A novel homozygous nonsense mutation in CAST associated with PLACK syndrome

Temel, Şehime Gülsün; Karakas, Bedri; Şeker, Ü; Türkgenç, Burcu; Zorlu, Özge; Sarıcaoğlu, Hayriye; Oğur, Çağrı; Kütük, Özgür; Kelsell, David P.; Yakıcıer, Mustafa Cengiz

doi:10.1007/s00441-019-03077-9

Cited by 9 publications

(8 citation statements)

References 29 publications

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“…Loss of calpastatin in affected individuals leads to defective keratinocyte adhesion as well as increased keratinocyte apoptosis 2 . All causative mutations reported to date in this rare syndrome are loss‐of‐function mutations in CAST namely: c.424A > T, c.607dup, c.1750delG, c.461dupGCAT, c.544G > T, c.507_508insA 2‐5 . The core clinical features of this syndrome, in addition to less frequently observed findings previously reported in the literature, are shown in Table 1.…”

Section: Discussionmentioning

confidence: 83%

“…It is an autosomal recessive condition and has been shown to result from loss‐of‐function mutations in CAST , the gene encoding calpastatin, a specific inhibitor of calpains, which function as calcium‐dependent cysteine proteases 1,2 . To date, six homozygous pathogenic variants in CAST gene (c.424A > T, c.607dup, c.1750delG, c.461dupGCAT, c.544G > T, c.507_508insA) have been associated with PLACK syndrome 2‐5 …”

Section: Introductionmentioning

confidence: 99%

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PLACK syndrome resulting from a novel homozygous variant in CAST

Boggs

Irvine

2020

Pediatric Dermatology

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Peeling skin, leukonychia, acral punctate keratoses, cheilitis and knuckle pads (PLACK syndrome, OMIM 616295) is a recently described form of peeling skin syndrome (PSS). It is an autosomal recessive condition and has been shown to result from loss-of-function mutations in CAST, the gene encoding calpastatin, a specific inhibitor of calpains, which function as calcium-dependent cysteine proteases. 1,2 To date, six homozygous pathogenic variants in CAST gene (c.424A > T, c.607dup, c.1750delG, c.461dupGCAT, c.544G > T, c.507_508insA) have been associated with PLACK syndrome. 2-5 2 | C A S E REP ORT A 5-year-old girl, born to consanguineous parents, was referred for evaluation of skin fragility. Dry skin was noted at birth and at 6 months of age, she developed erythematous, itchy, eczematous patches on face, arms, and lower limbs. At 12 months, she was admitted with Staphylococcus aureus bullous impetigo, and a keratosis pilaris-like eruption was observed on the arms, abdomen, and legs. By 18 months, punctate keratoderma developed on the palms and plantar feet and became extremely troublesome, with resultant difficulty walking. The patient also began walking on tiptoes at this

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

PLACK syndrome resulting from a novel homozygous variant in CAST

Boggs

Irvine

2020

Pediatric Dermatology

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“…In 1965, Nasr and Shostak found that mice with essential fatty acid deficiency (EFAD) had nearly three‐fold thicker epidermal layers compared to mice with normal essential fatty acid levels. This greater thickness was attributed by those authors to a decrease in the rate of epidermal keratinization and cell sloughing, a decrease in the rate of cellular proliferation or a combination of both mechanisms 12,14 …”

Section: Discussionmentioning

confidence: 92%

“…In 2018, Mohamad et al, reported a 30‐year old man with the same manifestations in addition to mild asthma 11 . More recently, Temel et al, reported two family members with the same clinical manifestations of PLACK syndrome; yet the proband had additional clinical findings 12 (Table 2). Thus, our report represents the fifth family with this very rare syndrome.…”

Section: Discussionmentioning

confidence: 99%

PLACK syndrome is potentially treatable with intralipids

et al. 2021

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We describe an 11‐year‐old girl with PLACK Syndrome (peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads), who was found to have a novel homozygous variant in CAST, the pathogenicity of which was confirmed using blood‐derived RNA. There is no established treatment for PLACK syndrome. However, we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids, which prompted us to consider a potential treatment strategy. Indeed, we initiated this patient on intravenous lipid infusion (Vitalipid®; an emulsion of fat‐soluble vitamins and lipofundin‐MCT/LCT 20%) and the response was dramatic. Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement. PLACK syndrome is a very rare genodermatosis and only six families have been described to date with pathogenic CAST variants. This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition. The remarkable response we report and the relative safety of the intervention should prompt healthcare providers who care for PLACK syndrome patients to explore this as a potential treatment strategy in future studies.

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“…This rare syndrome has only been recognized as a distinct clinical entity in recent years. Six homozygous nonsense mutations in CAST have previously been reported: c.607dup (p.Ile203Asnfs*8), 1 c.424A>T (p.Lys142*), 1 c.1750delG (p.Val584Trpfs*37), 1 c.461dupGCAT (p.Ser154Cysfs*6), 2 c.507508insA (p.Glu172Argfs*11) 3 and c.544G>T (p.Glu182*) 4 . The homozygous p.Gly191* mutation identified in our proband is novel, and expands the database of CAST mutations giving rise to PLACK syndrome.…”

mentioning

confidence: 99%