Acrocapitofemoral dysplasia

Summary

Acrocapitofemoral dysplasia (MONDO:0011907) is a disease caused by IHH (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: IHH (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 16
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003367	Abnormal femoral neck morphology	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0010579	Cone-shaped epiphysis	Very frequent (80-99%)
HP:0001792	Small nail	Frequent (30-79%)
HP:0001821	Broad nail	Frequent (30-79%)
HP:0002869	Flared iliac wings	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0003300	Ovoid vertebral bodies	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0006059	Cone-shaped metacarpal epiphyses	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0010306	Short thorax	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acrocapitofemoral dysplasia
Mondo ID	MONDO:0011907
MeSH	C564334
OMIM	607778
Orphanet	63446
DOID	DOID:0050604
ICD-11	687396416
SNOMED CT	720416007
UMLS	C1843096
MedGen	334681
GARD	0010605
Is cancer (heuristic)	no

Also known as: ACFD · acrocapitofemoral dysplasia

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

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › acrocapitofemoral dysplasia

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, achondroplasia, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia, Spahr type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, Pyle disease, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, brachyolmia, Desbuquois dysplasia, fibrochondrogenesis, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

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:

7 uncertain significance, 3 pathogenic, 3 benign, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1217222	NM_002181.4(IHH):c.478C>T (p.Arg160Cys)	IHH	Pathogenic	criteria provided, single submitter
8870	NM_002181.4(IHH):c.137C>T (p.Pro46Leu)	IHH	Pathogenic	no assertion criteria provided
8871	NM_002181.4(IHH):c.569T>C (p.Val190Ala)	IHH	Pathogenic	criteria provided, single submitter
2584388	NM_002181.4(IHH):c.1A>G (p.Met1Val)	IHH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
800918	NM_002181.4(IHH):c.352G>A (p.Val118Met)	IHH	Likely pathogenic	no assertion criteria provided
1030530	NM_002181.4(IHH):c.88C>A (p.Pro30Thr)	IHH	Uncertain significance	criteria provided, single submitter
1683475	NM_002181.4(IHH):c.1021G>A (p.Glu341Lys)	IHH	Uncertain significance	criteria provided, single submitter
1683476	NM_002181.4(IHH):c.851C>T (p.Thr284Met)	IHH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691308	NM_002181.4(IHH):c.217C>T (p.Arg73Cys)	IHH	Uncertain significance	criteria provided, single submitter
2572410	NM_002181.4(IHH):c.518C>A (p.Ala173Asp)	IHH	Uncertain significance	criteria provided, single submitter
3382985	NM_002181.4(IHH):c.1088C>T (p.Pro363Leu)	IHH	Uncertain significance	criteria provided, single submitter
800998	NM_002181.4(IHH):c.53_78delinsGGGCC (p.Leu18_Trp26delinsArgAla)	IHH	Uncertain significance	no assertion criteria provided
334437	NM_002181.4(IHH):c.819C>T (p.Pro273=)	IHH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
334440	NM_002181.4(IHH):c.753T>C (p.Pro251=)	IHH	Benign	criteria provided, multiple submitters, no conflicts
334443	NM_002181.4(IHH):c.600G>A (p.Thr200=)	IHH	Benign	criteria provided, multiple submitters, no conflicts
593247	NM_002181.4(IHH):c.1128T>C (p.Thr376=)	IHH	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
IHH	Definitive	Autosomal recessive	acrocapitofemoral dysplasia	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IHH	Orphanet:63446	Acrocapitofemoral dysplasia
IHH	Orphanet:93388	Brachydactyly type A1

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
IHH	HGNC:5956	ENSG00000163501	Q14623	Indian hedgehog protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IHH	Indian hedgehog protein	Plays a role in embryonic morphogenesis; it is involved in the regulation of endochondral skeleton formation, and the development of retinal pigment epithelium (RPE), photoreceptors and periocular tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint

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
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IHH	94	broad	marker	mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IHH	2,370

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IHH	Q14623	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	2284.0×	0.001	IHH
RUNX2 regulates chondrocyte maturation	1	2284.0×	0.001	IHH
Formation of lateral plate mesoderm	1	2284.0×	0.001	IHH
Release of Hh-Np from the secreting cell	1	1427.5×	0.001	IHH
Ligand-receptor interactions	1	1427.5×	0.001	IHH
Activation of SMO	1	634.4×	0.002	IHH
Hedgehog ligand biogenesis	1	211.5×	0.006	IHH
Class B/2 (Secretin family receptors)	1	190.3×	0.006	IHH
Hedgehog ‘on’ state	1	158.6×	0.006	IHH

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
vitelline membrane formation	1	16852.0×	0.001	IHH
negative regulation of eye pigmentation	1	16852.0×	0.001	IHH
camera-type eye photoreceptor cell fate commitment	1	16852.0×	0.001	IHH
intein-mediated protein splicing	1	8426.0×	0.002	IHH
negative regulation of alpha-beta T cell differentiation	1	5617.3×	0.002	IHH
embryonic skeletal joint development	1	3370.4×	0.002	IHH
chondrocyte differentiation involved in endochondral bone morphogenesis	1	2808.7×	0.002	IHH
negative regulation of T cell differentiation in thymus	1	2808.7×	0.002	IHH
negative regulation of immature T cell proliferation in thymus	1	2808.7×	0.002	IHH
head morphogenesis	1	2106.5×	0.002	IHH
proteoglycan metabolic process	1	1872.4×	0.002	IHH
retinal pigment epithelium development	1	1685.2×	0.002	IHH
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	IHH
positive regulation of T cell differentiation in thymus	1	1532.0×	0.002	IHH
self proteolysis	1	1532.0×	0.002	IHH
epithelial cell-cell adhesion	1	1203.7×	0.002	IHH
embryonic camera-type eye morphogenesis	1	1123.5×	0.002	IHH
somite development	1	1123.5×	0.002	IHH
chondrocyte proliferation	1	1053.2×	0.002	IHH
smooth muscle tissue development	1	1053.2×	0.002	IHH
epithelial cell morphogenesis	1	936.2×	0.002	IHH
regulation of growth	1	936.2×	0.002	IHH
embryonic digestive tract morphogenesis	1	936.2×	0.002	IHH
maternal process involved in female pregnancy	1	936.2×	0.002	IHH
pancreas development	1	674.1×	0.003	IHH
negative regulation of chondrocyte differentiation	1	674.1×	0.003	IHH
protein autoprocessing	1	648.1×	0.003	IHH
positive regulation of collagen biosynthetic process	1	648.1×	0.003	IHH
positive regulation of mesenchymal cell proliferation	1	601.9×	0.003	IHH
bone resorption	1	581.1×	0.003	IHH

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
IHH	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	IHH

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)
IHH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.