Clouston syndrome

Summary

Clouston syndrome (MONDO:0007510) is a disease caused by GJB6 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: GJB6 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 134
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000653	Sparse eyelashes	Frequent (30-79%)
HP:0000972	Palmoplantar hyperkeratosis	Frequent (30-79%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0045075	Sparse eyebrow	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000953	Hyperpigmentation of the skin	Occasional (5-29%)
HP:0001072	Thickened skin	Occasional (5-29%)
HP:0001792	Small nail	Occasional (5-29%)
HP:0001798	Anonychia	Occasional (5-29%)
HP:0002209	Sparse scalp hair	Occasional (5-29%)
HP:0002213	Fine hair	Occasional (5-29%)
HP:0002215	Sparse axillary hair	Occasional (5-29%)
HP:0002221	Absent axillary hair	Occasional (5-29%)
HP:0002223	Absent eyebrow	Occasional (5-29%)
HP:0002225	Sparse pubic hair	Occasional (5-29%)
HP:0002555	Absent pubic hair	Occasional (5-29%)
HP:0004528	Generalized hypotrichosis	Occasional (5-29%)
HP:0004779	Brittle scalp hair	Occasional (5-29%)
HP:0005599	Hypopigmentation of hair	Occasional (5-29%)
HP:0008383	Slow-growing nails	Occasional (5-29%)
HP:0011911	Abnormality of metacarpophalangeal joint	Occasional (5-29%)
HP:0031288	Cobblestone-like hyperkeratosis	Occasional (5-29%)
HP:0045059	Hyperkeratotic papule	Occasional (5-29%)
HP:0100759	Clubbing of fingers	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Clouston syndrome
Mondo ID	MONDO:0007510
OMIM	129500
Orphanet	189
DOID	DOID:14693
SNOMED CT	54209007
UMLS	C0162361
MedGen	56416
GARD	0002056
Is cancer (heuristic)	no

Also known as: alopecia, dysplastic nails, palmar and plantar hyperkeratosis · autosomal dominant hidrotic ectodermal dysplasia · Clouston syndrome · ectodermal dysplasia, hidrotic · ectodermal dysplasia, hidrotic, 2 · ED2 · hidrotic ectodermal dysplasia · hidrotic ectodermal dysplasia, autosomal dominant · palmoplantar hyperkeratosis and alopecia · Patel Bixler syndrome

Data availability: 134 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 › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › Clouston syndrome

