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Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis
Author(s) -
Doolan Brent J.,
Gomaa Nesrin S.,
Fawzy Mohamed M.,
Dogheim Noha N.,
Liu Lu,
Mellerio Jemima E.,
Onoufriadis Alexandros,
McGrath John A.
Publication year - 2020
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.14096
Subject(s) - genodermatosis , hypotrichosis , frameshift mutation , palmoplantar keratoderma , ectodermal dysplasia , dermatology , desmosome , medicine , genetics , desmoplakin , mutation , biology , hyperkeratosis , gene , cell
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.