Ectodermal dysplasia-skin fragility syndrome – identification of a novel plakophilin1 (PKP1) gene variant through whole exome sequencing

Discussion

Desmosomes are junctions essential for preserving tissue integrity by tethering adjoining cells and anchoring the cell membrane to the keratin intermediate filament cytoskeleton internally. These are intercellular junctional complexes primarily found in epithelial tissues but also in meninges, lymph node follicles, and myocardium.¹ The main structural constituents of desmosomes are a) the cadherins – desmogleins and desmocollins; b) the plakins – desmoplakin, periplakin, and envoplakin; and c) the armadillo family of proteins – plakoglobin, plakophilins (PKP1 and 2). These interact with one another near the plasma membrane and with keratin intermediate filaments in the cytoplasm. Ectodermal dysplasia-skin fragility syndrome, first described by McGrath et al.² is a rare autosomal recessive genodermatosis characterised by cutaneous erosions/blisters, palmoplantar keratoderma, hair abnormalities/alopecia, characteristic lip scaling with fissures and nail dystrophy resulting from loss of function mutations in the Plakophilin 1 (PKP1) gene.²

An ectodermal dysplasia-skin fragility syndrome patient born out of consanguineous marriage and possessing a homozygous variant in the PKP1 gene causing a substitution of leucine with proline at codon 1061 is described here. In the literature review of all reported cases [ Table 1], homozygosity was present in 87% and parental consanguinity was present in 66% of cases, including the present case. Twenty three cases have been reported with confirmed bi-allelic mutations in the PKP1 gene, ours being the latest. Structurally, PKP1 is located close to the plasma membrane in the desmosomal plaque, binding and interacting primarily with desmoplakin (via the amino-terminal domain).^2,3

Desmosomal PKP1 distribution is concentrated in the suprabasal layers of stratified and complex epithelia such as skin, outer root sheath cells of hair follicles, etc. ⁴ PKP1 is a multifunctional protein promoting desmosomal stability. ⁵ In previously reported studies, skin fragility, and nail involvement were present in all 23 cases, as in our case. Perioral and lip erythema, scaling and fissures were reported in 18/23 cases, palmoplantar keratoderma in 21/23 cases and alopecia/hypotrichosis/woolly hair in 22/23 cases. Additionally, hypohidrosis was reported in 6/23 cases and pruritus, dental anomalies, recurrent cutaneous infections, pneumonia, delayed milestones, and low height and weight centiles were present in a few cases. ³ We observed that ectodermal dysplasia-skin fragility syndrome occurred in all ethnic populations [ Table 1 ]. Mutations in the head domain (5’N-terminal) resulted in absent or markedly decreased PKP1 with an early onset of symptoms that were severe in nature, especially skin fragility (average age 2.9 years). Further down mutations towards the C-terminal/3’end resulted in reduced PKP1 and milder symptoms with later onset) (average age 28.2 years). Mutations in the armadillo repeat units 1, 2, and 3 were associated with woolly/curly/wiry hair, including our case.

Perioral and lip scaling and fissuring is a persistent and prominent distinguishing feature that should prompt the clinician to consider ectoderma dysplasis-skin fragility syndrome. Hair pathology varied from total alopecia to sparse and woolly hair, which is due to abnormal or absent PKP1 in the suprabasal cells of the outer root sheath of hair follicles. The hair in our patient was normal at birth but subsequently became woolly and was strikingly easily pluckable, which was not reported in any other case. Similar trichogram and scanning electron microscopy hair findings were reported in 2020 by Sun et al.⁶

Conclusion

PKP1 mutations, though rare, constitute an important disorder of desmosomes with core clinical features of skin fragility, lip, and perioral scaling, nail abnormalities, palmoplantar keratoderma and alopecia/hypotrichosis/woolly hair. We herewith report a case of ectodermal dysplasia-skin fragility/McGrath syndrome in an Indian boy with a novel homozygous missense mutation in the PKP1 gene, in exon 6 in the armadillo repeat region motif-3 with a review and expansion of current literature on the PKP1 mutation database and phenotype–genotype correlation.