PLACK Syndrome (MONDO:0014574): Research Report

How this was assembled and what it can support

• Primary source: 17 PubMed records already cached in this worktree's references_cache/, plus targeted web searches.
• Usable quotes: Every quotation below is copied exactly from a cached abstract or from cached PMC full text. Only those can serve as snippet: values.
• Records with no content: Seven cached records have no abstract text:
• PMID:28851602
• PMID:30656735
• PMID:32918489
• PMID:37140444
• PMID:37317743
• PMID:37387535
• PMID:39931923 (has only a one-sentence abstract)

What this report says about these papers comes from their titles, their MeSH headings, or other papers describing them. They cannot carry quoted evidence until full text is obtained. - Ontology IDs: IDs marked ✔ were read from cache/<prefix>/terms.csv in this repo. IDs marked ⚠ are suggestions that have not been looked up yet and must be checked before binding. - No deep-research report exists under research/ for this disease.

1. Disease information

What it is. PLACK syndrome is an ultra-rare autosomal recessive genodermatosis (an inherited skin disorder). It is a form of generalized peeling skin syndrome caused by biallelic loss-of-function variants in CAST, which encodes calpastatin, the cell's own specific inhibitor of calpain. The acronym lists its five defining features:

• Peeling skin
• Leukonychia (white nails)
• Acral punctate keratoses (small hard spots on the hands and feet)
• Cheilitis (inflamed lips)
• Knuckle pads

Since 2023, childhood-onset dilated cardiomyopathy (DCM) has emerged as a serious systemic manifestation.

"loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome." (PMID:25683118, Lin et al., Am J Hum Genet 2015)

"PLACK syndrome (OMIM 616295) is a form of generalized peeling skin syndrome (GPSS; OMIM 270300)." (PMID:33010050)

Synonyms: - PLACK syndrome - Peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads - Generalized peeling skin syndrome, CAST-related - "PLACK-C" has been proposed if cardiomyopathy is confirmed as a consistent feature (PMID:41300744)

Data basis. All evidence is aggregated case reports and small families. There are no registries or EHR cohorts.

2. Etiology

• Cause: biallelic germline loss-of-function variants in CAST (hgnc:1515 ✔). Every reported variant is truncating: nonsense, frameshift, splice-site, or a large deletion.

  "Previously reported variants in CAST associated with PLACK syndrome have been truncating in nature (frameshift, splice-site, and nonsense mutations)." (PMID:41300744, full text)

• Risk factor: consanguinity. Most families are consanguineous (PMID:28851602 MeSH "Consanguinity"; PMID:33410500; PMID:41300744; PMID:42256365).
• Environmental, protective, or gene–environment factors: none documented.
• Possible nutritional link. Low vitamin A and essential fatty acids were reported in one patient (PMID:33410500), and severe protein-calorie malnutrition in another (PMID:42742298). Whether these are consequences of the disease or coincidental is unresolved.

3. Phenotypes

The phenotype is called "remarkably homogeneous" (PMID:30656735, title only). The table counts reported cases: - 19 cases in 12 articles as of the 2025 review (PMID:40387456) - 21 cases (PMID:41300744) - 27 patients, including 7 with DCM (PMID:42256365)

Frequency estimates are qualitative because no curated per-feature table was accessible.

Evidence for the cardiac phenotype:

"Four developed severe DCM, two of whom required orthotopic heart transplantation." (PMID:41300744)

"To date, there are 27 patients with PLACK syndrome reported, including ours, with 7 patients developed DCM. Among these, 3 had heart transplantation, 1 required a biventricular assist device, and 3 succumbed to progressive heart failure. The reported age of onset of DCM ranged from 4 to 15 years." (PMID:42256365)

Quality of life. No formal quality-of-life measures (EQ-5D, DLQI) have been published. The burden described is chronic pruritus, cosmetic impact, and, where present, life-threatening heart failure.

