmoplantar psoriasis were recruited for this study. Thirty patients with psoriasis vulgaris completed a total of 16 treatments with 308‐nm MEL twice a week, and 15 patients palmoplantar psoriasis completed 25 treatments administered once weekly. The clinical response to therapy and adverse effects were recorded. Results: Patients with psoriasis vulgaris (n=30) showed a 74.6% improvement in the mean psoriasis area and severity index score after a total of 16 MEL treatments (2 ×/week) with 36.7% of the patients (n=11) achieving clearance. Patients with palmoplantar psoriasis (n=15) showed a 52.5% improvement in the mean severity index score after a total of 25 MEL treatments (1 ×/week) with only one patient (6.7%) achieving clearance. The MEL therapy was well tolerated with a low incidence of side effects, which included pruritus, erythema and blister formation. Conclusion: The 308‐nm MEL can be utilized as an effective and safe treatment modality for patients with mild‐to‐moderate psoriasis vulgaris and palmoplantar psoriasis.     

Comparative study of the bactericidal effects of indocyanine green‐ and methyl aminolevulinate‐based photodynamic therapy on Propionibacterium acnes as a new treatment for acne

Acne vulgaris is one of the most common dermatological problems, and its therapeutic options include topical and systemic retinoids and antibiotics. However, increase in problems associated with acne treatment, such as side‐effects from conventional agents and bacterial resistance to antibiotics, has led to greater use of photodynamic therapy. The purpose of this study was to compare the bactericidal effects of indocyanine green‐ and methyl aminolevulinate‐based photodynamic therapy on Propionibacterium acnes. P. acnes were cultured under anaerobic conditions; then they were divided into three groups (control, treated with indocyanine green and treated with methyl aminolevulinate) and illuminated with different lights (630‐nm light‐emitting diode, 805‐nm diode laser and 830‐nm light‐emitting diode). The bactericidal effects were evaluated by comparing each group's colony‐forming units. The cultured P. acnes were killed with an 805‐nm diode laser and 830‐nm light‐emitting diode in the indocyanine green group. No bactericidal effects of methyl aminolevulinate‐based photodynamic therapy were identified. The clinical efficacy of indocyanine green‐based photodynamic therapy in 21 patients was retrospectively analyzed. The Korean Acne Grading System was used to evaluate treatment efficacy, which was significantly decreased after treatment. The difference in the efficacy of the 805‐nm diode laser and 830‐nm light‐emitting diode was not statistically significant. Although the methyl aminolevulinate‐based photodynamic therapy showed no bactericidal effect, the indocyanine green‐based photodynamic therapy has bactericidal effect and clinical efficacy.     

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E,NOTCH1, ERBB3, and PTEN mutations

Pigment‐synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36‐year‐old woman. Next‐generation sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy.     

Loss of FAS/FASL signalling does not reduce apoptosis in Sharpin null mice

Mice with mutations in SHANK‐associated RH domain interactor (Sharpin) develop a hypereosinophilic auto‐inflammatory disease known as chronic proliferative dermatitis. Affected mice have increased apoptosis in the keratinocytes of the skin, oesophagus and forestomach driven by extrinsic TNF receptor‐mediated apoptotic signalling pathways. FAS receptor signalling is an extrinsic apoptotic signalling mechanism frequently involved in inflammatory skin diseases. Compound mutations in Sharpin and Fas or Fasl were created to determine whether these death domain proteins influenced the cutaneous phenotype in Sharpin null mice. Both Sharpin/Fas and Sharpin/Fasl compound mutant mice developed an auto‐inflammatory phenotype similar to that seen in Sharpin null mice, indicating that initiation of apoptosis by FAS signalling is likely not involved in the pathogenesis of this disease.     

Mutation analysis of IL36RN gene in Japanese patients with palmoplantar pustulosis

Loss‐of‐function mutations of the IL36RN gene, encoding interleukin‐36 receptor antagonist (IL‐36Ra), have been reported as major pathogenic causes of generalized pustular psoriasis (GPP), especially in cases lacking previous histories of psoriasis vulgaris. Palmoplantar pustulosis (PPP), which is traditionally included among GPP‐related diseases, has a controversial association with IL36RN. While a negative view about the said association has been recently published from Europe, variations of the IL36RN gene show great ethnic differences. In this study, we performed mutation analysis of the IL36RN gene in 88 Japanese patients with PPP and identified three types of single base substitutions in four patients, namely, p.Pro82Leu in two patients, p.Asn47Ser in one and p.Thr123Met in another. All variations were heterozygous and different from previous European reports. We compared the immunohistochemical findings of IL‐36Ra on patients with and without variation of the IL36RN gene; however, no significant differences were observed. Our data and the previous European study suggest that PPP is not associated with mutations of the IL36RN gene.     

Identification of two Chinese oculocutaneous albinism type 6 patients and mutation updates of the SLC24A5 gene

Oculocutaneous albinism (OCA) is a rare and heterogeneous disorder characterized by hypopigmentation of the skin, hair and eyes. Thirty OCA type 6 (OCA6) patients with 24 mutations in SLC24A5 have been reported across various populations; however, only one patient has been identified in a Chinese population. This study identifies two novel SLC24A5 frame‐shift variants in two unrelated Chinese patients and both are predicted to be pathogenic by American College of Medical Genetics guidelines. The genotypes and phenotypes of all three Chinese OCA6 patients are unique compared with those identified in other populations. All of the mutations identified to date in Chinese OCA6 patients are predicted to be non‐functional, a finding that is useful in guiding genetic diagnosis and counseling for OCA6 in China.     

Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3

Olmsted syndrome (OS) is a rare congenital skin disorder characterized by palmoplantar keratoderma, periorificial hyperkeratotic lesions and alopecia. Constriction of digits, onychodystrophy and pruritus may also occur. Recently, pathogenic heterozygous mutations in TRPV3 were identified, with most cases showing de novo dominant inheritance. We present the clinical and molecular features of OS in a 10‐year‐old Iranian boy. He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits. TRPV3 was sequenced and a new de novo heterozygous missense mutation, c.2076G>C (p.Trp692Cys), was identified. This case illustrates the characteristic clinical features and complications that can present in OS, and further expands the molecular basis of this genodermatosis.     

Novel homozygous mutation,c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate‐ectodermal dysplasia syndrome in an Asian patient

Cleft lip/palate‐ectodermal dysplasia syndrome is a rare, autosomal recessive disorder caused by homozygous loss‐of‐function mutations of the poliovirus receptor‐like 1 (PVRL1) gene encoding nectin‐1. Nectin‐1 is a cell–cell adhesion molecule that is important for the initial step in the formation of adherens junctions and tight junctions; it is expressed in keratinocytes, neurons, and the developing face and palate. Clinical manifestations comprise a unique facial appearance with cleft lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers and/or toes, and in some cases, mental retardation. We present the first report, to our knowledge, of an Asian individual with cleft lip/palate‐ectodermal dysplasia syndrome with a novel PVRL1 mutation. A 7‐year‐old Japanese boy, the first child of a consanguineous marriage, showed hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair and hypodontia, the unique facial appearance with cleft lip/palate, cutaneous syndactyly of the fingers and mild mental retardation. Scanning electron microscopic examination of the hair demonstrated pili torti and pili trianguli et canaliculi. Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense mutation, c.400C>T (p.Arg134*). His parents were heterozygous for the mutant alleles. All four PVRL1 mutations identified in cleft lip/palate‐ectodermal dysplasia syndrome to date, including this study, resulted in truncated proteins that lack the transmembrane domain and intracellular domain of nectin‐1, which is necessary to initiate the cell–cell adhesion process.     

BRAF,KIT and NRAS mutations and expression of c‐KIT,phosphorylated extracellular signal‐regulated kinase and phosphorylated AKT in Japanese melanoma patients

To clarify the status of gene mutation and activation of growth signal in melanoma of Japanese patients in vivo, we analyzed the mutation of BRAF exon 15, NRAS exon 2, and KIT exons 9, 11, 13, 17 and 18 in melanoma cells obtained by laser capture microdissection, and performed direct sequencing in 20 cases of acral lentiginous melanoma (ALM) and 17 cases of superficial spreading melanoma (SSM). In the study of the mutation of BRAF, pyrosequencing was also done. To examine the cell proliferation signaling, immunohistochemistry for phosphorylated extracellular signal‐regulated kinase (pERK), phosphorylated AKT (phosphorylated AKT) and c‐KIT was done. The mutation of BRAF p.V600E was detected in 13 cases of ALM (65.0%) and 12 cases of SSM (70.6%). No NRAS mutation was found in all cases. The mutation in exons 9, 11, and 18 of KIT was detected in nine cases. The mutation of BRAF and KIT showed no correlation with clinical stage, lymph node metastasis, tumor thickness, ulceration and histology. pERK and pAKT was observed in small population of melanoma cells and there was no correlation with gene mutation. Our results indicate that the mutations of BRAF and KIT exist in Japanese melanoma patients, however, the cell growth signaling may be regulated by not only these mutated genes, but by other unknown regulatory factors, which may affect the prognosis of melanoma.     

NEMO gene rearrangement (exon 4–10 deletion) and genotype–phenotype relationship in Japanese patients with incontinentia pigmenti and review of published work in Japanese patients

Incontinentia pigmenti (IP) is a rare X‐linked dominant genodermatosis caused by mutations of the NEMO gene, which is required for activation of the nuclear factor‐κB signaling pathway. NEMO gene rearrangement, exon 4–10 deletion, is the most common mutation with a frequency of 60–80%. Only four case reports about NEMO rearrangement in Japanese IP cases have been published. In our study, NEMO gene rearrangement was examined in 10 Japanese IP patients and their mothers and was revealed in five of 10 patients and three of their mothers. Interestingly, NEMO gene rearrangement was confirmed in the mothers of two patients without clinical symptoms; thus, NEMO mutation analysis is helpful to detect subclinical IP patients. The clinical symptoms of recently diagnosed Japanese IP patients were summarized for examination of the phenotype–genotype relationship and for comparison between those with and without NEMO gene rearrangement. Results revealed no definite difference in extracutaneous manifestations between the patients with NEMO rearrangement in our study and in other Japanese IP patients previously reported in both Japanese and English‐language published work. However, there is higher frequency of ocular manifestation in our study than in other reports. Furthermore, evaluation of dental and nail abnormalities was difficult because most of our patients were observed for 1 year only. Long‐term observation is needed for proper evaluation of the clinical status and phenotype–genotype relationship in IP patients.