👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"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"

The founding report establishes autosomal recessive inheritance of CAST loss of function.

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Mechanistic Hypotheses

1

Unopposed cardiomyocyte calpain activity causes the dilated cardiomyopathy of PLACK syndrome

calpain_driven_cardiomyopathy EMERGING

Evidence balance 1 support

Dilated cardiomyopathy segregates with biallelic CAST loss in several families, with no other cardiomyopathy gene found in the best-studied one. The proposed link is unopposed calpain proteolysis in cardiomyocytes, which is supported only by mouse calpain-overexpression models. It has not been tested in patient tissue or in a CAST-deficient animal, and penetrance appears incomplete and age-dependent.

Pathograph links

Unrestrained Calpain Proteolytic Activity -> Cardiomyocyte Calpain Overactivity

Cardiomyocyte Calpain Overactivity -> Dilated Cardiomyopathy INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:41300744 SUPPORT Human Clinical

"Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy."

The family study proposes CAST deficiency as a cause of recessive cardiomyopathy.

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Discussions and Knowledge Gaps

1

Is calpain activity increased in PLACK skin and myocardium, which calpain substrates mediate the adhesion and cardiac defects, and why do only some patients develop cardiomyopathy?

KNOWLEDGE GAP OPEN gap_plack_calpain_activity_untested

Attached to

pathophysiology#Unrestrained Calpain Proteolytic Activity pathophysiology#Cardiomyocyte Calpain Overactivity

Every node downstream of calpastatin loss rests on calpastatin's known biochemistry and on mouse calpain-overexpression models. No patient tissue has been assayed for calpain activity, no adhesion substrate has been identified, and no CAST-deficient animal with a skin or cardiac phenotype has been described. The incomplete, age-dependent cardiac penetrance has no explanation.

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Pathophysiology

5

Biallelic CAST Loss of Function

Homozygous or compound heterozygous truncating CAST variants (frameshift, nonsense, splice-site, and one large deletion) abolish calpastatin. Patient cells show reduced CAST transcript through nonsense-mediated decay, reduced protein, and reduced calpastatin inhibitory activity.

CAST hgnc:1515

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

calpain inhibitor activity GO:0010859 ↓ DECREASED

Downstream

Unrestrained Calpain Proteolytic Activity

Show evidence (4 references)

PMID:25683118 SUPPORT Human Clinical

"we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins"

All founding-family variants are biallelic truncating CAST alleles.

PMID:25683118 SUPPORT Human Clinical

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

Calpastatin protein is reduced in patient skin.

PMID:31392520 SUPPORT In Vitro

"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."

Patient fibroblasts show loss of calpastatin protein and inhibitory activity.

+ 1 more reference

Unrestrained Calpain Proteolytic Activity

Calpastatin is the specific endogenous inhibitor of calpain-1 and calpain-2, so its loss is expected to leave calcium-activated calpain proteolysis unchecked. Calpain activity has not been measured in patient tissue, and the calpain substrates whose cleavage disrupts adhesion are not known; this node is inferred from the known function of calpastatin.

Unopposed cardiomyocyte calpain activity causes the dilated cardiomyopathy of PLACK syndrome

calpain activity GO:0004198 ↑ INCREASED

Downstream

Impaired Keratinocyte Intercellular Adhesion

Keratinocyte Apoptosis

Cardiomyocyte Calpain Overactivity

Show evidence (1 reference)

PMID:25683118 SUPPORT INDIRECT BACKGROUND Human Clinical

"Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease."

States the inhibitor relationship from which increased calpain activity follows; the paper does not measure calpain activity itself.

Impaired Keratinocyte Intercellular Adhesion

Lesional skin shows widened intercellular spaces in the upper stratum spinosum, and CAST knockdown in cultured keratinocytes impairs their adhesion. Loss of cohesion between suprabasal keratinocytes is the structural basis of the superficial peeling.

epidermal keratinocyte CL:4052061

keratinocyte cell-cell adhesion GO:0090136 ↓ DECREASED

upper stratum spinosum UBERON:0002026

Downstream

Generalized Superficial Skin Peeling

Show evidence (3 references)

PMID:25683118 SUPPORT Human Clinical

"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."

Ultrastructure of patient skin shows loss of intercellular adhesion in the upper spinous layer.

PMID:25683118 SUPPORT In Vitro

"In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion."

CAST knockdown in keratinocytes reproduces the adhesion defect.

ORPHA:444138 SUPPORT Other

"Histopathologic examination of affected skin areas is not specific and shows hyperkeratosis, acanthosis, and occasional intraepidermal clefting with irregular acantholysis."

Orphanet records intraepidermal clefting and acantholysis, the histological sign of lost keratinocyte cohesion.

Keratinocyte Apoptosis

TUNEL staining shows a significant increase in apoptotic keratinocytes in lesional skin, and electron microscopy shows chromatin condensation and margination in the upper stratum spinosum.

epidermal keratinocyte CL:4052061

keratinocyte apoptotic process GO:0097283 ↑ INCREASED

upper stratum spinosum UBERON:0002026

Downstream

Generalized Superficial Skin Peeling

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"A significant increase of apoptotic keratinocytes was also observed in TUNEL assays."

Direct measurement of increased keratinocyte apoptosis in patient skin.

Cardiomyocyte Calpain Overactivity

Proposed mechanism for the dilated cardiomyopathy seen in several PLACK families: calpastatin loss raises calpain activity in cardiomyocytes, degrading cytoskeletal and sarcomeric proteins and causing cardiomyocyte loss and fibrosis. Transgenic mice with cardiomyocyte-restricted calpain-1 or calpain-2 overexpression develop dilated cardiomyopathy. No patient myocardium has been examined for calpain activity, and the explanted-heart histology reported so far (hypertrophied cardiomyocytes, bizarre nuclei, fibrosis) is nonspecific.

