Tricho-dento-osseous syndrome

Summary

Tricho-dento-osseous syndrome (MONDO:0008592) is a disease caused by DLX3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DLX3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 11
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000264	Abnormality of the mastoid	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000679	Taurodontia	Frequent (30-79%)
HP:0000687	Widely spaced teeth	Frequent (30-79%)
HP:0000691	Microdontia	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0001808	Fragile nails	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0006285	Enamel hypomineralization	Frequent (30-79%)
HP:0009722	Dental enamel pits	Frequent (30-79%)
HP:0011001	Increased bone mineral density	Frequent (30-79%)
HP:0011362	Abnormal hair quantity	Frequent (30-79%)
HP:0030312	Obliteration of the calvarial diploe	Frequent (30-79%)
HP:0030758	Periapical tooth abscess	Frequent (30-79%)
HP:0006485	Agenesis of incisor	Occasional (5-29%)
HP:0040019	Finger clinodactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tricho-dento-osseous syndrome
Mondo ID	MONDO:0008592
MeSH	C536549
OMIM	190320
Orphanet	3352
DOID	DOID:0111565
ICD-11	131993435
SNOMED CT	38993008
UMLS	C0265333
MedGen	78555
GARD	0007799
NORD	1786
Is cancer (heuristic)	no

Also known as: enamel hypoplasia and hypocalcification with associated strikingly curly hair · kinky or curly hair, dolichocephaly, enamel hypoplasia, increased dental caries, radial dense bones, and brittle nails · TDO · TDO syndrome · TDO syndrome 1 · Tricho Dento Osseous Syndrome · Tricho-dento-osseous syndrome 1 · TRICHODENTOOSSEOUS syndrome

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › tricho-dento-osseous syndrome

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, 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, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

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

11 retrieved; paginated sample, class counts are floors:

3 benign, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2692407	Single allele	ABCC3	Pathogenic	criteria provided, single submitter
1341362	NM_005220.3(DLX3):c.534G>C (p.Gln178His)	DLX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430609	NM_005220.3(DLX3):c.476G>T (p.Arg159Leu)	DLX3	Pathogenic	no assertion criteria provided
9072	NM_005220.3(DLX3):c.571_574del (p.Gly191fs)	DLX3	Pathogenic	criteria provided, multiple submitters, no conflicts
9073	NM_005220.3(DLX3):c.561_562del (p.Tyr188fs)	DLX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430607	NM_005220.3(DLX3):c.574del (p.Glu192fs)	DLX3	Likely pathogenic	criteria provided, single submitter
1326290	NM_005220.3(DLX3):c.263A>G (p.Tyr88Cys)	DLX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800783	NM_005220.3(DLX3):c.337GAG[1] (p.Glu114del)	DLX3	Uncertain significance	no assertion criteria provided
1221806	NM_005220.3(DLX3):c.516+23C>T	DLX3	Benign	criteria provided, multiple submitters, no conflicts
259675	NM_005220.3(DLX3):c.138C>T (p.Pro46=)	DLX3	Benign	criteria provided, multiple submitters, no conflicts
259676	NM_005220.3(DLX3):c.402G>A (p.Thr134=)	DLX3	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
DLX3	Strong	Autosomal dominant	tricho-dento-osseous syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLX3	Orphanet:100034	Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism
DLX3	Orphanet:3352	Tricho-dento-osseous syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLX3	HGNC:2916	ENSG00000064195	O60479	Homeobox protein DLX-3	gencc,clinvar
ABCC3	HGNC:54	ENSG00000108846	O15438	ATP-binding cassette sub-family C member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLX3	Homeobox protein DLX-3	Transcriptional activator.
ABCC3	ATP-binding cassette sub-family C member 3	ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Transporter	1	38.9×	0.051
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLX3	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
ABCC3	Transporter	yes	7.6.2.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
skin of leg	1
zone of skin	1
pancreatic ductal cell	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLX3	133	broad	marker	skin of leg, skin of abdomen, zone of skin
ABCC3	231	ubiquitous	marker	pancreatic ductal cell, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCC3	1,937
DLX3	1,382

