RESUMO
BACKGROUND: Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997. METHODS: To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019. RESULTS: Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections. CONCLUSION: These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.