Unopposed cardiomyocyte calpain activity causes the dilated cardiomyopathy of PLACK syndrome

cardiomyocyte CL:0000746

calpain activity GO:0004198 ↑ INCREASED

Downstream

Dilated Cardiomyopathy

Show evidence (2 references)

PMID:42256365 SUPPORT INDIRECT BACKGROUND Human Clinical

"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."

The case authors propose calpain-mediated cardiomyocyte cytoskeletal degradation as the cardiac mechanism.

PMID:30874894 SUPPORT INDIRECT Model Organism

"Transgenic up-regulation of mitochondria-targeted CAPN1 dose-dependently induced cardiac cell death, adverse myocardial remodeling, heart failure, and early death in mice"

Excess mitochondrial calpain-1 in mouse cardiomyocytes causes cardiomyocyte death and heart failure; this is an overexpression model, not calpastatin loss.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 2

Dilated Cardiomyopathy OCCASIONAL HP:0001644

Show evidence (5 references)

PMID:42256365 SUPPORT REVIEW SYNTHESIS Human Clinical

"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."

Literature tally giving the frequency, outcomes, and onset age of dilated cardiomyopathy.

PMID:41300744 SUPPORT Human Clinical

"All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation."

Four of five CAST-homozygous children in one family developed severe dilated cardiomyopathy.

PMID:41300744 SUPPORT Human Clinical

"No other variants in the genes known to cause cardiomyopathy were found."

Genome sequencing excluded other known cardiomyopathy genes in this family.

+ 2 more references

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:41300744 SUPPORT BACKGROUND Human Clinical

"Remarkably, seven of his family members who were affected by PLACK syndrome had sudden cardiac death between the ages of 8 and 14 years."

Describes a previously reported PLACK family with seven sudden cardiac deaths in affected members.

PMID:41300744 SUPPORT BACKGROUND Human Clinical

"two of her brothers had similar dermatological features and died suddenly at the ages of 3 and 4 years"

Sudden death of two affected brothers in the first PLACK family reported with dilated cardiomyopathy.

Head and Neck 1

Cheilitis VERY_FREQUENT HP:0100825

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"

Cheilitis is a defining feature.

Integument 7

Generalized Superficial Skin Peeling VERY_FREQUENT Scaling skin HP:0040189

Onset: INFANTILE

Show evidence (2 references)

PMID:25683118 SUPPORT Human Clinical

"an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"

Generalized peeling skin is the first defining feature of the syndrome.

PMID:41300744 SUPPORT Human Clinical

"Dermatological manifestations had been apparent since the first six months of life"

Skin findings began in the first six months of life in the index patient of the 2025 family.

Superficial Blistering Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

ORPHA:444138 SUPPORT Other

"A rare genetic skin disease characterized by generalized skin peeling or superficial blisters without scarring"

Orphanet definition lists superficial blisters without scarring.

Leukonychia VERY_FREQUENT HP:0001820

Show evidence (2 references)

PMID:25683118 SUPPORT Human Clinical

"an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"

Leukonychia is a defining feature.

PMID:42256365 SUPPORT Human Clinical

"Fingernails and toenails showed leukonychia with unremarkable hair examination."

Case report showing leukonychia of fingernails and toenails.

Acral Punctate Keratoses VERY_FREQUENT Punctate palmoplantar hyperkeratosis HP:0007530

Show evidence (2 references)

PMID:25683118 SUPPORT Human Clinical

"an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"

Acral punctate keratoses are a defining feature.

PMID:42256365 SUPPORT Human Clinical

"multiple hyperkeratotic papules on palms and soles"

Case report describing palmoplantar hyperkeratotic papules.

Knuckle Pads HP:0032541

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"

Knuckle pads are a defining feature.

Follicular Hyperkeratosis HP:0007502

Show evidence (1 reference)

PMID:42256365 SUPPORT Human Clinical

"Skin examination revealed generalized xerosis with follicular hyperkeratosis, cheilitis, and multiple hyperkeratotic papules on palms and soles."

Follicular hyperkeratosis reported alongside the classic features in a CAST-confirmed case.

Pruritus HP:0000989

Show evidence (1 reference)

PMID:33410500 SUPPORT Human Clinical

"Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement."

Pruritus was present before treatment in this CAST-confirmed patient.

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Genetic Associations

1

CAST (Autosomal recessive)

Gene: CAST hgnc:1515 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25683118 SUPPORT Human Clinical

"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"

Establishes CAST as the causal gene.

PMID:40387456 SUPPORT Human Clinical

"We describe two pediatric PLACK cases with a homozygous loss-of-function CAST variant (c.571G>T, p.Gly191Ter) which represents the only recurrent genetic variant of PLACK syndrome reported in the literature."

Identifies the only recurrent CAST variant.

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Medical Actions

3

Emollients and Keratolytics

Action: Supportive skin care with emollients and keratolytics Ontology label: Supportive Care NCIT:C15747

Symptomatic topical skin care, the mainstay of management.

Show evidence (1 reference)

PMID:42256365 SUPPORT Human Clinical

"Management of PLACK syndrome remains symptomatic and supportive, primarily with emollients and keratolytics."

States the current standard of skin care.

Intravenous Lipid Emulsion

Action: Intravenous lipid emulsion pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Dosing: monthly every 30 days

Monthly intravenous lipid emulsion (Vitalipid with Lipofundin MCT/LCT 20%) produced resolution of pruritus and marked skin improvement in one 11-year-old patient with low vitamin A and essential fatty acids. Single-patient report; no controlled data.

