Hand-foot-genital syndrome

Summary

Hand-foot-genital syndrome (MONDO:0007698) is a disease caused by HOXA13 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HOXA13 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 65
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000074	Ureteropelvic junction obstruction	Very frequent (80-99%)
HP:0000130	Abnormality of the uterus	Very frequent (80-99%)
HP:0000813	Bicornuate uterus	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0006110	Shortening of all middle phalanges of the fingers	Very frequent (80-99%)
HP:0009623	Proximal placement of thumb	Very frequent (80-99%)
HP:0009778	Short thumb	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0010034	Short 1st metacarpal	Very frequent (80-99%)
HP:0010105	Short first metatarsal	Very frequent (80-99%)
HP:0010109	Short hallux	Very frequent (80-99%)
HP:0000010	Recurrent urinary tract infections	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000076	Vesicoureteral reflux	Frequent (30-79%)
HP:0000795	Abnormality of the urethra	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0007477	Abnormal dermatoglyphics	Frequent (30-79%)
HP:0008080	Hallux varus	Frequent (30-79%)
HP:0011937	Hypoplastic fifth toenail	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000960	Sacral dimple	Occasional (5-29%)
HP:0001162	Postaxial hand polydactyly	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0005268	Spontaneous abortion	Occasional (5-29%)
HP:0008551	Microtia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hand-foot-genital syndrome
Mondo ID	MONDO:0007698
MeSH	C535627
OMIM	140000
Orphanet	2438
DOID	DOID:0060739
SNOMED CT	702425002
UMLS	C1841679
MedGen	331103
GARD	0002594
MedDRA	10072361
Is cancer (heuristic)	no

Also known as: hand foot genital syndrome · hand foot uterus syndrome · hand-foot-genital syndrome · hand-foot-uterus syndrome · HFG · HFG syndrome · HFGS · HFU syndrome

Data availability: 65 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hand-foot-genital syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

