Fuhrmann syndrome

Summary

Fuhrmann syndrome (MONDO:0009232) is a disease caused by WNT7A (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WNT7A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Fuhrmann syndrome
Mondo ID	MONDO:0009232
MeSH	C538189
OMIM	228930
Orphanet	2854
DOID	DOID:0090067
SNOMED CT	721296004
UMLS	C1856728
MedGen	346429
GARD	0002410
Is cancer (heuristic)	no

Also known as: bowing of the femurs, aplasia or hypoplasia of the fibula, and digital anomalies · fibular hypoplasia or aplasia-femoral bowing-oligodactyly syndrome · Fuhrmann syndrome · Fuhrmann-Rieger-de Sousa syndrome

Data availability: 8 ClinVar variants · 4 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 › dysostosis › Fuhrmann syndrome

Related subtypes (107): trigonocephaly, spondylocostal dysostosis, synostosis, Adams-Oliver syndrome, adactylia, unilateral, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Cooks syndrome, brachydactyly-arterial hypertension syndrome, fibular aplasia-ectrodactyly syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, congenital pseudoarthrosis of clavicle, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, hand-foot-genital syndrome, oculoauriculovertebral spectrum with radial defects, IVIC syndrome, nail-patella syndrome, patella aplasia/hypoplasia, pelvis-shoulder dysplasia, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, postaxial tetramelic oligodactyly, Currarino triad, radio-renal syndrome, splenogonadal fusion-limb defects-micrognathia syndrome, Karsch-Neugebauer syndrome, tetramelic monodactyly, tibia, hypoplasia or aplasia of, with polydactyly, humerus trochlea aplasia, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, camptodactyly syndrome, Guadalajara type 2, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, split hand-foot malformation 1 with sensorineural hearing loss, EEM syndrome, lethal faciocardiomelic dysplasia, femur-fibula-ulna complex, Gollop-Wolfgang complex, acromesomelic dysplasia 2B, absence deformity of leg-cataract syndrome, intellectual disability-spasticity-ectrodactyly syndrome, fibular aplasia, tibial campomelia, and oligosyndactyly syndrome, otoonychoperoneal syndrome, pelviscapular dysplasia, rapadilino syndrome, EEC syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, tetraamelia-multiple malformations syndrome, thrombocytopenia-absent radius syndrome, phocomelia, Schinzel type, ulna hypoplasia-intellectual disability syndrome, absent radius-anogenital anomalies syndrome, ulnar hypoplasia-split foot syndrome, aphalangy-syndactyly-microcephaly syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, autosomal recessive amelia, pelvic dysplasia-arthrogryposis of lower limbs syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, genitopatellar syndrome, Duane-radial ray syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, camptodactyly syndrome, Guadalajara type 3, mammary-digital-nail syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, split-foot malformation-mesoaxial polydactyly syndrome, amniotic band syndrome, radial deficiency-tibial hypoplasia syndrome, mandibulofacial dysostosis, oromandibular-limb anomalies syndrome, congenital pseudoarthrosis of the limbs, oculomaxillofacial dysostosis, shoulder and thorax deformity-congenital heart disease syndrome, femoral agenesis/hypoplasia, progressive non-infectious anterior vertebral fusion, hemimelia, heart-hand syndrome, split hand-foot malformation, Melhem-Fahl syndrome, limb transversal defect-cardiac anomaly syndrome, frontonasal dysplasia, imperforate oropharynx-costo vetebral anomalies syndrome, non-syndromic amelia, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, split hand, split foot, hyperphalangy, Prata-Liberal-Goncalves syndrome, syngnathia multiple anomalies, hereditary thrombocytosis with transverse limb defect, thalidomide embryopathy, tibial aplasia-ectrodactyly syndrome, bipartite talus, acrofacial dysostosis, adactyly of foot, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, Rubinstein-Taybi syndrome, ischio-vertebral syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, preaxial digit brachydactyly-webbed fingers, proximal femoral focal deficiency, dysostosis multiplex, Ain-Naz type

