Tooth and nail syndrome

Summary

Tooth and nail syndrome (MONDO:0008582) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 86
• Phenotypes (HPO): 16

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000668	Hypodontia	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0000698	Conical tooth	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0001800	Hypoplastic toenails	Very frequent (80-99%)
HP:0001804	Hypoplastic fingernail	Very frequent (80-99%)
HP:0001808	Fragile nails	Very frequent (80-99%)
HP:0006349	Agenesis of permanent teeth	Very frequent (80-99%)
HP:0006482	Abnormal dental morphology	Very frequent (80-99%)
HP:0008402	Ridged fingernail	Very frequent (80-99%)
HP:0012746	Thin toenail	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0002213	Fine hair	Frequent (30-79%)
HP:0000147	Polycystic ovaries	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tooth and nail syndrome
Mondo ID	MONDO:0008582
MeSH	C536736
OMIM	189500
Orphanet	2228
DOID	DOID:6678
NCIT	C40553
SNOMED CT	400036004
UMLS	C0406735
MedGen	140809
GARD	0005587
NORD	1777
Is cancer (heuristic)	no

Also known as: dysplasia of nails with hypodontia · HND · hypodontia - dysplasia of nails · hypodontia and nail dysplasia · hypodontia with nail dysplasia · hypodontia-nail dysgenesis syndrome · hypodontia-nail dysplasia · hypoplastic enamel-onycholysis-hypohidrosis syndrome · TNS · tooth and nail syndrome · Witkop syndrome

Data availability: 86 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › tooth and nail syndrome

Related subtypes (119): ADULT syndrome, autosomal dominant palmoplantar keratoderma and congenital alopecia, ameloonychohypohidrotic syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, anonychia with flexural pigmentation, Böök syndrome, blepharocheilodontic syndrome, Stern-Lubinsky-Durrie syndrome, dermatopathia pigmentosa reticularis, dermo-odonto dysplasia, Rapp-Hodgkin syndrome, Clouston syndrome, ectodermal dysplasia, trichoodontoonychial type, gingival fibromatosis-hypertrichosis syndrome, hypertrichosis cubiti-short stature syndrome, Johnson neuroectodermal syndrome, Marshall syndrome, Naegeli-Franceschetti-Jadassohn syndrome, oculodentodigital dysplasia, Cronkhite-Canada syndrome, scalp-ear-nipple syndrome, tricho-dento-osseous syndrome, tricho-retino-dento-digital syndrome, acrofacial dysostosis, Weyers type, Ackerman syndrome, alopecia - contractures - dwarfism - intellectual disability syndrome, AREDYLD syndrome, Barber-Say syndrome, oculoosteocutaneous syndrome, cataract-hypertrichosis-intellectual disability syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, cerebellar ataxia-ectodermal dysplasia syndrome, cranioectodermal dysplasia, conductive deafness-ptosis-skeletal anomalies syndrome, dermatoosteolysis, Kirghizian type, Dubowitz syndrome, ectodermal dysplasia-sensorineural deafness syndrome, ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, cleft lip/palate-ectodermal dysplasia syndrome, EEM syndrome, Ellis-van Creveld syndrome, amelocerebrohypohidrotic syndrome, GAPO syndrome, ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome, Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome, Dahlberg-Borer-Newcomer syndrome, cartilage-hair hypoplasia, oculotrichodysplasia, pilodental dysplasia-refractive errors syndrome, Bartsocas-Papas syndrome 1, ectodermal dysplasia-blindness syndrome, Schinzel-Giedion syndrome, Teebi-Shaltout syndrome, taurodontia-absent teeth-sparse hair syndrome, odontotrichomelic syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, trichoodontoonychial dysplasia, CHIME syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, Ito hypomelanosis, contractures-ectodermal dysplasia-cleft lip/palate syndrome, incontinentia pigmenti, Toriello-Lacassie-Droste syndrome, odontomicronychial dysplasia, ectodermal dysplasia with natal teeth, Turnpenny type, hidrotic ectodermal dysplasia, Christianson-Fourie type, trichodental syndrome, congenital hypotrichosis with juvenile macular dystrophy, tricho-oculo-dermo-vertebral syndrome, odonto-tricho-ungual-digito-palmar syndrome, Fried’s tooth and nail syndrome, limb-mammary syndrome, epidermolysis bullosa simplex due to plakophilin deficiency, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Curly hair - acral keratoderma - caries syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, Lelis syndrome, Fontaine progeroid syndrome, ectodermal dysplasia-syndactyly syndrome, ectodermal dysplasia 5, hair/nail type, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, cardiofaciocutaneous syndrome, choroidal atrophy-alopecia syndrome, dyskeratosis congenita, hidrotic ectodermal dysplasia, Halal type, hypertrichosis lanuginosa congenita, hypohidrotic ectodermal dysplasia, odonto-onycho dysplasia-alopecia syndrome, pili torti-onychodysplasia syndrome, chondroectodermal dysplasia with night blindness, trichorhinophalangeal syndrome, trichothiodystrophy, trichodermodysplasia-dental alterations syndrome, autosomal dominant trichoodontoonychodysplasia-syndactyly, focal facial dermal dysplasia, KID syndrome, pure hair and nail ectodermal dysplasia, circumscribed palmoplantar hypokeratosis, trichodysplasia-amelogenesis imperfecta syndrome, dermotrichic syndrome, alves Castelo dos Santos syndrome, Brunoni syndrome, ectodermal dysplasia Bartalos type, ectodermal dysplasia margarita type, ectodermal dysplasia alopecia preaxial polydactyly, ectodermal dysplasia arthrogryposis diabetes mellitus, ectodermal dysplasia blindness, ectodermal dysplasia neurosensory deafness, ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, ectodermal dysplasia 15, hypohidrotic/hair type, linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies, jones hersh yusk syndrome, ectodermal dysplasia 13, hair/tooth type, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ectodermal dysplasia WNT10A related, CTSC-related disorder, ectodermal dysplasia 17 with or without limb malformations