Show evidence (1 reference)

PMID:33410500 SUPPORT Human Clinical

"This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition."

Single-case report of objective response to intravenous lipid therapy.

Heart Transplantation

Action: Heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Platform: Surgery

Orthotopic heart transplantation for end-stage dilated cardiomyopathy; the two transplanted children in the 2025 family were clinically stable at five months and one year.

Target Phenotypes: Dilated cardiomyopathy HP:0001644

Show evidence (1 reference)

PMID:41300744 SUPPORT Human Clinical

"The favorable short-term outcome following transplantation highlights a potential therapeutic option."

Short-term outcome of heart transplantation in CAST-related cardiomyopathy.

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Biochemical Markers

1

Low vitamin A and essential fatty acids (DECREASED)

Show evidence (1 reference)

PMID:33410500 SUPPORT Human Clinical

"we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids"

Reports the biochemical finding in a single CAST-confirmed patient.

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Diagnosis

2

Molecular confirmation of biallelic CAST variants

Diagnosis is suspected from the clinical pentad and confirmed by exome or genome sequencing; RNA studies can confirm splice and novel variants. Reduced calpastatin immunostaining in skin supports the diagnosis. Naxos and Carvajal syndromes, which combine palmoplantar keratoderma with cardiomyopathy, are distinguished by woolly hair.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:41300744 SUPPORT Human Clinical

"GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family."

Genome sequencing established the molecular diagnosis in this family.

PMID:42256365 SUPPORT Human Clinical

"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."

Gives the clinical feature that separates PLACK from the keratoderma-cardiomyopathy differential.

Lifelong Echocardiographic Surveillance

Periodic echocardiography is suggested for all patients, because cardiomyopathy penetrance appears age-dependent and cannot be predicted from genotype.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:41300744 SUPPORT Human Clinical

"Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested."

Recommendation for lifelong cardiac surveillance.

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Prevalence

2

Worldwide (published case literature)

Cases In Literature Ultra Rare

27 published patients by 2026 according to PMID:42256365; earlier tallies were 19 (PMID:40387456) and 21 (PMID:41300744).

Show evidence (2 references)

PMID:42256365 SUPPORT REVIEW SYNTHESIS Human Clinical

"To date, there are 27 patients with PLACK syndrome reported, including ours, with 7 patients developed DCM."

Most recent literature count of reported PLACK patients.

PMID:40387456 SUPPORT REVIEW SYNTHESIS Human Clinical

"A total of 19 cases have been described in 12 articles"

Literature count of reported PLACK cases at the time of the 2025 review.

Worldwide

Point Prevalence <1 in 1,000,000

Orphanet worldwide point-prevalence class <1 / 1,000,000.

Show evidence (1 reference)

ORPHA:444138 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25683118"

Orphanet epidemiology table for PLACK syndrome.