Inheritance term: HP:0000007 Autosomal recessive inheritance ✔.

4. Genetic and molecular information

• Gene: CAST, calpastatin. hgnc:1515 ✔; OMIM 114090 ⚠; 5q15.
• Variant spectrum: all predicted loss-of-function and germline. Most are homozygous; one compound heterozygote is reported.

Functional evidence for loss of function:

"Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals." (PMID:31392520)

• Functional impact category: LOSS_OF_FUNCTION. NMD is shown for the splice allele in PMID:37221445.
• Population frequency: no carrier-frequency data. gnomAD values were not checked here.
• ClinVar / ClinGen: no ClinGen gene–disease validity record was found in the local cache.
• Genotype–phenotype: no correlation for cardiac involvement.

  "no distinct variant hotspots for cardiomyopathy can been identified" (PMID:41300744, full text)

• Modifier or confounding genes. One child with PLACK and DCM also carried a heterozygous MYBPC3 variant (hgnc:7551 ✔) that the authors judged sufficient to explain the cardiomyopathy (PMID:42742298). This caveat matters when counting DCM in PLACK.

  "Although the patient's cardiomyopathy is attributable to her MYBPC3 variant, this case adds to the growing list of reports describing PLACK syndrome with coinciding cardiomyopathy" (PMID:42742298)

• Epigenetic or chromosomal findings: none apart from the 326.7 kb deletion above.

5. Environmental information

No environmental, lifestyle, or infectious triggers have been described.

6. Mechanism and pathophysiology

Causal chain

1. Biallelic truncating CAST variants lead to NMD or truncated protein, which results in loss of calpastatin protein and inhibitory activity. This is demonstrated by IHC (PMID:25683118), immunoblot and activity assays (PMID:31392520), and mRNA analysis (PMID:37221445).
2. Loss of calpastatin leads to unopposed calpain (CAPN1/CAPN2) protease activity. This is inferred from calpastatin's known biochemistry. Calpain activity has not been measured directly in patient tissue in the available abstracts.
3. Excess calpain proteolysis in the epidermis results in impaired keratinocyte cell–cell adhesion. The siRNA knockdown result is demonstrated; the identity of the cleaved substrates is not.

   "Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis." (PMID:25683118) "In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion." (PMID:25683118)

4. Branch: keratinocyte apoptosis increases in the upper stratum spinosum (demonstrated by TUNEL).

   "A significant increase of apoptotic keratinocytes was also observed in TUNEL assays." (PMID:25683118)

5. Steps 3 and 4 together lead to defective epidermal adhesion and barrier, which manifests as generalized peeling, cheilitis, and pruritus. Repeated friction at acral sites and knuckles produces punctate keratoses and knuckle pads; nail-matrix involvement produces leukonychia. The site-specific step is inferred.

   "we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST." (PMID:25683118)

6. Cardiac branch (hypothesis). Unopposed calpain activity in cardiomyocytes is proposed to degrade cytoskeletal and sarcomeric proteins such as desmin and titin, causing myocardial fibrosis and impaired contractility, and then DCM. Support comes from mouse calpain-overexpression models and from explant histology (hypertrophied cardiomyocytes, fibrosis, bizarre nuclei). It has not been shown in patient myocardium.

   "Excessive calpain activity may also lead to the degradation of key cytoskeletal proteins such as desmin and titin in myocardial fibers, leading to myocardial fibrosis and impaired contractility." (PMID:42256365) "Histopathological examination of the explanted heart demonstrated hypertrophied cardiomyocytes with nuclear enlargement, hyperchromasia, and fibrosis." (PMID:41300744)

7. Possible secondary metabolic step (unproven). Low vitamin A and essential fatty acids were found in one patient (PMID:33410500). Whether this is a consequence of barrier failure or a contributor is unknown.

