A novel heterozygous nonsense mutation of keratin 5 in a chinese family with Dowling–Degos disease

Background Dowling–Degos disease (DDD; MIM 179850) is an autosomal dominant genodermatosis caused by mutations in keratin 5 gene (KRT5). KRT5 is specifically expressed in basal layer of epidermis and plays an important role in protecting epithelial cells from mechanical and non‐mechanical stresses. Objective We analysed the molecular basis of DDD in a Chinese family. Methods Genomic DNA of the Chinese DDD family and a matched control cohort was isolated according to standard techniques. All exons of the KRT5 gene and adjacent exon–intron border sequences were amplified using PCR and directly sequenced. Results We identified a novel keratin 5 (K5) nonsense mutation designated c.C10T (p.Gln4X) in exon 1 of the KRT5 gene. Conclusion Our data expand the spectrum of mutations in the KRT5 gene underlying DDD.     

Dowling–Degos disease co‐presenting with Darier disease

We present a case of a patient with long‐standing hyperpigmented macules and erythematous papules over his chest, abdomen, back and arms, suggestive of Dowling‐Degos disease (DDD). In addition, there were hyperkeratotic papules, alternating red and white nail‐bed discolouration, and V‐shaped nail notching consistent with Darier disease (DD). Histology showed findings consistent with DDD and DD on separate specimens. The lack of acantholysis in areas of filiform hyperpigmented rete ridges ruled out Galli–Galli disease (GGD). DDD results from mutations in the genes encoding keratin 5 (KRT5), protein O‐glucosyltransferase 1 (POGLUT1) or protein O‐fucosyltransferase 1 (POFUT1), while DD results from mutations in the ATP2A2 gene. Both genes are present on chromosome 12. In this case, the patient presented with features of both DDD and DD, which suggests that either a cooperating mutation or a mutation in an unrelated gene locus may underlie the findings in this patient.     

Systematic mutation screening of KRT5 supports the hypothesis that Galli–Galli disease is a variant of Dowling–Degos disease

Background Galli–Galli disease (GGD) is a rare genodermatosis. Its clinical presentation is identical to that of Dowling–Degos disease (DDD), but the presence of the histopathological feature of acantholysis in GGD is thought to distinguish the two disorders. Mutations in the keratin 5 gene (KRT5) have been identified in the majority of patients with DDD and in a small number of patients with GGD. Objectives To provide further support for the hypothesis that GGD is merely a variant of DDD, and to examine whether acantholysis is genuinely rare in DDD or rather a common but under‐reported histological feature of DDD. Methods We conducted the first systematic mutational investigation of patients with GGD and re‐examined the histopathology of patients previously assigned a diagnosis of DDD. For the mutational investigation, KRT5 was sequenced in seven unrelated patients with clinically and histopathologically confirmed GGD. In addition, the histopathological findings of six patients with DDD were re‐evaluated. Results The mutation c.418dupA was found in five patients with GGD. The typical histopathological features of GGD were identified in six patients who had previously been assigned a diagnosis of DDD. Conclusions We found further evidence to suggest that GGD is indeed a variant of DDD and not a distinct disease entity. Two facts in particular support this conclusion: the same KRT5 mutation was found in patients with GGD and in patients with DDD, and acantholysis seems to be present in a large number of patients who had previously been assigned a diagnosis of DDD.     

Haploinsufficiency caused by a nonsense mutation in NCSTN underlying hidradenitis suppurativa in a Chinese family

Hidradenitis suppurativa (HS) is a chronic disease of follicular occlusion. It involves the axilla, groin, perianal and perineal regions, and is characterized by recurrent draining sinuses, skin abscesses and disfiguring scars. Loss‐of‐function mutations in the genes encoding γ‐secretase have been identified as a cause of HS. We collected skin samples from three patients with HS from a Chinese family carrying a NCSTN mutation (c.1258C>T (p.Q420X)) and three unrelated healthy controls (HCs). Expression level of nicastrin in skin tissue and cultured keratinocytes and fibroblasts of patients and HCs was determined by real‐time quantitative PCR and western blotting. We found that the mRNA and protein levels of nicastrin were significantly reduced in the whole skin, epidermis, dermis, and cultured keratinocytes and fibroblasts compared with HCs. Therefore, we conclude that haploinsufficiency of the NCSTN gene caused by the nonsense mutation c.1258C>T (p.Q420X) contributes to the occurrence of HS in this family.     

A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa

Background Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease with characteristic recurrent draining sinuses, skin abscesses and disfiguring scars, mainly involving the axilla, groin, perianal and perineal regions. While most HS cases are nonfamilial, familial cases showing autosomal dominant inheritance have been reported. Recently, loss‐of‐function mutations in the genes encoding γ‐secretase have been identified as a cause of familial HS in the Chinese and British populations. Objectives To identify mutations in the genes encoding γ‐secretase in Japanese patients with familial and nonfamilial HS. Methods Two affected and three unaffected individuals from a Japanese family with familial HS and nine patients with nonfamilial HS were recruited. We conducted mutation analysis of the γ‐secretase genes in Japanese patients with familial and nonfamilial HS. Results A novel splice site mutation in the nicastrin gene NCSTN, one of the six key component genes encoding γ‐secretase, was identified in the patients with familial HS. Neither unaffected individuals in the family nor 100 ethnically matched control alleles carry this mutation. None of the nine patients with nonfamilial HS carry nonsense, frameshift or splice site mutations in this gene. Conclusions A novel splice site mutation, c.582+1delG, in NCSTN was identified in the familial patients with HS. We also reveal for the first time that a γ‐secretase gene mutation is not linked to the development of nonfamilial HS. These results would further pave the way to a better understanding of the contribution of γ‐secretase and other genes to the pathogenesis of HS and to the development of a new therapeutic strategy for HS.     

Thyroid autoimmunity in patients with hidradenitis suppurativa: a case–control study

The aetiopathogenesis of hidradenitis suppurativa (HS) is not fully understood; however, increasing evidence suggests that it may be an immune‐mediated disorder. Autoimmune thyroid disease (AITD) has classically been considered as the ‘paradigm’ of autoimmunity, and it has been linked to a variety of skin disorders. To our knowledge, the prevalence of AITD has not been investigated in patients with HS. The aim of the present study was to assess and compare, for the first time, the prevalence of thyroid autoimmunity in 70 patients with HS and in 70 age‐ and sex‐matched controls. In all participants, thyroid autoantibodies and thyroid function tests were analysed. No statistically significant difference was detected between patients with HS and controls, either for the prevalence of thyroid antibodies or for thyroid function parameters. This lack of an association between HS and thyroid autoimmunity suggests that conventional autoimmune mechanisms may not be implicated in the pathogenesis of HS.