{ }

Source YAML

click to show

name: PLACK Syndrome
creation_date: "2026-10-14T17:23:46Z"
category: Mendelian
description: >-
  PLACK syndrome (peeling skin, leukonychia, acral punctate keratoses, cheilitis and
  knuckle pads) is an ultra-rare autosomal recessive genodermatosis caused by biallelic
  loss-of-function variants in CAST, which encodes calpastatin, the endogenous inhibitor
  of the calcium-dependent cysteine proteases calpain-1 and calpain-2. Generalized
  superficial skin peeling begins in infancy, together with white nails, punctate
  keratoses of the palms and soles, inflamed lips and thickened skin over the finger
  joints. Lesional epidermis shows widened intercellular spaces and apoptotic
  keratinocytes in the upper stratum spinosum, so the skin disease is a defect of
  suprabasal keratinocyte adhesion. About a quarter of reported patients develop
  childhood-onset dilated cardiomyopathy, which is the main reported cause of death
  and of heart transplantation in this disease.
synonyms:
- PLACK syndrome
- peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads
- peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
disease_term:
  preferred_term: PLACK syndrome
  term:
    id: MONDO:0014574
    label: peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
parents:
- Peeling Skin Syndrome
notes: >-
  Curated separately from Peeling_Skin_Syndrome, where it appears as the PLACK-CAST
  subtype, because MONDO does not place MONDO:0014574 under peeling skin syndrome (MONDO:0019347), because the
  cleavage and apoptosis sit in the upper stratum spinosum rather than the stratum
  corneum, and because a subset of patients develop dilated cardiomyopathy, an organ
  system no other peeling skin subtype involves. No GeneReviews chapter covers this
  disease: a PubMed search for "(PLACK OR calpastatin OR peeling skin) AND
  genereviews[book]" returned no records.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: The founding report establishes autosomal recessive inheritance of CAST loss of function.
prevalence:
- population: Worldwide (published case literature)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    27 published patients by 2026 according to PMID:42256365; earlier tallies were 19
    (PMID:40387456) and 21 (PMID:41300744).
  evidence:
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "To date, there are 27 patients with PLACK syndrome reported, including ours, with 7 patients developed DCM."
    explanation: Most recent literature count of reported PLACK patients.
  - reference: PMID:40387456
    reference_title: "Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis and Knuckle Pads (PLACK) Syndrome: An Updated Review of Cases and Identification of a Recurrent CAST Variant in Two Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A total of 19 cases have been described in 12 articles"
    explanation: Literature count of reported PLACK cases at the time of the 2025 review.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class <1 / 1,000,000.
  evidence:
  - reference: ORPHA:444138
    reference_title: "Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25683118"
    explanation: Orphanet epidemiology table for PLACK syndrome.
pathophysiology:
- name: Biallelic CAST Loss of Function
  description: >-
    Homozygous or compound heterozygous truncating CAST variants (frameshift, nonsense,
    splice-site, and one large deletion) abolish calpastatin. Patient cells show reduced
    CAST transcript through nonsense-mediated decay, reduced protein, and reduced
    calpastatin inhibitory activity.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: CAST
    term:
      id: hgnc:1515
      label: CAST
  molecular_functions:
  - preferred_term: calpain inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0010859
      label: calcium-dependent cysteine-type endopeptidase inhibitor activity
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins"
    explanation: All founding-family variants are biallelic truncating CAST alleles.
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals."
    explanation: Calpastatin protein is reduced in patient skin.
  - reference: PMID:31392520
    reference_title: "A novel homozygous nonsense mutation in CAST associated with PLACK syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: Patient fibroblasts show loss of calpastatin protein and inhibitory activity.
  - reference: PMID:37221445
    reference_title: "A patient with PLACK syndrome with a novel splicing mutation in CAST: the evidence for a loss-of-function mechanism through mis-splicing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Segregation and expression analysis revealed that this loss-of-function via mRNA nonsense-mediated decay could be the causative pathogenic mechanism responsible for this patient's phenotype."
    explanation: A splice variant causes loss of function through nonsense-mediated decay of CAST mRNA.
  downstream:
  - target: Unrestrained Calpain Proteolytic Activity
    causal_link_type: DIRECT
- name: Unrestrained Calpain Proteolytic Activity
  description: >-
    Calpastatin is the specific endogenous inhibitor of calpain-1 and calpain-2, so its
    loss is expected to leave calcium-activated calpain proteolysis unchecked. Calpain
    activity has not been measured in patient tissue, and the calpain substrates whose
    cleavage disrupts adhesion are not known; this node is inferred from the known
    function of calpastatin.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: calpain activity
    modifier: INCREASED
    term:
      id: GO:0004198
      label: calcium-dependent cysteine-type endopeptidase activity
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease."
    explanation: >-
      States the inhibitor relationship from which increased calpain activity follows;
      the paper does not measure calpain activity itself.
  downstream:
  - target: Impaired Keratinocyte Intercellular Adhesion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42256365
      reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Loss of calpastatin leads to unopposed calpain activity and excessive proteolysis of structural proteins, resulting in impaired epidermal barrier stability and the characteristic skin findings of PLACK syndrome."
      explanation: >-
        States the proposed calpain-to-epidermal-instability step; the calpain
        substrates involved have not been identified.
  - target: Keratinocyte Apoptosis
  - target: Cardiomyocyte Calpain Overactivity
    hypothesis_groups:
    - calpain_driven_cardiomyopathy
- name: Impaired Keratinocyte Intercellular Adhesion
  description: >-
    Lesional skin shows widened intercellular spaces in the upper stratum spinosum, and
    CAST knockdown in cultured keratinocytes impairs their adhesion. Loss of cohesion
    between suprabasal keratinocytes is the structural basis of the superficial
    peeling.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:4052061
      label: epidermal keratinocyte
  biological_processes:
  - preferred_term: keratinocyte cell-cell adhesion
    modifier: DECREASED
    term:
      id: GO:0090136
      label: epithelial cell-cell adhesion
  locations:
  - preferred_term: upper stratum spinosum
    term:
      id: UBERON:0002026
      label: stratum spinosum of epidermis
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Ultrastructure of patient skin shows loss of intercellular adhesion in the upper spinous layer.
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion."
    explanation: CAST knockdown in keratinocytes reproduces the adhesion defect.
  - reference: ORPHA:444138
    reference_title: "Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histopathologic examination of affected skin areas is not specific and shows hyperkeratosis, acanthosis, and occasional intraepidermal clefting with irregular acantholysis."
    explanation: Orphanet records intraepidermal clefting and acantholysis, the histological sign of lost keratinocyte cohesion.
  downstream:
  - target: Generalized Superficial Skin Peeling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25683118
      reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST"
      explanation: The authors attribute the peeling phenotype to defective epidermal adhesion.
- name: Keratinocyte Apoptosis
  description: >-
    TUNEL staining shows a significant increase in apoptotic keratinocytes in lesional
