Macrodactyly of toes

Summary

Macrodactyly of toes (MONDO:0017475) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.8	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0100747	Macrodactyly of toe	Obligate (100%)
HP:0010165	Enlarged epiphyses of the toes	Very frequent (80-99%)
HP:0001783	Broad metatarsal	Frequent (30-79%)
HP:0008082	Medial deviation of the foot	Frequent (30-79%)
HP:0008108	Advanced tarsal ossification	Frequent (30-79%)
HP:0008371	Abnormal metatarsal ossification	Frequent (30-79%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0005830	Flexion contracture of toe	Occasional (5-29%)
HP:0000023	Inguinal hernia	Very rare (<1-4%)
HP:0000047	Hypospadias	Very rare (<1-4%)
HP:0001397	Hepatic steatosis	Very rare (<1-4%)
HP:0001629	Ventricular septal defect	Very rare (<1-4%)
HP:0001631	Atrial septal defect	Very rare (<1-4%)
HP:0001829	Foot polydactyly	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)
HP:0008551	Microtia	Very rare (<1-4%)
HP:0012032	Lipoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	macrodactyly of toes
Mondo ID	MONDO:0017475
MeSH	C537719
Orphanet	295047
ICD-11	1196147958
UMLS	C0158768
MedGen	510644
GARD	0006951
Is cancer (heuristic)	no

Also known as: macrodactyly of foot · macrodactyly of the foot · megalodactylism of the foot · Megalodactyly of the foot

Data availability: 1 ClinVar variant · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › macrodactyly of toes

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

Subtypes (2): macrodactyly of toes, unilateral, macrodactyly of toes, bilateral

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 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13653	NM_006218.4(PIK3CA):c.3140A>T (p.His1047Leu)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

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
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

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
adrenal tissue	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CA	5,157

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. 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
MET activates PI3K/AKT signaling	1	1903.3×	0.004	PIK3CA
Activated NTRK3 signals through PI3K	1	1903.3×	0.004	PIK3CA
Activated NTRK2 signals through PI3K	1	1631.4×	0.004	PIK3CA
Signaling by LTK in cancer	1	1631.4×	0.004	PIK3CA
PI3K/AKT activation	1	1268.9×	0.004	PIK3CA
IRS-mediated signalling	1	1038.2×	0.004	PIK3CA
PI3K events in ERBB4 signaling	1	1038.2×	0.004	PIK3CA
Co-stimulation by ICOS	1	1038.2×	0.004	PIK3CA
Signaling by FGFR4 in disease	1	951.7×	0.004	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.004	PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.004	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.004	PIK3CA
Signaling by LTK	1	878.5×	0.004	PIK3CA
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.004	PIK3CA
Constitutive Signaling by EGFRvIII	1	713.8×	0.004	PIK3CA
PI3K events in ERBB2 signaling	1	671.8×	0.004	PIK3CA
Signaling by ERBB2 ECD mutants	1	671.8×	0.004	PIK3CA
GAB1 signalosome	1	634.4×	0.004	PIK3CA
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.004	PIK3CA
PI-3K cascade:FGFR3	1	634.4×	0.004	PIK3CA
Tie2 Signaling	1	601.0×	0.004	PIK3CA
Role of LAT2/NTAL/LAB on calcium mobilization	1	601.0×	0.004	PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	571.0×	0.004	PIK3CA
Signaling by ALK	1	571.0×	0.004	PIK3CA
PI-3K cascade:FGFR4	1	571.0×	0.004	PIK3CA
Signaling by FLT3 fusion proteins	1	571.0×	0.004	PIK3CA
PI-3K cascade:FGFR1	1	519.1×	0.004	PIK3CA
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.004	PIK3CA
PI-3K cascade:FGFR2	1	496.5×	0.004	PIK3CA
Signaling by FGFR3 in disease	1	496.5×	0.004	PIK3CA

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
response to muscle inactivity	1	16852.0×	0.001	PIK3CA
response to butyrate	1	16852.0×	0.001	PIK3CA
response to L-leucine	1	5617.3×	0.002	PIK3CA
cellular response to hydrostatic pressure	1	5617.3×	0.002	PIK3CA
negative regulation of actin filament depolymerization	1	2808.7×	0.002	PIK3CA
regulation of cellular respiration	1	2808.7×	0.002	PIK3CA
regulation of actin filament organization	1	2407.4×	0.002	PIK3CA
autosome genomic imprinting	1	2407.4×	0.002	PIK3CA
negative regulation of fibroblast apoptotic process	1	2407.4×	0.002	PIK3CA
cardiac muscle cell contraction	1	1685.2×	0.002	PIK3CA
positive regulation of protein localization to membrane	1	1685.2×	0.002	PIK3CA
TORC2 signaling	1	1532.0×	0.002	PIK3CA
phosphatidylinositol-3-phosphate biosynthetic process	1	1296.3×	0.002	PIK3CA
anoikis	1	1296.3×	0.002	PIK3CA
relaxation of cardiac muscle	1	1296.3×	0.002	PIK3CA
response to dexamethasone	1	1203.7×	0.002	PIK3CA
vasculature development	1	1123.5×	0.002	PIK3CA
negative regulation of macroautophagy	1	1123.5×	0.002	PIK3CA
vascular endothelial growth factor signaling pathway	1	1053.2×	0.002	PIK3CA
negative regulation of anoikis	1	887.0×	0.003	PIK3CA
response to muscle stretch	1	766.0×	0.003	PIK3CA
phosphatidylinositol-mediated signaling	1	702.2×	0.003	PIK3CA
regulation of multicellular organism growth	1	648.1×	0.003	PIK3CA
positive regulation of lamellipodium assembly	1	601.9×	0.003	PIK3CA
positive regulation of TOR signaling	1	495.6×	0.004	PIK3CA
insulin-like growth factor receptor signaling pathway	1	495.6×	0.004	PIK3CA
phosphatidylinositol phosphate biosynthetic process	1	481.5×	0.004	PIK3CA
endothelial cell migration	1	411.0×	0.004	PIK3CA
cardiac muscle contraction	1	401.2×	0.004	PIK3CA
adipose tissue development	1	401.2×	0.004	PIK3CA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA
ZSTK-474	2	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PIK3CA	2,034

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

30 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)
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA
ZSTK-474	2	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CA
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.