PLACK syndrome Q80.8

CAST; genodermatosis; PLACK syndrome; acral punctate keratosis; cheilitis; genetic disorder/genodermatosis; ankle pads; leukonychia; peeling skin syndrome.

PLACK syndrome (OMIM 616295) is an autosomal recessive genodermatosis caused by pathogenic mutations in the CAST gene, which encodes calpastatin, an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease.

PLACK stands for:

- P – Peeling skin

- L – Leukonychia

- A – Acral punctate keratoses

- C – Cheilitis

- K – Knuckle pads

as well as ichthyosis with a confetti pattern.

Clinically, this is a generalized peeling syndrome (GPSS; OMIM 270300) that manifests as early as infancy.

An autosomal recessive genodermatosis caused by a biallelic loss-of-function variant in the CAST gene. The resulting calpastatin deficiency leads to inadequate control of calpain activity and is associated with impaired epidermal integrity and keratinization.

Immunohistochemistry shows that calpastatin staining is reduced in the skin of affected individuals.

Transmission electron microscopy reveals widening of the intercellular spaces with chromatin condensation and margination in the upper stratum spinosum of the affected skin, suggesting impaired intercellular adhesion and keratinocyte apoptosis.

A significant increase in apoptotic keratinocytes was observed.

PLACK syndrome is a striking example of how impaired proteasome regulation can lead to a clinically distinctive genodermatosis.

1. Boggs JME et al. (2021) PLACK syndrome resulting from a novel homozygous variant in CAST. Pediatr Dermatol 38:210–212.
2. Hanna RA et al. (2008): Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature 456:409–412.
3. Hu B et al. (2023) PLACK syndrome caused by novel pathogenic variants in CAST: a case report and literature review. Clin Exp Dermatol 48:1052–1055.

4. Lin Z et al. (2015) Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. Am J Hum Genet 96:440–447.

5. Ono Y et al. (2012): Regulation and physiological roles of the calpain system in muscular disorders. Cardiovasc Res 96:11–22.
6. Starska K et al. (2016) Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinase activity as well as progression and clinical outcome in human laryngeal cancer. Tumor Biol 37:13185–13203.
7. Wendt A et al. (2004) Interaction of calpastatin with calpain: a review. Biol Chem 3185:465–472.