65 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 7 pathogenic, 5 conflicting classifications of pathogenicity, 5 likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1202627	NM_000522.5(HOXA13):c.360_377dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAla)	HOXA13	Pathogenic/Likely pathogenic	no assertion criteria provided
14889	NM_000522.5(HOXA13):c.1107G>A (p.Trp369Ter)	HOXA13	Pathogenic	no assertion criteria provided
14890	NM_000522.5(HOXA13):c.407C>A (p.Ser136Ter)	HOXA13	Pathogenic	no assertion criteria provided
14891	NM_000522.5(HOXA13):c.366_389dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAlaAlaAla)	HOXA13	Pathogenic	no assertion criteria provided
14892	NM_000522.5(HOXA13):c.1114A>C (p.Asn372His)	HOXA13	Pathogenic	no assertion criteria provided
14895	NM_000522.5(HOXA13):c.366_392dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAlaAlaAlaAla)	HOXA13	Pathogenic	no assertion criteria provided
14896	NM_000522.5(HOXA13):c.355_406dup (p.Ser136fs)	HOXA13	Pathogenic	no assertion criteria provided
3382721	NM_000522.5(HOXA13):c.730C>T (p.Gln244Ter)	HOXA13	Pathogenic	criteria provided, single submitter
1801485	NM_000522.5(HOXA13):c.869A>C (p.Tyr290Ser)	HOXA13	Likely pathogenic	no assertion criteria provided
1805747	NM_000522.5(HOXA13):c.741dup (p.Gly248fs)	HOXA13	Likely pathogenic	criteria provided, single submitter
3594500	NM_000522.5(HOXA13):c.837G>A (p.Trp279Ter)	HOXA13	Likely pathogenic	criteria provided, single submitter
3594514	NM_000522.5(HOXA13):c.423_424delinsA (p.Ala142fs)	HOXA13	Likely pathogenic	criteria provided, single submitter
1361685	NM_000522.5(HOXA13):c.46G>A (p.Val16Ile)	HOXA13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1672190	NM_000522.5(HOXA13):c.175C>G (p.Pro59Ala)	HOXA13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1928569	NM_000522.5(HOXA13):c.357_383del (p.Ala125_Ala133del)	HOXA13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2920192	NM_000522.5(HOXA13):c.366_374del (p.Ala131_Ala133del)	HOXA13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3594516	NM_000522.5(HOXA13):c.348_377del (p.Ala124_Ala133del)	HOXA13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306688	NM_000522.5(HOXA13):c.527G>A (p.Ser176Asn)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1307668	NM_000522.5(HOXA13):c.263G>A (p.Arg88His)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437472	NM_000522.5(HOXA13):c.431C>T (p.Pro144Leu)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1438660	NM_000522.5(HOXA13):c.175C>T (p.Pro59Ser)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1937756	NM_000522.5(HOXA13):c.191C>A (p.Ala64Glu)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1946001	NM_000522.5(HOXA13):c.448G>A (p.Ala150Thr)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
2181854	NM_000522.5(HOXA13):c.504_505delinsAG (p.Leu169Val)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
2210432	NM_000522.5(HOXA13):c.505C>G (p.Leu169Val)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
2325454	NM_000522.5(HOXA13):c.848A>G (p.Asn283Ser)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432524	NM_000522.5(HOXA13):c.133G>A (p.Ala45Thr)	HOXA13	Uncertain significance	criteria provided, multiple submitters, no conflicts
3234927	NM_000522.5(HOXA13):c.884A>C (p.Gln295Pro)	HOXA13	Uncertain significance	criteria provided, single submitter
3358798	NM_000522.5(HOXA13):c.67G>A (p.Gly23Ser)	HOXA13	Uncertain significance	criteria provided, single submitter
3382050	NM_000522.5(HOXA13):c.329_342del (p.Gly110fs)	HOXA13	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
HOXA13	Definitive	Autosomal dominant	hand-foot-genital syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HOXA13	Orphanet:2438	Hand-foot-genital syndrome
HOXA13	Orphanet:2957	Guttmacher syndrome

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
HOXA13	HGNC:5102	ENSG00000106031	P31271	Homeobox protein Hox-A13	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HOXA13	Homeobox protein Hox-A13	Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

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)
HOXA13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

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
endocervix	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HOXA13	84	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, endocervix, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HOXA13	1,200

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HOXA13	P31271	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
endothelial cell fate specification	1	16852.0×	0.001	HOXA13
embryonic hindgut morphogenesis	1	5617.3×	0.001	HOXA13
positive regulation of mesenchymal cell apoptotic process	1	5617.3×	0.001	HOXA13
branching involved in prostate gland morphogenesis	1	3370.4×	0.001	HOXA13
mitotic nuclear division	1	2808.7×	0.001	HOXA13
mesenchymal cell apoptotic process	1	1532.0×	0.002	HOXA13
regulation of BMP signaling pathway	1	1203.7×	0.002	HOXA13
endothelial cell morphogenesis	1	1053.2×	0.002	HOXA13
male genitalia development	1	887.0×	0.003	HOXA13
artery morphogenesis	1	674.1×	0.003	HOXA13
tissue homeostasis	1	561.7×	0.003	HOXA13
positive regulation of mitotic nuclear division	1	543.6×	0.003	HOXA13
ventricular septum development	1	495.6×	0.003	HOXA13
embryonic forelimb morphogenesis	1	495.6×	0.003	HOXA13
response to testosterone	1	468.1×	0.003	HOXA13
inner ear development	1	374.5×	0.003	HOXA13
vasculogenesis	1	255.3×	0.005	HOXA13
skeletal system development	1	125.8×	0.009	HOXA13
transcription by RNA polymerase II	1	70.5×	0.015	HOXA13
regulation of transcription by RNA polymerase II	1	11.7×	0.086	HOXA13

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
HOXA13	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	HOXA13

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)
HOXA13	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.