Suggested terms

Cell types (CL): - keratinocyte CL:0000312 ✔ - skin fibroblast CL:0002620 ✔ (the cell type used in functional assays) - cardiac muscle cell CL:0000746 ✔ - ventricular cardiac muscle cell CL:2000046 ✔

Biological processes (GO): - apoptotic process GO:0006915 ✔ (modifier INCREASED) - calcium-dependent cell-cell adhesion GO:0016339 ✔ or desmosome organization GO:0002934 ✔. Desmosomal involvement is suggested by the TEM findings but not demonstrated. - keratinocyte differentiation GO:0030216 ✔ - Calpain inhibition: ⚠ search for a calpain-inhibitor-activity molecular function term and a "negative regulation of cysteine-type endopeptidase activity" process term.

Anatomy (UBERON, ⚠ to look up): epidermis, stratum spinosum, nail, lip, palm, sole, knuckle skin, heart left ventricle.

Molecular profiling

No transcriptomic, proteomic, single-cell, or multi-omic data have been published for PLACK.

7. Anatomical structures affected

8. Temporal development

• Onset: skin features appear in the first months of life ("since the first six months of life", PMID:41300744, full text). Some cases present at school age.
• Course: the skin disease is chronic and lifelong. The oldest reported patients were 54 and 58 years old and had no cardiac disease (PMID:25683118, as described in PMID:41300744).
• Cardiac disease: onset at 4–15 years and rapidly progressive. The 2025 family study suggests penetrance is age-dependent:

  "Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested." (PMID:41300744)

• Remission: none spontaneous. One case of treatment-induced improvement is described in Section 12.

9. Inheritance and population

• Inheritance: autosomal recessive, with complete penetrance for the skin phenotype. Heterozygous parents are unaffected (PMID:41300744).
• Prevalence: unknown. About 27 published patients by 2026. A suitable prevalence_class would be CASES_IN_LITERATURE / ULTRA_RARE.
• Founder effects: none established. The only recurrent variant is p.Gly191* (PMID:40387456). There is a geographic cluster of DCM-associated families in Saudi Arabia.
• Ancestries reported: Chinese and others (founding families), French, Israeli, Turkish, Afghan, Irish, Saudi, Iranian, Indian, Canadian, and US.
• Sex ratio: both sexes are affected equally.
• Anticipation and germline mosaicism: not reported.

10. Diagnostics

• Clinical recognition: the pentad of features, plus consanguinity.
• Histology: epidermal acantholysis-like widening of intercellular spaces and apoptotic keratinocytes in the upper spinous layer. Calpastatin immunostaining is reduced:

  "Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals." (PMID:25683118)

• Genetic testing: whole-exome or whole-genome sequencing is the usual route (PMID:31392520, 37221445, 41300744). The title of PMID:32918489 ("the penny dropped") reflects diagnosis by exome sequencing in an Afghan child. RNA studies help confirm splice and novel variants (PMID:33410500, 37221445). Chromosomal microarray or copy-number analysis should be considered because of the 326.7 kb deletion case.
• Cardiac work-up: echocardiography at diagnosis and throughout life (PMID:41300744).
• Labs: vitamin A and essential fatty acid levels, which were low in PMID:33410500.
• Differential diagnosis:
• Other generalized peeling skin syndromes (CDSN, FLG2, SERPINB8, CSTA, TGM5)
• Epidermolysis bullosa simplex
• Pachyonychia congenita
• Naxos and Carvajal syndromes (palmoplantar keratoderma with cardiomyopathy, distinguished by woolly hair, HP:0002224 ✔)
• Vitamin A or zinc deficiency

  "Naxos and Carvajal syndromes are characterized by woolly hair, palmoplantar keratoderma, and right arrhythmogenic cardiomyopathy or left dilated cardiomyopathy, respectively. Woolly hair was not seen in our patient. Leukonychia is not a feature of vitamin A nor zinc deficiencies." (PMID:42256365)

• Screening: carrier testing and cascade testing within families. There is no newborn screening.

