Cronkhite-Canada syndrome

Summary

Cronkhite-Canada syndrome (MONDO:0008283) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0001800	Hypoplastic toenails	Very frequent (80-99%)
HP:0001810	Dystrophic toenail	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002232	Patchy alopecia	Very frequent (80-99%)
HP:0004390	Hamartomatous polyposis	Very frequent (80-99%)
HP:0007440	Generalized hyperpigmentation	Very frequent (80-99%)
HP:0008391	Dystrophic fingernails	Very frequent (80-99%)
HP:0200008	Intestinal polyposis	Very frequent (80-99%)
HP:0001004	Lymphedema	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002231	Sparse body hair	Frequent (30-79%)
HP:0002597	Abnormality of the vasculature	Frequent (30-79%)
HP:0004326	Cachexia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Frequent (30-79%)
HP:0000221	Furrowed tongue	Occasional (5-29%)
HP:0000224	Decreased taste sensation	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001182	Tapered finger	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002672	Gastrointestinal carcinoma	Occasional (5-29%)
HP:0003003	Colon cancer	Occasional (5-29%)
HP:0012126	Stomach cancer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cronkhite-Canada syndrome
Mondo ID	MONDO:0008283
MeSH	D044483
OMIM	175500
Orphanet	2930
DOID	DOID:6225
ICD-11	79007466
NCIT	C7035
SNOMED CT	76304001
UMLS	C0282207
MedGen	129128
GARD	0004427
MedDRA	10062907
NORD	1017
Is cancer (heuristic)	no

Also known as: Cronkhite-Canada disease · Cronkhite-Canada syndrome · gastric Cronkhite Canada polyposis · gastrointestinal polyposis-ectodermal changes syndrome · gastrointestinal polyposis-skin pigmentation-alopecia-fingernail changes syndrome · polyposis skin pigmentation alopecia fingernail changes

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › Cronkhite-Canada syndrome

Related subtypes (30): benign digestive system neoplasm, autoimmune disorder of gastrointestinal tract, gastrointestinal mucositis, diarrheal disease, pancreas disorder, hepatobiliary disorder, digestive system cancer, peptic ulcer disease, stomach disorder, intestinal disorder, Meckel diverticulum, diverticulosis, small-intestinal, diverticulosis of bowel, hernia, and retinal detachment, congenital enteropathy due to enteropeptidase deficiency, hereditary mixed polyposis syndrome, caudal duplication, Moyamoya disease with early-onset achalasia, hyperplastic polyposis syndrome, thoraco-abdominal enteric duplication, digestive duplication, juvenile polyposis syndrome, umbilical cord ulceration-intestinal atresia syndrome, growth retardation-mild developmental delay-chronic hepatitis syndrome, common mesentery, neoplasm of oropharynx, gastrointestinal polyp, digestive system neuroendocrine neoplasm, digestive system infectious disorder, upper digestive tract disorder, congenital peritoneal encapsulation

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
375468	NM_000168.6(GLI3):c.4436T>C (p.Leu1479Ser)	GLI3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory bulb	1
tendon of biceps brachii	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI3	2,825

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI3	P10071	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	1631.4×	0.003	GLI3
RUNX2 regulates osteoblast differentiation	1	456.8×	0.005	GLI3
GLI3 is processed to GLI3R by the proteasome	1	223.9×	0.006	GLI3
Hedgehog ‘off’ state	1	178.4×	0.006	GLI3
Hedgehog ‘on’ state	1	158.6×	0.006	GLI3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lateral ganglionic eminence cell proliferation	1	16852.0×	7e-04	GLI3
lambdoid suture morphogenesis	1	16852.0×	7e-04	GLI3
sagittal suture morphogenesis	1	16852.0×	7e-04	GLI3
mammary gland specification	1	16852.0×	7e-04	GLI3
anterior semicircular canal development	1	16852.0×	7e-04	GLI3
lateral semicircular canal development	1	16852.0×	7e-04	GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	8426.0×	9e-04	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	8426.0×	9e-04	GLI3
larynx morphogenesis	1	8426.0×	9e-04	GLI3
nose morphogenesis	1	5617.3×	1e-03	GLI3
negative regulation of alpha-beta T cell differentiation	1	5617.3×	1e-03	GLI3
frontal suture morphogenesis	1	5617.3×	1e-03	GLI3
cell differentiation involved in kidney development	1	5617.3×	1e-03	GLI3
hindgut morphogenesis	1	4213.0×	0.001	GLI3
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	4213.0×	0.001	GLI3
optic nerve morphogenesis	1	3370.4×	0.001	GLI3
regulation of bone development	1	3370.4×	0.001	GLI3
forebrain radial glial cell differentiation	1	2808.7×	0.001	GLI3
forebrain dorsal/ventral pattern formation	1	2106.5×	0.002	GLI3
tongue development	1	2106.5×	0.002	GLI3
alpha-beta T cell differentiation	1	1872.4×	0.002	GLI3
embryonic neurocranium morphogenesis	1	1872.4×	0.002	GLI3
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	GLI3
negative thymic T cell selection	1	1404.3×	0.002	GLI3
artery development	1	1404.3×	0.002	GLI3
thymocyte apoptotic process	1	1404.3×	0.002	GLI3
layer formation in cerebral cortex	1	1123.5×	0.002	GLI3
limb morphogenesis	1	1053.2×	0.002	GLI3
embryonic digestive tract development	1	991.3×	0.002	GLI3
embryonic digestive tract morphogenesis	1	936.2×	0.003	GLI3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
GLI3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	GLI3

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)
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.