Background: PLACK syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in CAST, which encodes calpastatin, an endogenous inhibitor of calpains. The syndrome is classically defined by peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. Although the phenotype has been largely restricted to dermatological manifestations, emerging reports suggest dilated cardiomyopathy (DCM) as a systemic complication. Methods: We investigated five affected children from three sibships of an extended consanguineous family. Clinical evaluation and genome sequencing (GS) followed by segregation analysis of the targeted mutation test (TMT) were performed. Histopathological examination of an explanted heart was conducted in one child who underwent heart transplantation. Results: All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation. GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family. No additional plausible variants in known cardiomyopathy-associated genes were detected. Histopathological examination of the explanted heart demonstrated hypertrophied cardiomyocytes with nuclear enlargement, hyperchromasia, and fibrosis. Conclusions: Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy. The favorable short-term outcome following transplantation highlights a potential therapeutic option. Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested. To emphasize cardiomyopathy as a critical and underrecognized component of the syndrome, we propose the consideration of modifying the acronym to PLACK-C.

Peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK) syndrome (OMIM616295) is an exceptionally rare autosomal recessive genodermatosis caused by loss-of-function pathogenic variants in the CAST gene, encoding calpastatin. A total of 19 cases have been described in 12 articles, among families with unique de novo genetic variants of CAST. We describe two pediatric PLACK cases with a homozygous loss-of-function CAST variant (c.571G>T, p.Gly191Ter) which represents the only recurrent genetic variant of PLACK syndrome reported in the literature.

GJB2 and GJB6 variants, encoding Cx26 and Cx30 respectively, are the most frequently involved genes commonly contributing to hereditary hearing loss either isolated or in combination with skin abnormalities. GJB6 variations are classically associated with two distinct conditions: non-syndromic hearing loss and hidrotic ectodermal dysplasia, type Clouston, the latter typically not involving deafness. Whole genome sequencing (WGS) was used to find genetic variants after clinical features of a 13-year-old female patient were recorded. In this report, we describe the association of congenital hearing loss and ectodermal anomalies (palmoplantar keratoderma, knuckle pads, and nail dystrophy) in a female with the ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) GJB6 variant. As a result, we report on the third case of individuals showing this same missense variant and syndromic hearing loss. This study underscores the overlapping phenotypes observed in patients with the p.Gly59Arg variant in the GJB6 gene. The findings suggest a continuum of phenotypic presentations for this variant, with the key clinical features being the combination of congenital hearing loss and hyperkeratosis.

PLACK syndrome is an autosomal recessively inherited genodermatosis characterized by peeling skin, leukonychia, acral keratoses, cheilitis, and knuckle pads caused by variants in CAST gene. This report describe two unrelated Indian children with typical features of PLACK syndrome and homozygous novel variants in the CAST gene.

PLACK syndrome (OMIM 616295) is a rare genodermatosis associated with peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads and is caused by loss-of-function mutations in the CAST gene, which encodes calpastatin, a calcium-dependent protease. This case report highlights a case of PLACK syndrome presenting with the unique findings of striate hyperkeratosis on the palms as well as life-threatening cardiomyopathy. We review why CAST mutations might impact cardiac function and raise awareness of the potential association between PLACK syndrome and cardiac manifestations.