    skin, and electron microscopy shows chromatin condensation and margination in the
    upper stratum spinosum.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: epidermal keratinocyte
    term:
      id: CL:4052061
      label: epidermal keratinocyte
  biological_processes:
  - preferred_term: keratinocyte apoptotic process
    modifier: INCREASED
    term:
      id: GO:0097283
      label: keratinocyte apoptotic process
  locations:
  - preferred_term: upper stratum spinosum
    term:
      id: UBERON:0002026
      label: stratum spinosum of epidermis
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A significant increase of apoptotic keratinocytes was also observed in TUNEL assays."
    explanation: Direct measurement of increased keratinocyte apoptosis in patient skin.
  downstream:
  - target: Generalized Superficial Skin Peeling
    evidence:
    - reference: PMID:25683118
      reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: >-
        Apoptotic keratinocytes sit at the same level as the epidermal separation in
        lesional skin; the paper places both at the lesion but does not test whether
        apoptosis itself drives the peeling.
- name: Cardiomyocyte Calpain Overactivity
  description: >-
    Proposed mechanism for the dilated cardiomyopathy seen in several PLACK families:
    calpastatin loss raises calpain activity in cardiomyocytes, degrading cytoskeletal
    and sarcomeric proteins and causing cardiomyocyte loss and fibrosis. Transgenic
    mice with cardiomyocyte-restricted calpain-1 or calpain-2 overexpression develop
    dilated cardiomyopathy. No patient myocardium has been examined for calpain
    activity, and the explanted-heart histology reported so far (hypertrophied
    cardiomyocytes, bizarre nuclei, fibrosis) is nonspecific.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: calpain activity
    modifier: INCREASED
    term:
      id: GO:0004198
      label: calcium-dependent cysteine-type endopeptidase activity
  evidence:
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "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."
    explanation: The case authors propose calpain-mediated cardiomyocyte cytoskeletal degradation as the cardiac mechanism.
  - reference: PMID:30874894
    reference_title: "Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic up-regulation of mitochondria-targeted CAPN1 dose-dependently induced cardiac cell death, adverse myocardial remodeling, heart failure, and early death in mice"
    explanation: >-
      Excess mitochondrial calpain-1 in mouse cardiomyocytes causes cardiomyocyte
      death and heart failure; this is an overexpression model, not calpastatin loss.
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - calpain_driven_cardiomyopathy
    evidence:
    - reference: PMID:35986214
      reference_title: "Sustained over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice through aberrant autophagy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "transgenic over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice, which may be mediated through aberrant autophagy and a reduction of junctophilin-2"
      explanation: >-
        Mouse evidence that cardiomyocyte calpain excess is sufficient for dilated
        cardiomyopathy; whether CAST-deficient human hearts follow the same path is
        untested.
mechanistic_hypotheses:
- hypothesis_group_id: calpain_driven_cardiomyopathy
  hypothesis_label: >-
    Unopposed cardiomyocyte calpain activity causes the dilated cardiomyopathy of
    PLACK syndrome
  status: EMERGING
  description: >-
    Dilated cardiomyopathy segregates with biallelic CAST loss in several families, with
    no other cardiomyopathy gene found in the best-studied one. The proposed link is
    unopposed calpain proteolysis in cardiomyocytes, which is supported only by mouse
    calpain-overexpression models. It has not been tested in patient tissue or in a
    CAST-deficient animal, and penetrance appears incomplete and age-dependent.
  evidence:
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy."
    explanation: The family study proposes CAST deficiency as a cause of recessive cardiomyopathy.
phenotypes:
- category: Integumentary
  name: Generalized Superficial Skin Peeling
  description: >-
    Superficial peeling of the skin over the whole body, beginning in infancy.
  phenotype_term:
    preferred_term: Generalized superficial skin peeling
    term:
      id: HP:0040189
      label: Scaling skin
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"
    explanation: Generalized peeling skin is the first defining feature of the syndrome.
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dermatological manifestations had been apparent since the first six months of life"
    explanation: Skin findings began in the first six months of life in the index patient of the 2025 family.
- category: Integumentary
  name: Superficial Blistering
  description: Superficial blisters that heal without scarring, in place of or alongside peeling.
  phenotype_term:
    preferred_term: Superficial blisters without scarring
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: ORPHA:444138
    reference_title: "Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare genetic skin disease characterized by generalized skin peeling or superficial blisters without scarring"
    explanation: Orphanet definition lists superficial blisters without scarring.
- category: Integumentary
  name: Leukonychia
  description: White discoloration of the fingernails and toenails.
  phenotype_term:
    preferred_term: Leukonychia
    term:
      id: HP:0001820
      label: Leukonychia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"
    explanation: Leukonychia is a defining feature.
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fingernails and toenails showed leukonychia with unremarkable hair examination."
    explanation: Case report showing leukonychia of fingernails and toenails.
- category: Integumentary
  name: Acral Punctate Keratoses
  description: Small punctate hyperkeratotic papules on the palms and soles.
  phenotype_term:
    preferred_term: Acral punctate keratoses
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"
    explanation: Acral punctate keratoses are a defining feature.
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple hyperkeratotic papules on palms and soles"
    explanation: Case report describing palmoplantar hyperkeratotic papules.
- category: Integumentary
  name: Cheilitis
  description: Inflammation and scaling of the lips.
  phenotype_term:
    preferred_term: Cheilitis
    term:
      id: HP:0100825
      label: Cheilitis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"
    explanation: Cheilitis is a defining feature.
- category: Integumentary
  name: Knuckle Pads
  description: Thickened, hyperkeratotic skin over the finger joints.
  phenotype_term:
    preferred_term: Knuckle pad
    term:
      id: HP:0032541
      label: Knuckle pad
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads"
    explanation: Knuckle pads are a defining feature.
- category: Integumentary
  name: Follicular Hyperkeratosis
  description: Keratotic follicular papules with generalized xerosis.
  phenotype_term:
    preferred_term: Follicular hyperkeratosis
    term:
      id: HP:0007502
      label: Follicular hyperkeratosis
  evidence:
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin examination revealed generalized xerosis with follicular hyperkeratosis, cheilitis, and multiple hyperkeratotic papules on palms and soles."
    explanation: Follicular hyperkeratosis reported alongside the classic features in a CAST-confirmed case.
- category: Integumentary
  name: Pruritus
  description: Itching, which resolved with intravenous lipid treatment in one patient.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:33410500
    reference_title: "PLACK syndrome is potentially treatable with intralipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement."
    explanation: Pruritus was present before treatment in this CAST-confirmed patient.
- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    Childhood-onset dilated cardiomyopathy (onset 4 to 15 years) in 7 of 27 reported
    patients, progressing to heart failure; three died, three received heart
    transplants and one needed a biventricular assist device. Penetrance appears
