PLACK syndrome shows remarkable phenotypic homogeneity

Mohamad, Janan; Samuelov, Liat; Ben-Amitai, Dani; Malchin, Natalia; Sarig, Ofer; Sprecher, Eli

doi:10.1111/ced.13887

Cited by 8 publications

(6 citation statements)

References 5 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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“…Subsequently, Al‐Khalifa et al added another case of biallelic CAST variant to the literature: a 10‐year old Tunisian boy with the same clinical constellation, referred to as PLACK syndrome 10 . 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).…”

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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“…The present report further emphasizes the importance of protease and protease inhibitor activity for proper epidermal differentiation as previously exemplified in inherited conditions, 19 including Papillon-Lef evre syndrome (MIM245000) associated with reduced cathepsin C expression, 21 exfoliative ichthyosis (MIM607936) resulting from abnormal cystatin A activity 20 and PLACK (peeling skin, leuconychia, acral punctate keratosis, cheilitis and knuckle pads) syndrome (MIM616295) resulting from loss-of-function mutations in the CAST gene, encoding calpastatin, a cysteine protease inhibitor. 22,23…”

Section: Discussionmentioning

confidence: 99%

Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B

Mohamad

Samuelov

Malki

et al. 2020

Clin Experimental Derm

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Background. Palmoplantar keratoderma (PPK) refers to a large group of disorders characterized by extensive genetic and phenotypic heterogeneity. PPK diagnosis therefore increasingly relies upon genetic analysis. Aim. To delineate the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. Methods. Whole exome and direct sequencing, real-time quantitative PCR, protein modelling and a cathepsin B enzymatic assay were used. Results. The patient studied had severe diffuse erythematous PPK transgrediens. Pedigree analysis suggested an autosomal dominant mode of inheritance. Whole exome sequencing revealed a heterozygous missense mutation in the CTSB gene, encoding the cysteine protease cathepsin B. Genomic duplications in a noncoding region, which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis, a rare autosomal dominant disorder of cornification. This mutation affects a highly conserved residue, and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase cathepsin B activity. Accordingly, the CTSB variant was found to result in increased cathepsin B proteolytic activity. Conclusion. In summary, we report the identification of the first gain-of-function missense mutation in CTSB, which was found to be associated in one individual with a dominant form of diffuse PPK.

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PLACK syndrome shows remarkable phenotypic homogeneity

Abstract: Click https://www.wileyhealthlearning.com/ced.aspx for the corresponding questions to this CME article.

Cited by 8 publications

References 5 publications

PLACK syndrome resulting from a novel homozygous variant in CAST

PLACK syndrome resulting from a novel homozygous variant in CAST

PLACK syndrome is potentially treatable with intralipids

Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B

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