M. Eskin-Schwartz

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.

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Mycophenolate Mofetil for the Management of Autoimmune Bullous Diseases

Immunosuppressive agents such as azathioprine, cyclophosphamide, and mycophenolate mofetil (MMF) are now widely used in the treatment of autoimmune bullous diseases. This article reviews the use of MMF for the treatment of several bullous conditions, and assesses the evidence gathered from clinical trials and case series. According to numerous case series, MMF could be of value in treating refractory disease. The few randomized clinical trials conducted to date of patients with pemphigus and bullous pemphigoid report a similar efficacy for MMF to other immunosuppressants.

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.

Epidermolytic Ichthyosis Sine Epidermolysis

Abstract: Epidermolytic ichthyosis (EI) is a rare disorder of cornification caused by mutations in KRT1 and KRT10, encoding two suprabasal epidermal keratins. Because of the variable clinical features and severity of the disease, histopathology is often required to correctly direct the molecular analysis. EI is characterized by hyperkeratosis and vacuolar degeneration of the upper epidermis, also known as epidermolytic hyperkeratosis, hence the name of the disease. In the current report, the authors describe members of 2 families presenting with clinical features consistent with EI. The patients were shown to carry classical mutations in KRT1 or KRT10, but did not display epidermolytic changes on histology. These observations underscore the need to remain aware of the limitations of pathological features when considering a diagnosis of EI.

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.

Somatic Mosaicism for a “Lethal” GJB2 Mutation Results in a Patterned Form of Spiny Hyperkeratosis without Eccrine Involvement

Spiny hyperkeratosis refers to a rare clinical phenotype characterized by nonfollicular keratotic projections and sometimes associated with other acquired and inherited conditions. We describe a case of congenital patterned spiny hyperkeratosis.