    incomplete and possibly age-dependent: affected siblings with the skin phenotype
    and normal echocardiograms have been reported, and no genotype-phenotype
    correlation for cardiac involvement has been found. One further patient's
    cardiomyopathy is attributed to a separate MYBPC3 variant.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Literature tally giving the frequency, outcomes, and onset age of dilated cardiomyopathy.
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation."
    explanation: Four of five CAST-homozygous children in one family developed severe dilated cardiomyopathy.
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No other variants in the genes known to cause cardiomyopathy were found."
    explanation: Genome sequencing excluded other known cardiomyopathy genes in this family.
  - reference: PMID:38994911
    reference_title: "CASTing the net wider: A case report of PLACK syndrome associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case report highlights a case of PLACK syndrome presenting with the unique findings of striate hyperkeratosis on the palms as well as life-threatening cardiomyopathy."
    explanation: An independent case with life-threatening cardiomyopathy.
  - reference: PMID:42742298
    reference_title: "Concomitant PLACK Syndrome, MYBPC3-Related Cardiomyopathy, and Nutritional Deficiency."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      This patient's cardiomyopathy is attributed to a separate MYBPC3 variant, so the
      case does not bear on whether CAST loss causes cardiomyopathy.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden death of affected children, reported in several PLACK families; most of
    these children were not genotyped or examined, so a cardiac cause is presumed.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Remarkably, seven of his family members who were affected by PLACK syndrome had sudden cardiac death between the ages of 8 and 14 years."
    explanation: Describes a previously reported PLACK family with seven sudden cardiac deaths in affected members.
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "two of her brothers had similar dermatological features and died suddenly at the ages of 3 and 4 years"
    explanation: Sudden death of two affected brothers in the first PLACK family reported with dilated cardiomyopathy.
biochemical:
- name: Low vitamin A and essential fatty acids
  presence: DECREASED
  notes: >-
    Found in one patient and prompted intravenous lipid treatment; a further patient had
    severe protein-calorie malnutrition (PMID:42742298). Whether these follow from the
    epidermal defect or are coincidental is unknown.
  evidence:
  - reference: PMID:33410500
    reference_title: "PLACK syndrome is potentially treatable with intralipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids"
    explanation: Reports the biochemical finding in a single CAST-confirmed patient.
genetic:
- name: CAST
  gene_term:
    preferred_term: CAST
    term:
      id: hgnc:1515
      label: CAST
  relationship_type: CAUSATIVE
  association: Autosomal recessive
  notes: >-
    Biallelic truncating variants (frameshift, nonsense, splice-site, and one large
    deletion in trans with a nonsense allele). c.571G>T (p.Gly191Ter) is the only
    variant reported in more than one family. No genotype-phenotype correlation for
    cardiac involvement has been found.
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: Establishes CAST as the causal gene.
  - reference: PMID:40387456
    reference_title: "Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis and Knuckle Pads (PLACK) Syndrome: An Updated Review of Cases and Identification of a Recurrent CAST Variant in Two Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two pediatric PLACK cases with a homozygous loss-of-function CAST variant (c.571G>T, p.Gly191Ter) which represents the only recurrent genetic variant of PLACK syndrome reported in the literature."
    explanation: Identifies the only recurrent CAST variant.
diagnosis:
- name: Molecular confirmation of biallelic CAST variants
  description: >-
    Diagnosis is suspected from the clinical pentad and confirmed by exome or genome
    sequencing; RNA studies can confirm splice and novel variants. Reduced calpastatin
    immunostaining in skin supports the diagnosis. Naxos and Carvajal syndromes, which
    combine palmoplantar keratoderma with cardiomyopathy, are distinguished by woolly
    hair.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family."
    explanation: Genome sequencing established the molecular diagnosis in this family.
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Gives the clinical feature that separates PLACK from the keratoderma-cardiomyopathy differential.
- name: Lifelong Echocardiographic Surveillance
  description: >-
    Periodic echocardiography is suggested for all patients, because cardiomyopathy
    penetrance appears age-dependent and cannot be predicted from genotype.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested."
    explanation: Recommendation for lifelong cardiac surveillance.
treatments:
- name: Emollients and Keratolytics
  description: Symptomatic topical skin care, the mainstay of management.
  treatment_term:
    preferred_term: Supportive skin care with emollients and keratolytics
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    No therapeutic_agent is bound: NCIT:C467 Emollient is not reachable from the
    ChemicalEntityTerm enum root NCIT:C1909 (Pharmacologic Substance), and the source
    names no specific product.
  evidence:
  - reference: PMID:42256365
    reference_title: "Leukonychia and peeling skin in an 11-year-old girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management of PLACK syndrome remains symptomatic and supportive, primarily with emollients and keratolytics."
    explanation: States the current standard of skin care.
- name: Intravenous Lipid Emulsion
  description: >-
    Monthly intravenous lipid emulsion (Vitalipid with Lipofundin MCT/LCT 20%) produced
    resolution of pruritus and marked skin improvement in one 11-year-old patient with
    low vitamin A and essential fatty acids. Single-patient report; no controlled data.
  dosing_interval: monthly
  dosing_interval_days: 30
  treatment_term:
    preferred_term: Intravenous lipid emulsion pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  notes: >-
    No therapeutic_agent is bound: NCIT:C79837 MCT/LCT Lipid Emulsion is not reachable
    from the ChemicalEntityTerm enum root NCIT:C1909 (Pharmacologic Substance), and
    binding one component such as soybean oil would misstate a two-product regimen.
  evidence:
  - reference: PMID:33410500
    reference_title: "PLACK syndrome is potentially treatable with intralipids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition."
    explanation: Single-case report of objective response to intravenous lipid therapy.
- name: Heart Transplantation
  description: >-
    Orthotopic heart transplantation for end-stage dilated cardiomyopathy; the two
    transplanted children in the 2025 family were clinically stable at five months and
    one year.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:41300744
    reference_title: "Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The favorable short-term outcome following transplantation highlights a potential therapeutic option."
    explanation: Short-term outcome of heart transplantation in CAST-related cardiomyopathy.
discussions:
- discussion_id: gap_plack_calpain_activity_untested
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is calpain activity increased in PLACK skin and myocardium, which calpain substrates
    mediate the adhesion and cardiac defects, and why do only some patients develop
    cardiomyopathy?
  rationale: >-
    Every node downstream of calpastatin loss rests on calpastatin's known biochemistry
    and on mouse calpain-overexpression models. No patient tissue has been assayed for
    calpain activity, no adhesion substrate has been identified, and no CAST-deficient
    animal with a skin or cardiac phenotype has been described. The incomplete,
    age-dependent cardiac penetrance has no explanation.
  attaches_to:
  - pathophysiology#Unrestrained Calpain Proteolytic Activity
  - pathophysiology#Cardiomyocyte Calpain Overactivity
references:
- reference: PMID:25683118
  title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."