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

8 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign, 1 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
8061	NM_004625.4(WNT7A):c.325G>A (p.Ala109Thr)	LOC126806608	Pathogenic	no assertion criteria provided
35537	NM_004625.4(WNT7A):c.610G>A (p.Gly204Ser)	WNT7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526604	NM_004625.4(WNT7A):c.399C>A (p.Cys133Ter)	LOC126806608	Likely pathogenic	criteria provided, single submitter
4056356	NM_004625.4(WNT7A):c.71+1G>A	WNT7A	Likely pathogenic	criteria provided, single submitter
1050186	NM_004625.4(WNT7A):c.470G>A (p.Arg157His)	LOC126806608	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497790	NM_004625.4(WNT7A):c.1028C>T (p.Thr343Met)	WNT7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3333230	NM_004625.4(WNT7A):c.889A>G (p.Thr297Ala)	WNT7A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1286438	NM_004625.4(WNT7A):c.298+37C>A	WNT7A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
WNT7A	Definitive	Autosomal recessive	Fuhrmann syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT7A	Orphanet:2854	Fuhrmann syndrome
WNT7A	Orphanet:2879	Phocomelia, Schinzel type

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
WNT7A	HGNC:12786	ENSG00000154764	O00755	Protein Wnt-7a	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT7A	Protein Wnt-7a	Ligand for members of the frizzled family of seven transmembrane receptors that functions in the canonical Wnt/beta-catenin signaling pathway.

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)
WNT7A	Other/Unknown	no		Wnt, Wnt7, Wnt_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
cortical plate	1
endometrium epithelium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT7A	96	broad	yes	cortical plate, endometrium epithelium, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNT7A	1,809

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WNT7A	O00755	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
WNT ligand biogenesis and trafficking	1	423.0×	0.005	WNT7A
Class B/2 (Secretin family receptors)	1	190.3×	0.005	WNT7A

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
asymmetric protein localization involved in cell fate determination	1	16852.0×	0.002	WNT7A
postsynapse assembly	1	8426.0×	0.002	WNT7A
positive regulation of protein localization to presynapse	1	8426.0×	0.002	WNT7A
skeletal muscle satellite cell activation	1	5617.3×	0.002	WNT7A
oviduct development	1	5617.3×	0.002	WNT7A
positive regulation of excitatory synapse assembly	1	5617.3×	0.002	WNT7A
central nervous system vasculogenesis	1	3370.4×	0.002	WNT7A
regulation of axon diameter	1	3370.4×	0.002	WNT7A
skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	1	2808.7×	0.002	WNT7A
uterus morphogenesis	1	2808.7×	0.002	WNT7A
embryonic axis specification	1	2407.4×	0.002	WNT7A
stem cell development	1	2407.4×	0.002	WNT7A
cerebellar granule cell differentiation	1	2106.5×	0.002	WNT7A
lens fiber cell development	1	2106.5×	0.002	WNT7A
positive regulation of epithelial cell proliferation involved in wound healing	1	1685.2×	0.002	WNT7A
somatic stem cell division	1	1532.0×	0.002	WNT7A
establishment of blood-brain barrier	1	1404.3×	0.002	WNT7A
cell proliferation in forebrain	1	1296.3×	0.002	WNT7A
excitatory synapse assembly	1	1296.3×	0.002	WNT7A
synaptic vesicle recycling	1	1203.7×	0.002	WNT7A
secondary palate development	1	1203.7×	0.002	WNT7A
presynapse assembly	1	1203.7×	0.002	WNT7A
wound healing, spreading of epidermal cells	1	1053.2×	0.002	WNT7A
positive regulation of protein metabolic process	1	991.3×	0.002	WNT7A
dendritic spine morphogenesis	1	887.0×	0.003	WNT7A
sex differentiation	1	842.6×	0.003	WNT7A
cartilage condensation	1	766.0×	0.003	WNT7A
neurotransmitter secretion	1	702.2×	0.003	WNT7A
negative regulation of neurogenesis	1	624.1×	0.003	WNT7A
embryonic hindlimb morphogenesis	1	581.1×	0.003	WNT7A

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
WNT7A	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	WNT7A

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)
WNT7A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.