Frontonasal dysplasia with alopecia and genital anomaly

Summary

Frontonasal dysplasia with alopecia and genital anomaly (MONDO:0013268) is a disease caused by ALX4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALX4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000289	Broad philtrum	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000430	Underdeveloped nasal alae	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001362	Skull defect	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002084	Encephalocele	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0004440	Coronal craniosynostosis	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0011803	Bifid nose	Very frequent (80-99%)
HP:0000046	Small scrotum	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000568	Microphthalmia	Frequent (30-79%)
HP:0000698	Conical tooth	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001562	Oligohydramnios	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002213	Fine hair	Frequent (30-79%)
HP:0002335	Agenesis of cerebellar vermis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	frontonasal dysplasia with alopecia and genital anomaly
Mondo ID	MONDO:0013268
OMIM	613451
Orphanet	228390
DOID	DOID:0081046
SNOMED CT	725029001
UMLS	C3150703
MedGen	462053
GARD	0012641
Is cancer (heuristic)	no

Also known as: ALX4-related FNDAG · craniofrontonasal dysplasia with alopecia and hypogonadism · FND2 · frontonasal dysplasia 2 · frontonasal dysplasia type 2 · frontonasal dysplasia with alopecia and genital abnomality

Data availability: 18 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › frontonasal dysplasia with alopecia and genital anomaly

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, ANE syndrome, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

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

18 retrieved; paginated sample, class counts are floors:

9 benign, 4 pathogenic, 3 uncertain significance, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
155903	NM_021926.4(ALX4):c.673C>G (p.Gln225Glu)	ALX4	Pathogenic	no assertion criteria provided
190380	NM_021926.4(ALX4):c.503del (p.Pro168fs)	ALX4	Pathogenic	no assertion criteria provided
225543	NM_021926.4(ALX4):c.291del (p.Gln98fs)	ALX4	Pathogenic	no assertion criteria provided
5020	NM_021926.4(ALX4):c.793C>T (p.Arg265Ter)	ALX4	Pathogenic	criteria provided, multiple submitters, no conflicts
735628	NM_021926.4(ALX4):c.440G>A (p.Ser147Asn)	ALX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3376224	NM_021926.4(ALX4):c.442G>A (p.Ala148Thr)	ALX4	Uncertain significance	criteria provided, single submitter
374798	NM_021926.4(ALX4):c.976G>A (p.Asp326Asn)	ALX4	Uncertain significance	criteria provided, multiple submitters, no conflicts
587597	NM_021926.4(ALX4):c.1192A>G (p.Met398Val)	ALX4	Uncertain significance	criteria provided, single submitter
1188923	NM_021926.4(ALX4):c.778-117T>C	ALX4	Benign	criteria provided, multiple submitters, no conflicts
1188924	NM_021926.4(ALX4):c.778-140G>C	ALX4	Benign	criteria provided, multiple submitters, no conflicts
1188925	NM_021926.4(ALX4):c.467-45T>C	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304701	NM_021926.4(ALX4):c.1074C>T (p.His358=)	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304703	NM_021926.4(ALX4):c.778-11G>A	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304706	NM_021926.4(ALX4):c.621A>G (p.Ser207=)	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304711	NM_021926.4(ALX4):c.304C>T (p.Pro102Ser)	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304715	NM_021926.4(ALX4):c.104G>C (p.Arg35Thr)	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304716	NM_021926.4(ALX4):c.69G>C (p.Pro23=)	ALX4	Benign	criteria provided, multiple submitters, no conflicts
304717	NM_021926.4(ALX4):c.63C>T (p.Tyr21=)	ALX4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
ALX4	Definitive	Autosomal recessive	frontonasal dysplasia with alopecia and genital anomaly	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX4	Orphanet:228390	Frontonasal dysplasia-alopecia-genital anomalies syndrome
ALX4	Orphanet:35093	Non-syndromic sagittal craniosynostosis
ALX4	Orphanet:52022	Potocki-Shaffer syndrome
ALX4	Orphanet:60015	Enlarged parietal foramina

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
ALX4	HGNC:450	ENSG00000052850	Q9H161	Homeobox protein aristaless-like 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX4	Homeobox protein aristaless-like 4	Transcription factor involved in skull and limb 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)
ALX4	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

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
buccal mucosa cell	1
cranial nerve II	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX4	82	broad	yes	primordial germ cell in gonad, buccal mucosa cell, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALX4	1,162

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALX4	Q9H161	4

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
embryonic hindlimb morphogenesis	1	581.1×	0.007	ALX4
digestive tract development	1	526.6×	0.007	ALX4
embryonic forelimb morphogenesis	1	495.6×	0.007	ALX4
embryonic skeletal system morphogenesis	1	391.9×	0.007	ALX4
hair follicle development	1	383.0×	0.007	ALX4
embryonic digit morphogenesis	1	300.9×	0.007	ALX4
neuron development	1	255.3×	0.007	ALX4
roof of mouth development	1	247.8×	0.007	ALX4
post-embryonic development	1	205.5×	0.008	ALX4
anterior/posterior pattern specification	1	181.2×	0.008	ALX4
muscle organ development	1	166.8×	0.008	ALX4
skeletal system development	1	125.8×	0.009	ALX4
regulation of apoptotic process	1	83.4×	0.013	ALX4
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ALX4

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
ALX4	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	ALX4

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)
ALX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.