📚

References & Deep Research

References

1

PMID:25683118

Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: PLACK_Syndrome · 2026-10-14T17:37:50Z · View source

Created a standalone entry for PLACK syndrome (MONDO:0014574, CAST). Before this it existed only as the PLACK-CAST subtype row of Peeling_Skin_Syndrome; that row now carries curated_in: PLACK_Syndrome and the MONDO subtype_term. Promoted because MONDO does not place MONDO:0014574 under peeling skin syndrome (MONDO:0019347), the cleavage and apoptosis are in the upper stratum spinosum rather than the stratum corneum, and about a quarter of patients develop childhood dilated cardiomyopathy, which no sibling subtype has. Deep research: falcon was requested but failed with '503 Failed to authenticate' on two runs, the second with --fallback, which did not switch providers. 'deep-research-client providers --check' reported falcon UNREACHABLE and claude_code OK, so the report used is research/PLACK_Syndrome-deep-research-claude_code.md, run explicitly. Its validation showed 21/21 references resolved, 18/18 quotes valid and 31/31 terms resolved. Primary sources were PubMed searches and cached abstracts or full text; seven PLACK case reports had no cached abstract text and were not cited. The cardiac mechanism is recorded as an EMERGING hypothesis (calpain_driven_cardiomyopathy) supported only by mouse calpain-overexpression models (PMID:35986214, PMID:30874894), with a KNOWLEDGE_GAP discussion. The calpastatin-knockout mouse paper (PMID:18803809) is a behavioural study that does not report skin, so it was not used to claim a model mismatch. NCIT:C467 Emollient and NCIT:C79837 MCT/LCT Lipid Emulsion are outside the ChemicalEntityTerm enum, so those treatments carry no therapeutic_agent. Validation: just validate-disorders on both changed files passed (90 snippets, 0 issues); count-verified-snippets reported 90/90; check-entity-refs, check-causal-targets, check-duplicate-keys and check-genereviews (NO_CHAPTER) were clean. A pre-PR review (fresh-context subagent) led to: rebinding the adhesion process to GO:0090136 epithelial cell-cell adhesion; edge evidence on the calpain-to-adhesion step (PMID:42256365, INDIRECT/BACKGROUND); dropping the unsupported knuckle-pad frequency; softening the claim that dilated cardiomyopathy explains every death; adding primary sudden-death evidence; and a sentence in Peeling_Skin_Syndrome's protease-inhibitor node noting that CAST separation is suprabasal. Not added: blistering, silver hair, warts, cerebral atrophy (single reports or MeSH only, no quotable text), and a DCM-to-sudden-death sequela (the sudden deaths were not attributed to cardiomyopathy). PR review round 1 (ai4c-reviewer, CHANGES_REQUESTED): added reference_title to all 47 evidence items, copied from each cached reference's title field. Also took the optional suggestions: evidence on the Keratinocyte Apoptosis to peeling edge (PMID:25683118, INDIRECT); moved echocardiographic surveillance from treatments to diagnosis; and cached Orphanet ORPHA:444138 (via MONDO's Orphanet:444138 xref), which supplies a point-prevalence record (<1 / 1,000,000), onset in infancy, a superficial-blistering phenotype (HP:0008066), and histology evidence on the adhesion node. Not taken: an animal_models FAILS_TO_RECAPITULATE entry for the calpastatin-knockout mouse, because its paper (PMID:18803809) is a behavioural study that does not report on skin. CI fix: the short-snippet gate (check_snippet_length.py) rejected the four-word Orphanet onset line 'Age of onset: Infancy'. It was replaced with the full sentence from PMID:41300744 stating that skin findings began in the first six months of life.

Claude Code ▸

PLACK Syndrome (MONDO:0014574): Research Report

claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-14T13:28:53.164358

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)

Identifier	Value	Status
MONDO	MONDO:0014574, "peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome" (MONDO's own spelling, "leukonuchia")	✔ (stub and draft entry)
OMIM (phenotype)	616295	✔ (quoted in PMID:31392520, 33010050, 38994911, 40387456)
OMIM (gene)	CAST 114090, chromosome 5q15	from the OMIM search snippet; ⚠ confirm
Orphanet	not confirmed; orpha.net was blocked and the local ORPHA cache has no match	⚠
ICD-10 / ICD-11 / MeSH	no disease-specific code; MeSH indexes these papers under "Skin Diseases, Genetic" and "Dermatitis, Exfoliative"	—

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.

