PLACK syndrome shows remarkable phenotypic homogeneity

Abstract

Peeling skin syndrome (PSS) refers to a large group of disorders featuring detachment of the epidermal uppermost layers. PSS involves either acral areas as in acral PSS (MIM 609796) caused by mutations in the transglutaminase 5 gene (TGM5) the cystatin A gene (CSTA; MIM 607936), or the entire surface of the skin as in PSS type A, caused by mutations in the filaggrin-2 gene (FLG2; MIM616265) or PSS type B, caused by mutations in the corneodesmosin gene (CDSN; MIM270300). Other forms of PSS are associated with systemic manifestations, such as SAM syndrome (MIM615508) or Netherton syndrome (MIM256500). More recently, a complex phenotype termed PLACK (peeling skin, leuconychia, acral punctate keratosis, cheilitis and knuckle pads) syndrome has been shown to result from loss-offunction mutations in CAST, the gene encoding calpastatin, a specific inhibitor of calpains, which function as a calcium-dependent cysteine proteases. A 30-year-old man presented with an almost lifetime history of thickened, peeling skin. He was the child of consanguineous parents of Arab Muslim origin (Patient 6 in Table 1). At 3 months of age, he had begun to display localized and painful thickening of the palmar and plantar skin associated with peeling of the skin over the shins and arms. Peeling was aggravated after exposure to heat or after minor trauma. His parents mentioned that the clinical manifestations worsened during summertime. He had previously been examined at 20 years of age, at which time he was found to exhibit keratosis pilaris, leuconychia and knuckle pads (Fig. 1a), peeling of the skin (Fig. 1c), punctuate plantar keratoderma on the foot (Fig. 1d) conjunctival injection and cheilitis (Fig. 1e). Hair scalp, general growth and development were normal and formal hearing testing was unremarkable. In addition, the patient presented with mild asthma since infancy. A skin biopsy obtained from the patient’s palmar skin showed marked orthohyperkeratosis, acanthosis and hypergranulosis (Fig. 1e). The patient and his father provided written and informed consent according to a protocol approved by our local institutional review board in adherence with the principles of the Declaration of Helsinki. Whole exome (Table S1) and direct sequencing (Table S2) were performed as previously described, and revealed a hitherto unreported homozygous insertion in CAST (c.507_508insA) in the patient (individual II:1 in the pedigree in Fig. 2a). The mutation was validated using direct sequencing (Fig. 2b) and was not found in available public databases including GnomAD, ExAc and HGMD, containing >20 000 individual CAST exome sequences. The patient’s father was found to be heterozygous for the mutation (no DNA sample from the patient’s mother was available for analysis). This mutation is predicted to result in frameshift and premature termination of translation. PLACK syndrome seems to be associated with genetic homogeneity, as all causative mutations reported to date in this rare disorder are loss-of-function mutations in CAST (Fig. 2c), encoding calpastatin, a calpain inhibitor. Calpains are calcium-dependent intracellular cysteine proteases normally expressed in human skin. They have been shown to play an important role in the regulation of keratinocyte proliferation, epidermal differentiation and cornification, cell cycle regulation and apoptosis. Downregulation of CAPN12, encoding calpain 12, which is predominantly expressed in the skin, has recently been shown to aggravate the clinical manifestations of ABCA12 mutations associated with Correspondence: Professor Eli Sprecher, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6, Weizmann Street, Tel Aviv 64239, Israel E-mail: [email protected]