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

86 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 22 likely benign, 14 pathogenic, 8 benign, 4 conflicting classifications of pathogenicity, 4 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424447	NC_000004.11:g.(?4861627)(6304195_?)del	C4orf50	Pathogenic	criteria provided, single submitter
1438990	NM_002448.3(MSX1):c.280C>T (p.Gln94Ter)	LOC129992137	Pathogenic	criteria provided, single submitter
4711875	NM_002448.3(MSX1):c.275C>A (p.Ser92Ter)	LOC129992137	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393580	NM_002448.3(MSX1):c.683dup (p.Arg229fs)	MSX1	Pathogenic	criteria provided, single submitter
14882	NM_002448.3(MSX1):c.623C>A (p.Ser208Ter)	MSX1	Pathogenic	criteria provided, single submitter
2010901	NM_002448.3(MSX1):c.487dup (p.Ala163fs)	MSX1	Pathogenic	criteria provided, single submitter
2424448	NC_000004.11:g.(?4859065)(4864603_?)del	MSX1	Pathogenic	criteria provided, single submitter
3246606	NC_000004.11:g.(?4861627)(4862115_?)del	MSX1	Pathogenic	criteria provided, single submitter
3246608	NC_000004.11:g.(?4864676)(4960528_?)del	MSX1	Pathogenic	criteria provided, single submitter
3646272	NM_002448.3(MSX1):c.668_669del (p.Arg223fs)	MSX1	Pathogenic	criteria provided, single submitter
3661406	NM_002448.3(MSX1):c.691_692del (p.Gln231fs)	MSX1	Pathogenic	criteria provided, single submitter
3687322	NM_002448.3(MSX1):c.365dup (p.Leu123fs)	MSX1	Pathogenic	criteria provided, single submitter
461602	NM_002448.3(MSX1):c.661C>T (p.Gln221Ter)	MSX1	Pathogenic	criteria provided, single submitter
4722939	NM_002448.3(MSX1):c.364_365dup (p.Leu123fs)	MSX1	Pathogenic	criteria provided, single submitter
845306	NM_002448.3(MSX1):c.655_659del (p.Trp219fs)	MSX1	Pathogenic	criteria provided, single submitter
931187	NM_002448.3(MSX1):c.89G>A (p.Gly30Asp)	LOC129992137	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2078308	NM_002448.3(MSX1):c.655T>C (p.Trp219Arg)	MSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225414	NM_002448.3(MSX1):c.471G>T (p.Arg157Ser)	MSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691922	NM_002448.3(MSX1):c.817G>A (p.Gly273Ser)	MSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14883	NM_002448.3(MSX1):c.251A>T (p.Glu84Val)	LOC129992137	Uncertain significance	criteria provided, single submitter
2142904	NM_002448.3(MSX1):c.100A>G (p.Ser34Gly)	LOC129992137	Uncertain significance	criteria provided, single submitter
3212852	NM_002448.3(MSX1):c.223G>C (p.Ala75Pro)	LOC129992137	Uncertain significance	criteria provided, multiple submitters, no conflicts
461605	NM_002448.3(MSX1):c.89G>C (p.Gly30Ala)	LOC129992137	Uncertain significance	criteria provided, single submitter
4809033	NM_002448.3(MSX1):c.97C>G (p.Pro33Ala)	LOC129992137	Uncertain significance	criteria provided, single submitter
4809344	NM_002448.3(MSX1):c.76G>T (p.Gly26Trp)	LOC129992137	Uncertain significance	criteria provided, single submitter
578158	NM_002448.3(MSX1):c.310G>C (p.Gly104Arg)	LOC129992137	Uncertain significance	criteria provided, multiple submitters, no conflicts
647201	NM_002448.3(MSX1):c.102C>G (p.Ser34Arg)	LOC129992137	Uncertain significance	criteria provided, single submitter
1022700	NM_002448.3(MSX1):c.623C>G (p.Ser208Trp)	MSX1	Uncertain significance	criteria provided, single submitter
1026068	NM_002448.3(MSX1):c.670C>T (p.Arg224Cys)	MSX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035233	NM_002448.3(MSX1):c.796G>A (p.Ala266Thr)	MSX1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
MSX1	Strong	Autosomal dominant	tooth agenesis, selective, 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSX1	Orphanet:141291	Cleft lip and alveolus
MSX1	Orphanet:199302	Isolated cleft lip
MSX1	Orphanet:199306	Cleft lip/palate
MSX1	Orphanet:2228	Hypodontia-dysplasia of nails syndrome
MSX1	Orphanet:99798	Oligodontia