Phenotype	HPO	Frequency	Onset and course	Key evidence
Generalized peeling skin (exfoliation)	HP:0025819 Palmoplantar peeling ✔ covers only the acral part; ⚠ look up a generalized exfoliation term	Defining (essentially all)	Infancy; chronic	PMID:25683118
Leukonychia	HP:0001820 ✔	Defining	Congenital or infancy	PMID:25683118, 42256365 ("Fingernails and toenails showed leukonychia")
Acral punctate keratoses	HP:0007530 Punctate palmoplantar hyperkeratosis ✔	Defining	Childhood; progressive	PMID:25683118, 42256365 ("multiple hyperkeratotic papules on palms and soles")
Cheilitis, including angular	HP:0100825 ✔ / HP:0030318 ✔	Defining	Childhood	PMID:25683118, 42256365
Knuckle pads	HP:0032541 Knuckle pad ✔	Defining but may appear later	Childhood	PMID:25683118
Pruritus	HP:0000989 ✔	Common	Chronic	PMID:33410500 ("pruritis disappeared" with treatment)
Follicular hyperkeratosis / xerosis	HP:0007502 ✔	Reported	—	PMID:42256365
Skin hypopigmentation	HP:0001010 ✔	Reported (MeSH "Hypopigmentation")	—	PMID:28851602, 32918489, 33410500
Blistering	HP:0008066 ✔	Occasional; the first 1986 family was misdiagnosed as epidermolysis bullosa simplex	—	PMID:33410500 (MeSH "Blister")
Oral leukokeratosis	HP:0002745 Oral leukoplakia ✔ (approximate)	OMIM synopsis	—	OMIM (web)
Striate palmar hyperkeratosis	⚠	Rare	—	PMID:38994911
Silver hair, cutaneous warts	HP:0002218 ✔, HP:0200043 ✔	Rare	—	PMID:41300744
Alopecia areata	⚠	Single case; likely coincidental	—	PMID:37317743 (title)
Mild cerebral atrophy, mild muscle involvement	HP:0002059 ✔	Single case	—	PMID:31392520
Dilated cardiomyopathy	HP:0001644 ✔	About 7/27 (~26%) in the 2026 tally; age-dependent	Onset 4–15 years; rapidly progressive to heart failure	PMID:38994911, 41300744, 42256365
Sudden cardiac death in family members	HP:0001645 ✔	Multiple families	Childhood	PMID:41300744, 42256365

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.

Variant	Type	Families or ancestry	PMID
c.607dup p.(Ile203Asnfs8); c.424A>T p.(Lys142); c.1750delG p.(Val584Trpfs*37)	frameshift / nonsense	3 families of different ethnicities (founding paper)	25683118
c.544G>T p.(Glu182*)	nonsense	Turkish boy and his aunt	31392520
c.571G>T p.(Gly191*)	nonsense; the only recurrent variant	2 patients	40387456
c.1209+2T>G (NM_001042440.5)	splice; +1 nt frameshift, then nonsense-mediated decay (NMD)	Iranian boy	37221445
c.1177dup p.(Arg393Profs*4) (NM_001750.7)	frameshift	Saudi extended family, 5 affected, 4 with DCM	41300744
c.1054dup	frameshift	Saudi girl with DCM	42256365
c.1882C>T p.(Gln628*)	nonsense	Turkish sibship with DCM and sudden deaths (Durmaz 2023, as described in 41300744)	37387535 (no abstract)
Nonsense variant + 326.7 kb deletion chr5:96037538_96364237 (also removes ERAP2 and LNPEP)	compound heterozygous	15-year-old with DCM	cited in 41300744 (likely 38994911; ⚠ confirm)
Novel insertion variants	insertion	French; Afghan; Indian (exon 18)	28851602, 32918489, 37317743
Novel homozygous variants	—	Irish; Saudi; Chinese; Indian	33010050, 33410500, 37140444, 39931923

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

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).
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.
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)
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)
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)
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)
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

Level	Structures
Primary organ	Skin and its appendages: epidermis (especially the upper stratum spinosum), nails, lips/oral mucosa, palms and soles, knuckles
Secondary organ	Heart: left ventricle, with atrial fibrosis in one explant (PMID:42256365)
Possible	Central nervous system and muscle (single case, PMID:31392520)
Subcellular	Cytosol (calpastatin and calpain), cell–cell junctions, nucleus (chromatin condensation in apoptosis)
Lateralization	Bilateral and symmetric

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

Treatment	Evidence	NCIT suggestion
Emollients and keratolytics (symptomatic)	Standard of care (PMID:42256365)	NCIT:C15747 Supportive Care (listed in CLAUDE.md; ⚠ verify)
IV lipid emulsion plus fat-soluble vitamins (Vitalipid® + Lipofundin MCT/LCT 20%), monthly	Single case with dramatic response	NCIT:C15986 Pharmacotherapy (⚠ verify), or NCIT:C15433 Nutritional Support (⚠; do not assign BEHAVIORAL modality); `therapeutic_agent` ⚠ look up a soybean-oil / lipid emulsion term in CHEBI or NCIT
Orthotopic heart transplantation for DCM	3 patients; good short-term outcome	NCIT:C15289 Organ Transplantation (⚠ verify; modality SURGERY)
Heart-failure pharmacotherapy and mechanical support	1 biventricular assist device	—

"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

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	21
Resolved	21
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	18
Quoted claims found in source	18
Quoted claims not found in source	0
Quoted claims with nothing to check against	1
References weighed for topical relevance	21
On topic	14
Off topic	0

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

PMID:30656735: "remarkably homogeneous"
Reference resolved but exposes no abstract or full text to search

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	31
Resolved	31
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

Every term resolved, and every label the report gave matched.

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PLACK Syndrome (MONDO:0014574): Research Report

How this was assembled and what it can support

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Suggested terms

Molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Notes for the KB entry

Reference Validation

Quotes that could not be checked

Term Validation