Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

Summary

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (MONDO:0014460) is a disease caused by GRHL2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRHL2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
Mondo ID	MONDO:0014460
OMIM	616029
Orphanet	423454
UMLS	C4014987
MedGen	863424
GARD	0017703
Is cancer (heuristic)	no

Also known as: ECTDS · ectodermal dysplasia-short stature syndrome · ectodermal dysplasia/short stature syndrome · short stature-nail dysplasia-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

Data availability: 8 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › focal palmoplantar keratoderma › nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

Related subtypes (11): hereditary painful callosities, palmoplantar keratoderma-esophageal carcinoma syndrome, focal palmoplantar and gingival keratoderma, tyrosinemia type II, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, palmoplantar keratoderma, nonepidermolytic, focal 1, wooly hair-palmoplantar keratoderma syndrome, isolated focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita, focal palmoplantar keratoderma with joint keratoses, striate palmoplantar keratoderma

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:

3 benign, 2 uncertain significance, 1 likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
156217	NM_024915.4(GRHL2):c.1445T>A (p.Ile482Lys)	GRHL2	Pathogenic	no assertion criteria provided
156216	NM_024915.4(GRHL2):c.1192T>C (p.Tyr398His)	GRHL2	Likely pathogenic	criteria provided, single submitter
178378	NM_024915.4(GRHL2):c.548G>A (p.Arg183Gln)	GRHL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
46216	NM_024915.4(GRHL2):c.1723G>A (p.Val575Met)	GRHL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1260503	NM_024915.4(GRHL2):c.*41G>A	GRHL2	Benign	criteria provided, multiple submitters, no conflicts
261793	NM_024915.4(GRHL2):c.1764-19C>T	GRHL2	Benign	criteria provided, multiple submitters, no conflicts
46214	NM_024915.4(GRHL2):c.1098+9C>T	GRHL2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
508097	NM_024915.4(GRHL2):c.-24C>G	GRHL2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · 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
GRHL2	Strong	Autosomal recessive	nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRHL2	Orphanet:423454	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
GRHL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GRHL2	Orphanet:98973	Posterior polymorphous corneal dystrophy

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
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.

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)
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C

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
buccal mucosa cell	1
cervix squamous epithelium	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRHL2	1,365

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRHL2	Q6ISB3	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
epithelium migration	1	16852.0×	0.001	GRHL2
epithelial cell morphogenesis involved in placental branching	1	5617.3×	0.002	GRHL2
anterior neural tube closure	1	4213.0×	0.002	GRHL2
lung lobe morphogenesis	1	2106.5×	0.002	GRHL2
cardiac ventricle morphogenesis	1	1872.4×	0.002	GRHL2
lung epithelial cell differentiation	1	1872.4×	0.002	GRHL2
cell junction assembly	1	1685.2×	0.002	GRHL2
epithelial cell morphogenesis	1	936.2×	0.003	GRHL2
face development	1	802.5×	0.003	GRHL2
embryonic cranial skeleton morphogenesis	1	581.1×	0.004	GRHL2
neural tube development	1	526.6×	0.004	GRHL2
camera-type eye development	1	358.6×	0.005	GRHL2
bicellular tight junction assembly	1	330.4×	0.005	GRHL2
embryonic digit morphogenesis	1	300.9×	0.005	GRHL2
keratinocyte differentiation	1	247.8×	0.006	GRHL2
neural tube closure	1	187.2×	0.007	GRHL2
multicellular organism growth	1	137.0×	0.009	GRHL2
brain development	1	79.5×	0.015	GRHL2
cell adhesion	1	37.5×	0.030	GRHL2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	GRHL2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	GRHL2

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
GRHL2	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	GRHL2

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)
GRHL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.