M. Pavlovsky

A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant adermatoglyphia.

Monogenic disorders offer unique opportunities for researchers to shed light upon fundamental physiological processes in humans. We investigated a large family affected with autosomal-dominant adermatoglyphia (absence of fingerprints) also known as the immigration delay disease. Using linkage and haplotype analyses, we mapped the disease phenotype to 4q22. One of the genes located in this interval is SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. We demonstrated the existence of a short isoform of SMARCAD1 exclusively expressed in the skin. Sequencing of all SMARCAD1 coding and noncoding exons revealed a heterozygous transversion predicted to disrupt a conserved donor splice site adjacent to the 3 end of a noncoding exon uniquely present in the skin-specific short isoform of the gene. This mutation segregated with the disease phenotype throughout the entire family. Using a minigene system, we found that this mutation causes aberrant splicing, resulting in decreased stability of the short RNA isoform as predicted by computational analysis and shown by RT-PCR. Taken together, the present findings implicate a skin-specific isoform of SMARCAD1 in the regulation of dermatoglyph development.

A phenotype combining hidradenitis suppurativa with Dowling‐Degos disease caused by a founder mutation in PSENEN

Dowling–Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ‐secretase subunit protein presenilin enhancer.

NB-UVB phototherapy for generalized granuloma annulare.

Granuloma annulare (GA) is a benign, usually self‐limited, granulomatous skin disease of unknown etiology. The generalized form of the disease shows a more chronic, relapsing course, rare spontaneous resolution, and poorer response to therapy. Psoralen plus UVA phototherapy has been reported to be effective for GA. However, little is known regarding the efficacy of narrowband UVB phototherapy. Our goal was to determine the efficacy of NB‐UVB phototherapy in generalized GA. We carried out a retrospective study of patients with generalized GA treated with NB‐UVB phototherapy over a period of 3 years. On completion of treatment, outcome was assessed as complete response (complete clearance of the lesions), partial response (>50% clearance of the lesions), and poor response (<50% clinical response). Therapy was stopped if no improvement was seen after 20 treatments. Thirteen patients were included in the study. 54% of patients treated with NB‐UVB had a complete/partial response by the end of the treatment period. NB‐UVB phototherapy was well‐tolerated, with no serious adverse effects. NB‐UVB phototherapy is effective in a substantial portion of patients with generalized GA. To determine the true efficacy of this therapeutic modality, a prospective study comparing it to PUVA is warranted.

Molecular evidence for the role of X-chromosome inactivation in linear presentation of X-linked hypohidrotic ectodermal dysplasia

stratum corneum, thereby impairing skin barrier function. In this series, we did not attempt to re-culture Pseudomonas from the healed skin. However, it is unlikely that the bacteria would be present because of the restored skinbarrier function. In conclusion, defective skin-barrier function and superinfection with Pseudomonas may cause a distinct dermatitis, not previously described. Eczema and use of topical antiseptic therapy are predisposing factors.

Filaggrin 2 deficiency results in abnormal cell-cell adhesion in the cornified cell layers and causes peeling skin syndrome type A

Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.

Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patients skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using exxa0vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

Gender Dermatology: Pigmentation Disorders

The fact that men and women are genetically different goes without saying. How does this factor affect various aspects of skin pigmentation is an extensive area of study.

Novel POFUT1 mutation associated with hidradenitis suppurativa-Dowling-Degos disease firm up a role for Notch signalling in the pathogenesis of this disorder: reply from the authors

O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet 2013; 92:895–903. 3 McMillan BJ, Zimmerman B, Egan ED et al. Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations. Glycobiology 2017. https://doi.org/10.1093/glycob/cwx020 4 Li CR, Brooks YS, Jia WX et al. Pathogenicity of POFUT1 mutations in two Chinese families with Dowling-Degos disease. J Eur Acad Dermatol Venereol 2016; 30:79–81.

Diffuse scalp alopecia in a middle‐aged patient

A 48-year-old woman initially presented with a 2-year history of progressive scalp alopecia associated with arthralgia and tenosynovitis, mainly in the joints of the hands, which had begun 3 years before that presentation. The patient had hypercholesterolaemia, but was otherwise healthy, and there was no family history of alopecia. The results of laboratory investigations carried out at the time were normal, apart from a mild elevation in her lactate dehydrogenase levels and liver-function tests. The persistent tenosynovitis was successfully treated with low-dose prednisolone and hydroxychloroquine. A few months later, the patient returned to our department, presenting with exerciseinduced and paroxysmal nocturnal dyspnoea, recurrent diarrhoea, and progressive worsening of the alopecia. On physical examination, diffuse alopecia was seen, without evidence of scarring. The scalp was diffusely thickened (Fig. 1), while the eyebrows, eyelashes, axillary, genital and body hair appeared normal. Skin biopsies were taken from the scalp.