Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

Summary

Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (MONDO:0014574) is a disease caused by CAST (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CAST (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
Mondo ID	MONDO:0014574
OMIM	616295
Orphanet	444138
DOID	DOID:0070526
UMLS	C4225381
MedGen	902464
GARD	0017764
Is cancer (heuristic)	no

Also known as: peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads · plack · plack syndrome

Data availability: 16 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

5 benign, 4 uncertain significance, 4 likely pathogenic, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
189334	NM_001750.7(CAST):c.730dup (p.Ile244fs)	CAST	Pathogenic	no assertion criteria provided
189335	NM_001750.7(CAST):c.547A>T (p.Lys183Ter)	CAST	Pathogenic	no assertion criteria provided
189336	NM_001750.7(CAST):c.1873del (p.Val625fs)	ERAP1	Pathogenic	no assertion criteria provided
3362485	NM_001750.7(CAST):c.1174dup (p.Leu392fs)	CAST	Likely pathogenic	criteria provided, single submitter
3902045	NM_001750.7(CAST):c.289C>T (p.Gln97Ter)	CAST	Likely pathogenic	criteria provided, single submitter
4076958	NM_001750.7(CAST):c.1882C>T (p.Gln628Ter)	CAST	Likely pathogenic	criteria provided, single submitter
4277782	NM_001750.7(CAST):c.630+2T>C	CAST	Likely pathogenic	criteria provided, single submitter
2665035	NM_001750.7(CAST):c.587G>T (p.Ser196Ile)	CAST	Uncertain significance	criteria provided, single submitter
2665036	NM_001750.7(CAST):c.1200+911C>A	CAST	Uncertain significance	criteria provided, single submitter
3592841	NM_001750.7(CAST):c.1284G>A (p.Thr428=)	CAST	Uncertain significance	criteria provided, single submitter
3902043	NM_001750.7(CAST):c.138+8410A>G	CAST	Uncertain significance	criteria provided, single submitter
1192696	NM_001750.7(CAST):c.168A>G (p.Gln56=)	CAST	Benign	criteria provided, multiple submitters, no conflicts
1192697	NM_001750.7(CAST):c.1472G>C (p.Cys491Ser)	CAST	Benign	criteria provided, multiple submitters, no conflicts
1192698	NM_001750.7(CAST):c.1525-106G>A	CAST	Benign	criteria provided, multiple submitters, no conflicts
1614516	NM_001750.7(CAST):c.1441G>A (p.Ala481Thr)	CAST	Benign	criteria provided, multiple submitters, no conflicts
791137	NM_001750.7(CAST):c.1207G>C (p.Ala403Pro)	CAST	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CAST	Strong	Autosomal recessive	peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAST	Orphanet:444138	Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome
ERAP1	Orphanet:117	Behçet disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CAST	HGNC:1515	ENSG00000153113	P20810	Calpastatin	gencc,clinvar
ERAP1	HGNC:18173	ENSG00000164307	Q9NZ08	Endoplasmic reticulum aminopeptidase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAST	Calpastatin	Specific inhibition of calpain (calcium-dependent cysteine protease).
ERAP1	Endoplasmic reticulum aminopeptidase 1	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CAST	Other/Unknown	no		Prot_inh_calpain, Calpastatin
ERAP1	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
calcaneal tendon	1
colonic epithelium	1
jejunal mucosa	1
monocyte	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAST	301	tissue_specific	marker	calcaneal tendon, bronchial epithelial cell, colonic epithelium
ERAP1	286	ubiquitous	marker	jejunal mucosa, rectum, monocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERAP1	2,107
CAST	1,152

Intra-cohort edges

A	B	Sources
CAST	ERAP1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERAP1	Q9NZ08	23

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CAST	P20810	59.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.008	CAST
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	196.9×	0.008	ERAP1
Degradation of the extracellular matrix	1	58.9×	0.017	CAST

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
presynaptic active zone organization	1	8426.0×	0.002	CAST
antigen processing and presentation of peptide antigen via MHC class I	1	1685.2×	0.003	ERAP1
antigen processing and presentation of endogenous peptide antigen via MHC class I	1	1053.2×	0.003	ERAP1
negative regulation of type B pancreatic cell apoptotic process	1	1053.2×	0.003	CAST
peptide catabolic process	1	526.6×	0.005	ERAP1
membrane protein ectodomain proteolysis	1	324.1×	0.006	ERAP1
regulation of innate immune response	1	324.1×	0.006	ERAP1
regulation of blood pressure	1	110.9×	0.015	ERAP1
response to bacterium	1	96.8×	0.015	ERAP1
fat cell differentiation	1	90.6×	0.015	ERAP1
positive regulation of angiogenesis	1	57.7×	0.022	ERAP1
adaptive immune response	1	42.1×	0.028	ERAP1
angiogenesis	1	31.2×	0.034	ERAP1
proteolysis	1	17.1×	0.058	ERAP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERAP1	2	2
CAST	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TOSEDOSTAT	2	ERAP1
UBENIMEX	2	ERAP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ERAP1	88	Binding:85, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERAP1	3.4.11.1, 3.4.11.22	leucyl aminopeptidase, aminopeptidase I

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TOSEDOSTAT	2	ERAP1
UBENIMEX	2	ERAP1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ERAP1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CAST

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CAST	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.