A number sign (#) is used with this entry because of evidence that peeling skin in association with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK) is caused by homozygous mutation in the CAST gene (114090) on chromosome 5q15.

Haber and Rose (1986) described 2 brothers from a consanguineous family who had been diagnosed with epidermolysis bullosa simplex (see 131760) in infancy. The proband was a 23-year-old man who had had blistering skin since 3 months of age, primarily on the hands and feet, which worsened in summer but healed without scarring and improved over time. He also had whitish thickening of the tongue and buccal mucosa that remained unchanged, as well as chronic angular cheilitis. Discrete yellowish thickenings appeared on his palms at 9 years of age, followed by more diffuse lesions on his soles, and his fingernails showed whitish discoloration beginning at age 12. Examination revealed leukokeratosis of the tongue and buccal mucosa, bilateral angular cheilitis, and keratoderma of the palms and soles with hyperkeratotic papules on the dorsa of fingers and toes. His fingernails showed proximal leukonychia, whereas his toenails showed mild onycholysis, with slight elevation of the nail plates by a small amount of yellowish subungual debris. The proband's 28-year-old brother was similarly affected. There was 1 intact bulla on the plantar surface of the proband's left fifth toe, and 1 erosion on the dorsum of his brother's right great toe. Biopsy of a follicular hyperkeratotic papule revealed a parakeratotic plug above the infundibular portion of a hair follicle. The granular layer of the epidermis was absent below the parakeratotic area, but no actual perforation into the dermis was observed. Teeth were normal in both brothers. Despite the absence of classic nail changes, Haber and Rose (1986) concluded that the brothers' clinical features were more compatible with a diagnosis of pachyonychia congenita (see 167200) than epidermolysis bullosa simplex.

Lin et al. (2015) reported 2 unrelated women with peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads; the authors proposed the acronym PLACK for the syndrome. The first patient was a 28-year-old Chinese woman who had infantile onset of trauma-induced blistering of the extremities, which worsened in the summer; she also had asymptomatic skin peeling with underlying erythema in the winter. After puberty, the blistering became confined to the distal extremities, whereas the skin peeling progressed to involve nearly the entire body. Examination revealed generalized dry, scaly skin with superficial exfoliation and underlying erythema. She had cheilitis with dry, shedding scales. Punctate palmoplantar keratoderma was observed, which coalesced into focal keratoderma predominantly on the weight-bearing areas. Knuckle pads with multiple hyperkeratotic micropapules were present at all interphalangeal joints. Nails showed proximal leukonychia with mild distal onycholysis. Histologic examination of scaly skin from her leg showed hyperkeratosis, acanthosis, and intraepidermal clefting with irregular acantholysis. The second patient was a woman from Nepal who developed painful lesions of the palms and soles at 1 year of age. Examination showed clinical features similar to those of the first patient, including skin peeling, cheilitis, punctate keratoses of the palms and soles, leukonychia, and knuckle pads with hyperkeratotic micropapules. Serum IgE levels and eosinophil counts were normal in both women. Lin et al. (2015) also restudied the brothers originally described by Haber and Rose (1986). At 54 and 58 years of age, respectively, they continued to have skin fragility induced by minor trauma and heat. Other features included leukonychia, leukokeratosis, angular cheilitis, papules on the extensor surfaces of fingers and toes, and punctate palmar keratoses with plantar keratoderma.

In a 28-year-old Chinese woman with PLACK, who was negative for mutation in the CDSN (602593), TGM5 (603805), CHST8 (610190), and CSTA (184600) genes, Lin et al. (2015) performed exome sequencing and identified homozygosity for a 1-bp duplication in the CAST gene (114090.0001). The proband's unaffected parents, sibs, and daughters were heterozygous for the duplication, which was not found in 200 ethnically matched controls. Exome sequencing in a similarly affected woman from Nepal revealed homozygosity for a nonsense mutation in the CAST gene (K142X; 114090.0002) that segregated with disease in the family. In 2 brothers with blistering skin, palmoplantar keratoderma, angular cheilitis, and leukonychia, who were originally reported by Haber and Rose (1986), Lin et al. (2015) identified homozygosity for a 1-bp deletion in CAST (114090.0003).