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

134 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 28 likely benign, 14 conflicting classifications of pathogenicity, 9 benign/likely benign, 5 pathogenic, 4 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072828	NC_000013.10:g.(?_20797176)_21105944del	GJB6	Pathogenic	criteria provided, single submitter
4783767	NM_001110219.3(GJB6):c.31G>C (p.Gly11Arg)	GJB6	Pathogenic	criteria provided, single submitter
5544	NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg)	GJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
5545	NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)	GJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
5547	NM_001110219.3(GJB6):c.110T>A (p.Val37Glu)	GJB6	Pathogenic	no assertion criteria provided
986211	NM_001110219.3(GJB6):c.148G>C (p.Asp50His)	GJB6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1474469	NM_001110219.3(GJB6):c.223C>T (p.Arg75Trp)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196442	NM_001110219.3(GJB6):c.177A>G (p.Gly59=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1967071	NM_001110219.3(GJB6):c.94C>T (p.Arg32Ter)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225377	NM_001110219.3(GJB6):c.301G>A (p.Glu101Lys)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285401	NM_001110219.3(GJB6):c.672A>G (p.Arg224=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311381	NM_001110219.3(GJB6):c.405G>A (p.Thr135=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311382	NM_001110219.3(GJB6):c.63del (p.Lys22fs)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311383	NM_001110219.3(GJB6):c.60C>T (p.Ile20=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45501	NM_001110219.3(GJB6):c.15G>A (p.Thr5=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45503	NM_001110219.3(GJB6):c.489G>A (p.Leu163=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498602	NM_001110219.3(GJB6):c.111G>A (p.Val37=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724026	NM_001110219.3(GJB6):c.30C>T (p.Ile10=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881662	NM_001110219.3(GJB6):c.212T>C (p.Val71Ala)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95435	NM_001110219.3(GJB6):c.689dup (p.Asn230fs)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2425644	NC_000013.10:g.(?20796834)(21099933_?)del	CRYL1	Uncertain significance	criteria provided, single submitter
656832	NC_000013.10:g.(?20716100)(21398980_?)dup	CRYL1	Uncertain significance	criteria provided, single submitter
2424812	NC_000013.10:g.(?20763040)(20797619_?)dup	GJB2	Uncertain significance	criteria provided, single submitter
1043052	NM_001110219.3(GJB6):c.352A>G (p.Ile118Val)	GJB6	Uncertain significance	criteria provided, single submitter
1303411	NM_001110219.3(GJB6):c.61G>A (p.Gly21Arg)	GJB6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1308146	NM_001110219.3(GJB6):c.323G>A (p.Arg108Gln)	GJB6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1391604	NM_001110219.3(GJB6):c.371A>G (p.Gln124Arg)	GJB6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1408221	NM_001110219.3(GJB6):c.428G>A (p.Arg143Gln)	GJB6	Uncertain significance	criteria provided, single submitter
1447347	NM_001110219.3(GJB6):c.95G>A (p.Arg32Gln)	GJB6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447794	NM_001110219.3(GJB6):c.458T>C (p.Val153Ala)	GJB6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 11 · 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
GJB6	Definitive	Autosomal dominant	Clouston syndrome	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB6	Orphanet:189	Hidrotic ectodermal dysplasia
GJB6	Orphanet:477	KID syndrome
GJB6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	gencc,clinvar
CRYL1	HGNC:18246	ENSG00000165475	Q9Y2S2	Lambda-crystallin homolog	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB6	Gap junction beta-6 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
CRYL1	Lambda-crystallin homolog	Catalyzes the conversion of L-gulonate to 3-dehydro-L-gulonate.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB6	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
CRYL1	Other/Unknown	no		3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
upper arm skin	1
C1 segment of cervical spinal cord	1
adult mammalian kidney	1
right lobe of liver	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB6	187	broad	marker	upper arm skin, gingiva, gingival epithelium
CRYL1	268	ubiquitous	marker	adult mammalian kidney, right lobe of liver, C1 segment of cervical spinal cord
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYL1	2,064
GJB2	1,391
GJB6	1,219

Intra-cohort edges

A	B	Sources
GJB2	GJB6	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
CRYL1	Q9Y2S2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB6	O95452	82.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	2	195.2×	2e-04	GJB6, GJB2
Oligomerization of connexins into connexons	1	1268.9×	0.001	GJB2
Transport of connexins along the secretory pathway	1	1268.9×	0.001	GJB2
Formation of xylulose-5-phosphate	1	634.4×	0.002	CRYL1
Transport of connexons to the plasma membrane	1	181.3×	0.006	GJB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	2	1872.4×	4e-06	GJB6, GJB2
gap junction assembly	2	1404.3×	4e-06	GJB6, GJB2
transmembrane transport	2	112.3×	5e-04	GJB6, GJB2
sensory perception of sound	2	67.3×	0.001	GJB6, GJB2
ear morphogenesis	1	1404.3×	0.002	GJB6
cell-cell signaling	2	46.4×	0.002	GJB6, GJB2
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	936.2×	0.002	CRYL1
sinoatrial node development	1	702.2×	0.003	GJB6
response to electrical stimulus	1	216.1×	0.008	GJB6
maintenance of blood-brain barrier	1	160.5×	0.009	GJB6
inner ear development	1	124.8×	0.011	GJB6
cellular response to glucose stimulus	1	89.2×	0.014	GJB6
fatty acid metabolic process	1	64.6×	0.018	CRYL1
response to lipopolysaccharide	1	41.6×	0.026	GJB6
negative regulation of cell population proliferation	1	14.0×	0.070	GJB6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4
GJB6	0	0
CRYL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
KANAMYCIN	4	GJB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	GJB6, CRYL1

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)
GJB6	0	GJB2
CRYL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.