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The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders. [ABSTRACT FROM AUTHOR]

Hereditary palmoplantar keratodermas (PPK) comprise a clinically and genetically heterogeneous group of genodermatoses, which share the characteristic of impaired epidermal differentiation, resulting in prominent palmoplantar hyperkeratosis. Molecular genetic analyses have helped characterize the underlying genetic defects in an increasing number of hereditary PPKs over the past two decades, and thus a pathophysiological classificaiton seems more reasonable. Today PPK can be classified based on defects in keratins, loricrin, desmosomes, connexins and cathepsins. In this report, we describe a 22-year-old man who had been born a collodion baby, and later developed diffuse PPK with pseudoainhum and generalized ichthyosis. His mother and grandmother had similar characteristics. Direct sequencing of genomic DNA identified a frameshift insertion mutation (730insG) in the loricrin gene. This family had the typical presentation of loricrin keratoderma. It also indicates that collodion baby may be the first presentation in patients with loricrin keratoderma. [ABSTRACT FROM AUTHOR]

The trichorhinophalangeal syndromes (TRPSs) are rare hereditary diseases with mainly autosomal dominant inheritance. Three different forms sharing similar clinical features with heterogeneous mutations have been identified: type I (TRPS I), type II (TRPS II) and type III (TRPS III). These syndromes have characteristic facial abnormalities such as sparse and slow-growing scalp hair, laterally sparse eyebrows, bulbous pear-shaped nose, elongated and flat philtrum, thin upper lip, and protruding ears. Various skeletal abnormalities are also frequently noted: short stature, shortening of the phalanges and metacarpals, cone-shaped epiphyses and Perthes-like change of the hips. 1–4 The TRPS1 gene was first identified in 2000 and mapped to 8q24.1. 1 More than 50 mutations have been found in the gene to date. We here report mutation analysis of eight patients with the typical phenotype of TRPS I, revealing five novel mutations. [ABSTRACT FROM AUTHOR]

Background Mutations in the gene encoding filaggrin ( FLG) were identified to underlie ichthyosis vulgaris (IV) and also shown to predispose to atopic eczema. Until now, no FLG mutations have been described in the Taiwanese population. Objectives To elucidate filaggrin mutations in the Taiwanese population and further to clarify the population genetics of filaggrin gene mutations in the Asian populations. Methods In the present study, 12 individuals from four unrelated Taiwanese IV families were examined for FLG mutations. We carried out comprehensive sequencing of the entire FLG coding region using an overlapping polymerase chain reaction strategy. Results We identified three FLG mutations in the Taiwanese IV families. One mutation E1795X was a previously unidentified FLG mutation, which might be specific to the Taiwanese. Interestingly, another FLG mutation 3321delA is prevalent in the Japanese population and the other mutation Q2417X was found in the Singaporean Chinese population. No FLG mutation identified in the white European population was found in the Taiwanese population. Conclusions The present findings suggest that the Taiwanese population, as an East Asian group, share FLG mutations with both the Japanese and the Singaporean Chinese population. In addition, these results exemplify differences in the population genetics of filaggrin between Europe and Asia. [ABSTRACT FROM AUTHOR]

Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease characterized by numerous skin-coloured papules on the central face. Mutations in the CYLD gene, which is also the gene responsible for familial cylindromatosis, have been reported recently. Recent studies indicate that CYLD is a tumour-suppressor gene. The CYLD protein is a negative regulator of the activation of transcription factor nuclear factor-κB, and loss of CYLD contributes to oncogenesis. We report a novel splicing mutation (IVS12 + 1 G→A) in the CYLD gene in a Taiwanese pedigree with MFT, and discuss new developments in treatment options. [ABSTRACT FROM AUTHOR]

Infantile systemic hyalinosis (ISH) is a very rare infantile stiff-skin syndrome characterized by extensive deposits of hyaline material in various organs, especially the skin and gingiva. Recent studies identified pathogenic mutations in the capillary morphogenesis gene 2 (CMG2) in both ISH and juvenile hyaline fibromatosis (JHF). Capillary morphogenesis protein-2 is an integrin-like cell surface receptor for laminins and type IV collagen, and may play a key role in cell–matrix or cell–cell interactions. We report a case of ISH in a 13-month-old Taiwanese girl who manifested progressive joint contractures, recurrent chest infections, chronic diarrhoea with severe hypoalbuminemia and ascites, gum hypertrophy, and violaceous papules and nodules over the occipital area, neck, lumbosacral and anogenital areas since birth. Skin biopsy revealed a thickened and hyalinized papillary dermis. Electron microscopy showed abundant extracellular fibrillogranular material and active fibroblasts with conspicuous Golgi complex filled with fibrillar material. Mutation analysis identified a homozygous 1073–1074insC mutation ofCMG2which had been reported in four other families and may represent a mutation hot spot. [ABSTRACT FROM AUTHOR]

Summary Background Darier's disease (DD) is an autosomal dominant skin disorder characterized by abnormal keratinization and acantholysis. Pathogenic mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the sarco/endoplasmic reticulum, have recently been identified. Objectives To identify mutations of the ATP2A2 gene in Taiwanese patients with DD. Methods Mutation analysis of genomic DNA was performed on five families with DD and two sporadic cases. All 21 exons and the flanking intron boundaries were amplified and followed by direct sequencing. Restriction fragment analysis or direct sequencing in each family and in normal controls further verified the mutations. Results Mutations in the functional domains of the ATP2A2 gene were identified and verified in all seven pedigrees. They consisted of four mis-sense mutations (R131Q, P680L, G703S, G807R), one altered splice-site mutation (2980 + 5insA) and one frameshift deletion mutation (1457–1458delAG). Of these, R131Q, which was reported twice previously, was detected in two unrelated families. The remaining five were novel mutations. Conclusions Six pathogenic mutations in the ATP2A2 gene were identified in seven Taiwanese DD pedigrees. The results confirmed that most mutations in the ATP2A2 gene are private and of the mis-sense type. [ABSTRACT FROM AUTHOR]

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant inherited disorder of keratinization. Recent molecular studies have shown that EPPK is caused by mutations in keratin 9 gene (KRT9). We report a Taiwanese family with EPPK with a novel mutation with an A → C transition at the first nucleotide of codon 160 in KR T9. The mutation is predicted to result in an asparagine to histidine substitution (N160H) at the beginning of the α-helical 1 A domain of keratin 9. Mutations in this region could disrupt keratin filament assembly, leading to degeneration or cytolysis of keratinocytes. Our mutation analysis confirms that codon 160 in KRT9 is one of the mutation hot spots in EPPK. [ABSTRACT FROM AUTHOR]

The article presents a study on a missense mutation of a gap junction protein beta 2 (GJB2) gene in a Taiwanese family with knuckle pads, sensorineural hearing loss (SNHL), and palmoplantar keratoderma (PPK). It says that a genetic study on the family was performed, in which peripheral blood samples were collected and genomic DNA were extracted. Furthermore, it mentions that a mutation analysis upheld the participation of the missense mutation in the syndromic form of hearing loss.