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCC3	O15438	4
DLX3	O60479	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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
NFE2L2 regulating MDR associated enzymes	1	1427.5×	0.008	ABCC3
Recycling of bile acids and salts	1	601.0×	0.008	ABCC3
Bile acid and bile salt metabolism	1	496.5×	0.008	ABCC3
Paracetamol ADME	1	423.0×	0.008	ABCC3
Nuclear events mediated by NFE2L2	1	335.9×	0.008	ABCC3
Aspirin ADME	1	317.2×	0.008	ABCC3
Drug ADME	1	228.4×	0.010	ABCC3
Cellular response to chemical stress	1	142.8×	0.012	ABCC3
Metabolism of steroids	1	137.6×	0.012	ABCC3
ABC-family protein mediated transport	1	121.5×	0.012	ABCC3
KEAP1-NFE2L2 pathway	1	120.2×	0.012	ABCC3
Cellular responses to stress	1	36.8×	0.036	ABCC3
Metabolism of lipids	1	31.6×	0.036	ABCC3
Cellular responses to stimuli	1	31.5×	0.036	ABCC3
Transport of small molecules	1	25.1×	0.042	ABCC3
Metabolism	1	11.6×	0.086	ABCC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hair follicle cell proliferation	1	8426.0×	0.002	DLX3
leukotriene transport	1	1203.7×	0.005	ABCC3
hair cell differentiation	1	1053.2×	0.005	DLX3
odontoblast differentiation	1	1053.2×	0.005	DLX3
xenobiotic transmembrane transport	1	468.1×	0.008	ABCC3
xenobiotic transport	1	421.3×	0.008	ABCC3
bile acid and bile salt transport	1	324.1×	0.009	ABCC3
hair follicle morphogenesis	1	247.8×	0.010	DLX3
placenta development	1	221.7×	0.010	DLX3
embryonic skeletal system development	1	195.9×	0.010	DLX3
blood vessel development	1	187.2×	0.010	DLX3
odontogenesis of dentin-containing tooth	1	150.5×	0.012	DLX3
BMP signaling pathway	1	100.3×	0.016	DLX3
transport across blood-brain barrier	1	89.6×	0.016	ABCC3
epithelial cell differentiation	1	87.8×	0.016	DLX3
transmembrane transport	1	84.3×	0.016	ABCC3
xenobiotic metabolic process	1	74.6×	0.017	ABCC3
Wnt signaling pathway	1	49.9×	0.023	DLX3
gene expression	1	39.9×	0.028	DLX3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.136	DLX3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	DLX3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ABCC3	TELMISARTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCC3	43	4
DLX3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	ABCC3
VALRUBICIN	4	ABCC3
SAQUINAVIR	4	ABCC3
OLMESARTAN MEDOXOMIL	4	ABCC3
LOTEPREDNOL ETABONATE	4	ABCC3
TEMSIROLIMUS	4	ABCC3
REPAGLINIDE	4	ABCC3
CLOFAZIMINE	4	ABCC3
TOLCAPONE	4	ABCC3
BUDESONIDE	4	ABCC3
GLIMEPIRIDE	4	ABCC3
IRBESARTAN	4	ABCC3
CYCLOSPORINE	4	ABCC3
RIFAXIMIN	4	ABCC3
RITONAVIR	4	ABCC3
RIFAPENTINE	4	ABCC3
ROSUVASTATIN CALCIUM	4	ABCC3
EVEROLIMUS	4	ABCC3
RACECADOTRIL	4	ABCC3
FLUVASTATIN	4	ABCC3
SITAXENTAN	4	ABCC3
ETRAVIRINE	4	ABCC3
ETHAMBUTOL HYDROCHLORIDE	4	ABCC3
RIFAMPIN	4	ABCC3
ATORVASTATIN CALCIUM	4	ABCC3
TROGLITAZONE	4	ABCC3
SULFASALAZINE	4	ABCC3
TENIPOSIDE	4	ABCC3
ETHACRYNIC ACID	4	ABCC3
GLYBURIDE	4	ABCC3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ABCC3	37	Binding:21, ADMET:16

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCC3	7.6.2.3	ABC-type glutathione-S-conjugate transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
TELMISARTAN	4	ABCC3
VALRUBICIN	4	ABCC3
SAQUINAVIR	4	ABCC3
OLMESARTAN MEDOXOMIL	4	ABCC3
LOTEPREDNOL ETABONATE	4	ABCC3
TEMSIROLIMUS	4	ABCC3
REPAGLINIDE	4	ABCC3
CLOFAZIMINE	4	ABCC3
TOLCAPONE	4	ABCC3
BUDESONIDE	4	ABCC3
GLIMEPIRIDE	4	ABCC3
IRBESARTAN	4	ABCC3
CYCLOSPORINE	4	ABCC3
RIFAXIMIN	4	ABCC3
RITONAVIR	4	ABCC3
RIFAPENTINE	4	ABCC3
ROSUVASTATIN CALCIUM	4	ABCC3
EVEROLIMUS	4	ABCC3
RACECADOTRIL	4	ABCC3
FLUVASTATIN	4	ABCC3
SITAXENTAN	4	ABCC3
ETRAVIRINE	4	ABCC3
ETHAMBUTOL HYDROCHLORIDE	4	ABCC3
RIFAMPIN	4	ABCC3
ATORVASTATIN CALCIUM	4	ABCC3
TROGLITAZONE	4	ABCC3
SULFASALAZINE	4	ABCC3
TENIPOSIDE	4	ABCC3
ETHACRYNIC ACID	4	ABCC3
GLYBURIDE	4	ABCC3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCC3
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	DLX3

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)
DLX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.