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
MSX1	HGNC:7391	ENSG00000163132	P28360	Homeobox protein MSX-1	gencc,clinvar
C4orf50	HGNC:33766	ENSG00000181215	Q6ZRC1	Uncharacterized protein C4orf50	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSX1	Homeobox protein MSX-1	Acts as a transcriptional repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
C4orf50	Other/Unknown	no		DUF4527

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
buccal mucosa cell	1
choroid plexus epithelium	1
endocervix	1
male germ line stem cell (sensu Vertebrata) in testis	1
nucleus accumbens	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSX1	222	ubiquitous	marker	buccal mucosa cell, choroid plexus epithelium, endocervix
C4orf50	49	broad	marker	nucleus accumbens, superior frontal gyrus, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSX1	2,261
C4orf50	54

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MSX1	P28360	66.06
C4orf50	Q6ZRC1	55.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Specification of the neural plate border	1	634.4×	0.005	MSX1
Gastrulation	1	259.6×	0.006	MSX1
Developmental Biology	1	14.5×	0.069	MSX1

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
negative regulation of odontoblast differentiation	1	16852.0×	0.002	MSX1
cell surface receptor signaling pathway involved in heart development	1	8426.0×	0.002	MSX1
positive regulation of mesenchymal cell apoptotic process	1	5617.3×	0.002	MSX1
negative regulation of striated muscle cell differentiation	1	4213.0×	0.002	MSX1
activation of meiosis	1	4213.0×	0.002	MSX1
embryonic nail plate morphogenesis	1	3370.4×	0.002	MSX1
regulation of odontogenesis	1	3370.4×	0.002	MSX1
positive regulation of odontogenesis	1	3370.4×	0.002	MSX1
cartilage morphogenesis	1	3370.4×	0.002	MSX1
positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2808.7×	0.002	MSX1
nose development	1	2407.4×	0.002	MSX1
cellular response to nicotine	1	2106.5×	0.002	MSX1
mammary gland epithelium development	1	1872.4×	0.002	MSX1
embryonic morphogenesis	1	1532.0×	0.002	MSX1
mesenchymal cell apoptotic process	1	1532.0×	0.002	MSX1
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	MSX1
mesenchymal cell proliferation	1	1123.5×	0.002	MSX1
cardiac conduction system development	1	1053.2×	0.002	MSX1
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	991.3×	0.002	MSX1
signal transduction involved in regulation of gene expression	1	702.2×	0.003	MSX1
middle ear morphogenesis	1	702.2×	0.003	MSX1
pituitary gland development	1	648.1×	0.003	MSX1
midbrain development	1	601.9×	0.003	MSX1
bone morphogenesis	1	601.9×	0.003	MSX1
embryonic hindlimb morphogenesis	1	581.1×	0.003	MSX1
embryonic forelimb morphogenesis	1	495.6×	0.003	MSX1
face morphogenesis	1	495.6×	0.003	MSX1
positive regulation of BMP signaling pathway	1	455.5×	0.004	MSX1
positive regulation of cell cycle	1	443.5×	0.004	MSX1
inner ear development	1	374.5×	0.004	MSX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
MSX1	0	0
C4orf50	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	MSX1, C4orf50

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MSX1	0	—
C4orf50	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.