J. Mohamad

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.

SAM syndrome is characterized by extensive phenotypic heterogeneity

Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life‐threatening inherited condition caused by bi‐allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome‐causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits.

Punctate palmoplantar keratoderma: an unusual mutation causing an unusual phenotype

Palmoplantar keratodermas (PPKs, OMIM #144200) refers to a large phenotypically and genetically heterogeneous group of keratinization disorders characterized by marked hyperkeratosis on the surface of palms and soles. Punctate PPK (PPKP) features multiple hyperkeratotic papules that develop in early adolescence or later and are irregularly distributed on the palms and soles. The disease is clinically classified into three autosomal dominant subtypes: PPKP1 (OMIM #148600, 614936) characterized by multiple tiny punctate keratoses and caused by mutations in the AAGAB or COL14A1 genes; PPKP2 (OMIM #175860) which features tiny hyperkeratotic spinous papules and PPKP3 or acrokeratoelastoidosis (AKE, OMIM # 101850) which manifests with small hyperkeratotic papules located over the peripheral margins of the palms and soles and is typically associated with degeneration of elastic fibers on histology. The molecular etiology of PPKP2 and AKE remains unknown. This article is protected by copyright. All rights reserved.