11. Outcome and prognosis

• Skin: not life-limiting; chronic morbidity.
• Heart: the main determinant of mortality. Of 7 patients with DCM: 3 died, 3 received transplants, and 1 needed a biventricular assist device (PMID:42256365). Families also report sudden cardiac deaths between ages 2 and 14.
• After transplant: short-term outcome is favourable (alive and stable at 5 months and 1 year, PMID:41300744).
• Prognostic factors: none identified. There is no genotype–phenotype correlation.

12. Treatment

"There is no established treatment for PLACK syndrome... 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." (PMID:33410500)

Not available: - Clinical trials: none (no NCT or ICTRP records found) - Gene therapy, RNA-based, or targeted therapy: none - Calpain inhibitors: a mechanistically logical idea, but untested in PLACK

13. Prevention

• Primary: genetic counselling for consanguineous families; carrier testing; prenatal or preimplantation diagnosis once the familial variants are known.
• Secondary: early molecular diagnosis in children with peeling skin and leukonychia.
• Tertiary: lifelong echocardiographic surveillance (PMID:41300744, 42256365); monitoring nutritional status and vitamin A (PMID:33410500, 42742298).

14. Other species and natural disease

• No naturally occurring CAST-deficiency skin disease has been found in animals. OMIA was not searched in depth.
• Bovine and ovine CAST polymorphisms are well known in meat science, where they affect post-mortem calpain-driven tenderization. They have no reported skin phenotype.
• Calpastatin is conserved across vertebrates.

15. Model organisms

• Cast knockout mouse: "essentially normal in terms of their reproduction, development, growth, anatomy, and cognition", with a modest abnormality in affective behaviour (PMC2561015). No skin phenotype has been reported. This is a candidate FAILS_TO_RECAPITULATE / HUMAN_MODEL_MISMATCH point, pending a published skin examination.
• Calpastatin-overexpressing mouse: delayed wound re-epithelialization (PMC3353912). This is the inverse genotype and is only indirectly informative.
• Cardiac models:
• Mitochondria-targeted Capn1 transgenic and Tg-Capn2 mice develop DCM and fibrosis (cited in PMID:41300744). These support the calpain-excess cardiac hypothesis.
• Calpastatin-transgenic hearts show sarcomeric disruption and autophagic vacuoles (cited in PMID:41300744).
• In vitro systems:
• siRNA CAST knockdown in keratinocytes reduces adhesion (PMID:25683118). Evidence type: IN_VITRO.
• Patient skin fibroblasts show reduced calpastatin expression and activity (PMID:31392520).
• Not available: iPSC, organoid, or zebrafish models specific to PLACK.

Notes for the KB entry

• The stub is stubs/Peeling_Skin-leukonuchia-acral_Punctate_Keratoses-cheilitis-knuckle_Pads_Syndrome.yaml. The curation PR should delete it.
• Missing identifiers to fill in: the Orphanet code and the OMIM gene ID, ideally via just fetch-reference ORPHA:… once identified.
• Seven cached references have no abstract text. Fetch full text, or cite them only for non-snippet context.
• When counting cardiomyopathy as a PLACK feature, handle PMID:42742298 carefully, since that child's DCM is attributed to MYBPC3. The cardiac node is best modelled as an emerging hypothesis (a mechanistic_hypotheses entry with status: EMERGING). The mouse cardiac models fit a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion.

Sources: - PMC12652073 – Severe DCM with PLACK syndrome (Alkorashy 2025) - PubMed 41300744 - PubMed 38994911 – CASTing the net wider - PubMed 40387456 – Updated review (Haxho 2025) - Wiley – Haxho 2025 full text - Hacettepe record – Durmaz 2023 - OMIM 616295 (mirror) - Comprehensive behavioral phenotyping of calpastatin-knockout mice - Calpain activity is essential in skin wound healing - Temel 2019 PDF

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