Lethal occipital encephalocele-skeletal dysplasia syndrome

Summary

Lethal occipital encephalocele-skeletal dysplasia syndrome (MONDO:0013740) is a disease caused by CYP26B1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CYP26B1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

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

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal occipital encephalocele-skeletal dysplasia syndrome
Mondo ID	MONDO:0013740
OMIM	614416
Orphanet	293925
UMLS	C3280729
MedGen	482359
GARD	0017348
Is cancer (heuristic)	no

Also known as: craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies · radiohumeral fusions with other skeletal and craniofacial anomalies · RHFCA

Data availability: 10 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › lethal occipital encephalocele-skeletal dysplasia syndrome

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, Baller-Gerold syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, TCF12-related craniosynostosis, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka 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

10 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
30447	NM_019885.4(CYP26B1):c.1088G>T (p.Arg363Leu)	CYP26B1	Pathogenic	no assertion criteria provided
30448	NM_019885.4(CYP26B1):c.436T>C (p.Ser146Pro)	CYP26B1	Pathogenic	no assertion criteria provided
3393285	NM_019885.4(CYP26B1):c.3G>T (p.Met1Ile)	CYP26B1	Pathogenic	criteria provided, single submitter
1809805	NM_019885.4(CYP26B1):c.86C>A (p.Ser29Ter)	CYP26B1	Likely pathogenic	criteria provided, single submitter
432606	NM_019885.4(CYP26B1):c.1190G>A (p.Arg397Gln)	CYP26B1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380344	NM_019885.4(CYP26B1):c.1208C>T (p.Ala403Val)	CYP26B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310354	NM_019885.4(CYP26B1):c.344C>T (p.Thr115Ile)	CYP26B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236381	NM_019885.4(CYP26B1):c.584G>A (p.Arg195Gln)	CYP26B1	Uncertain significance	criteria provided, single submitter
3779211	NM_019885.4(CYP26B1):c.731A>G (p.Gln244Arg)	CYP26B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
997465	NM_019885.4(CYP26B1):c.1333C>T (p.His445Tyr)	CYP26B1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
CYP26B1	Strong	Autosomal recessive	lethal occipital encephalocele-skeletal dysplasia syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP26B1	Orphanet:293925	Lethal occipital encephalocele-skeletal dysplasia syndrome

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
CYP26B1	HGNC:20581	ENSG00000003137	Q9NR63	Cytochrome P450 26B1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP26B1	Cytochrome P450 26B1	A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP26B1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CS

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
cerebellar vermis	1
pons	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP26B1	239	broad	marker	pons, upper arm skin, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP26B1	2,349

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP26B1	Q9NR63	90.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Defective CYP26B1 causes RHFCA	1	11420.0×	3e-04	CYP26B1
Vitamins	1	1903.3×	8e-04	CYP26B1
RA biosynthesis pathway	1	475.8×	0.002	CYP26B1

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
positive regulation of tongue muscle cell differentiation	1	8426.0×	0.002	CYP26B1
retinoic acid catabolic process	1	3370.4×	0.002	CYP26B1
tongue morphogenesis	1	3370.4×	0.002	CYP26B1
vitamin metabolic process	1	2808.7×	0.002	CYP26B1
establishment of T cell polarity	1	1872.4×	0.003	CYP26B1
negative regulation of retinoic acid receptor signaling pathway	1	1532.0×	0.003	CYP26B1
regulation of T cell differentiation	1	1203.7×	0.003	CYP26B1
response to vitamin A	1	1053.2×	0.003	CYP26B1
cornification	1	1053.2×	0.003	CYP26B1
cell fate determination	1	936.2×	0.003	CYP26B1
retinoic acid metabolic process	1	802.5×	0.003	CYP26B1
proximal/distal pattern formation	1	648.1×	0.003	CYP26B1
retinoic acid receptor signaling pathway	1	648.1×	0.003	CYP26B1
bone morphogenesis	1	601.9×	0.003	CYP26B1
male meiotic nuclear division	1	543.6×	0.003	CYP26B1
establishment of skin barrier	1	455.5×	0.003	CYP26B1
embryonic limb morphogenesis	1	401.2×	0.004	CYP26B1
cellular response to retinoic acid	1	234.1×	0.006	CYP26B1
xenobiotic metabolic process	1	149.1×	0.008	CYP26B1
kidney development	1	140.4×	0.009	CYP26B1
central nervous system development	1	115.4×	0.010	CYP26B1
positive regulation of gene expression	1	38.7×	0.028	CYP26B1
inflammatory response	1	37.7×	0.028	CYP26B1
spermatogenesis	1	35.2×	0.028	CYP26B1

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
CYP26B1	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP26B1	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEXAROTENE	4	CYP26B1
KETOCONAZOLE	4	CYP26B1
LIAROZOLE	2	CYP26B1
TALAROZOLE	2	CYP26B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CYP26B1	6	Binding:6

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

4 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)
BEXAROTENE	4	CYP26B1
KETOCONAZOLE	4	CYP26B1
LIAROZOLE	2	CYP26B1
TALAROZOLE	2	CYP26B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP26B1
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.