Acral peeling skin syndrome

Summary

Acral peeling skin syndrome (MONDO:0012345) is a disease caused by TGM5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TGM5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 76
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0008064	Ichthyosis	Frequent (30-79%)
HP:0008066	Abnormal blistering of the skin	Frequent (30-79%)
HP:0008499	High hypermetropia	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0012393	Allergy	Frequent (30-79%)
HP:0040189	Scaling skin	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Occasional (5-29%)
HP:0007605	Excessive wrinkling of palmar skin	Occasional (5-29%)
HP:0012733	Macule	Occasional (5-29%)
HP:0200034	Papule	Occasional (5-29%)
HP:0200041	Skin erosion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acral peeling skin syndrome
Mondo ID	MONDO:0012345
MeSH	C536316
OMIM	609796
Orphanet	263534
DOID	DOID:0070521
SNOMED CT	709416009
UMLS	C1853354
MedGen	342862
GARD	0012863
Is cancer (heuristic)	no

Also known as: acral deciduous skin · acral peeling skin syndrome · acral PSS · localised deciduous skin · localised PSS · localized deciduous skin · localized PSS · peeling skin syndrome 2 · peeling skin syndrome type 2 · PSS2

Data availability: 76 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › peeling skin syndrome › acral peeling skin syndrome

Related subtypes (4): generalized peeling skin syndrome, peeling skin syndrome 4, peeling skin syndrome 5, peeling skin syndrome 6

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

76 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 15 benign, 9 likely pathogenic, 6 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 pathogenic, 3 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
157568	NM_201631.4(TGM5):c.763T>C (p.Trp255Arg)	TGM5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157570	NM_201631.4(TGM5):c.640del (p.Leu214fs)	TGM5	Pathogenic	criteria provided, single submitter
157571	NM_201631.4(TGM5):c.1811_1815delinsTCCTTCA (p.Ser604fs)	TGM5	Pathogenic	no assertion criteria provided
420028	NM_201631.4(TGM5):c.1001+2_1001+3del	TGM5	Pathogenic	criteria provided, multiple submitters, no conflicts
6039	NM_201631.4(TGM5):c.337G>T (p.Gly113Cys)	TGM5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631730	NM_201631.4(TGM5):c.255del (p.Ser86fs)	TGM5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325190	NM_201631.4(TGM5):c.393C>A (p.Tyr131Ter)	TGM5	Likely pathogenic	criteria provided, single submitter
1325191	NM_201631.4(TGM5):c.829C>T (p.Gln277Ter)	TGM5	Likely pathogenic	criteria provided, single submitter
1685463	NM_201631.4(TGM5):c.10+2T>C	TGM5	Likely pathogenic	criteria provided, single submitter
2664323	NM_201631.4(TGM5):c.115T>A (p.Phe39Ile)	TGM5	Likely pathogenic	criteria provided, single submitter
3065974	NM_201631.4(TGM5):c.2161T>C (p.Ter721Gln)	TGM5	Likely pathogenic	criteria provided, single submitter
3577130	NM_201631.4(TGM5):c.1037G>A (p.Arg346Gln)	TGM5	Likely pathogenic	criteria provided, single submitter
3577131	NM_201631.4(TGM5):c.643C>T (p.Arg215Trp)	TGM5	Likely pathogenic	criteria provided, single submitter
3780711	NM_201631.4(TGM5):c.1664del (p.Leu555fs)	TGM5	Likely pathogenic	criteria provided, single submitter
4845841	NM_201631.4(TGM5):c.700_709dup (p.Val237delinsGlyTer)	TGM5	Likely pathogenic	criteria provided, single submitter
157567	NM_201631.4(TGM5):c.1335G>C (p.Lys445Asn)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316040	NM_201631.4(TGM5):c.1689G>A (p.Ala563=)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316047	NM_201631.4(TGM5):c.1209C>T (p.Cys403=)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316059	NM_201631.4(TGM5):c.723C>G (p.Asn241Lys)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
778097	NM_201631.4(TGM5):c.125C>A (p.Thr42Asn)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887642	NM_201631.4(TGM5):c.1868C>T (p.Thr623Met)	TGM5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157569	NM_201631.4(TGM5):c.122T>C (p.Leu41Pro)	TGM5	Uncertain significance	criteria provided, single submitter
2355114	NM_201631.4(TGM5):c.380C>T (p.Ser127Phe)	TGM5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437072	NM_201631.4(TGM5):c.1518A>T (p.Gln506His)	TGM5	Uncertain significance	criteria provided, single submitter
2692374	NM_201631.4(TGM5):c.774C>G (p.Ser258Arg)	TGM5	Uncertain significance	criteria provided, single submitter
316034	NM_201631.4(TGM5):c.*430C>T	TGM5	Uncertain significance	criteria provided, single submitter
316036	NM_201631.4(TGM5):c.*56T>C	TGM5	Uncertain significance	criteria provided, single submitter
316044	NM_201631.4(TGM5):c.1471C>T (p.Pro491Ser)	TGM5	Uncertain significance	criteria provided, single submitter
316046	NM_201631.4(TGM5):c.1252C>A (p.Gln418Lys)	TGM5	Uncertain significance	criteria provided, single submitter
316049	NM_201631.4(TGM5):c.1104C>T (p.Asn368=)	TGM5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
TGM5	Definitive	Autosomal recessive	acral peeling skin syndrome	6
CSTA	Strong	Autosomal recessive	peeling skin syndrome 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGM5	Orphanet:263534	Acral peeling skin syndrome
CSTA	Orphanet:263534	Acral peeling skin syndrome
CSTA	Orphanet:289586	Exfoliative ichthyosis

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
TGM5	HGNC:11781	ENSG00000104055	O43548	Protein-glutamine gamma-glutamyltransferase 5	gencc,clinvar
CSTA	HGNC:2481	ENSG00000121552	P01040	Cystatin-A	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGM5	Protein-glutamine gamma-glutamyltransferase 5	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
CSTA	Cystatin-A	This is an intracellular thiol proteinase inhibitor.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGM5	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
CSTA	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS

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
skin of abdomen	1
skin of leg	1
zone of skin	1
gingiva	1
oral cavity	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGM5	155	tissue_specific	marker	skin of leg, skin of abdomen, zone of skin
CSTA	248	ubiquitous	marker	pharyngeal mucosa, oral cavity, gingiva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSTA	2,102
TGM5	845

Intra-cohort edges

A	B	Sources
CSTA	TGM5	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSTA	P01040	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TGM5	O43548	91.68

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
Formation of the cornified envelope	2	87.8×	4e-04	TGM5, CSTA
Keratinization	1	27.9×	0.053	TGM5
Developmental Biology	1	7.2×	0.134	TGM5

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
peptide cross-linking	1	702.2×	0.009	CSTA
negative regulation of proteolysis	1	337.0×	0.009	CSTA
keratinocyte differentiation	1	123.9×	0.011	CSTA
protein modification process	1	122.1×	0.011	TGM5
epidermis development	1	105.3×	0.011	TGM5
cell-cell adhesion	1	50.8×	0.020	CSTA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGM5	0	0
CSTA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM5	2.3.2.13	protein-glutamine gamma-glutamyltransferase

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TGM5
E	Difficult family or no structure, no drug	1	CSTA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TGM5	0	—
CSTA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.