Short stature-pituitary and cerebellar defects-small sella turcica syndrome
diseaseOn this page
Also known as CPHD4pituitary hormone deficiency, combined 4pituitary hormone deficiency, combined with or without cerebellar defectspituitary hormone deficiency, combined, 4pituitary hormone deficiency, combined, type 4short stature, pituitary and cerebellar defects and small sella turcica
Summary
Short stature-pituitary and cerebellar defects-small sella turcica syndrome (MONDO:0009880) is a disease caused by LHX4 (GenCC Definitive), with 3 cohort genes.
At a glance
- Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
- Causal gene: LHX4 (GenCC Definitive)
- Cohort genes: 3
- ClinVar variants: 76
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 | short stature-pituitary and cerebellar defects-small sella turcica syndrome |
| Mondo ID | MONDO:0009880 |
| MeSH | C567492 |
| OMIM | 262700 |
| Orphanet | 85442 |
| DOID | DOID:0061017 |
| UMLS | C2678408 |
| MedGen | 394816 |
| GARD | 0010604 |
| Is cancer (heuristic) | no |
Also known as: CPHD4 · pituitary hormone deficiency, combined 4 · pituitary hormone deficiency, combined with or without cerebellar defects · pituitary hormone deficiency, combined, 4 · pituitary hormone deficiency, combined, type 4 · short stature, pituitary and cerebellar defects and small sella turcica
Data availability: 76 ClinVar variants · 5 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › short stature-pituitary and cerebellar defects-small sella turcica syndrome
Related subtypes (8): isolated congenital growth hormone deficiency, septooptic dysplasia, congenital isolated adrenocorticotropic hormone deficiency, non-acquired combined pituitary hormone deficiency with spine abnormalities, pituitary hormone deficiency, combined, 6, panhypopituitarism, pituitary hormone deficiency, combined, 1, pituitary hormone deficiency, combined or isolated, 8
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
76 retrieved; paginated sample, class counts are floors:
38 uncertain significance, 13 benign, 7 conflicting classifications of pathogenicity, 6 pathogenic, 6 benign/likely benign, 5 likely benign, 1 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 189234 | NM_033343.4(LHX4):c.452-2A>C | ACBD6 | Pathogenic | criteria provided, single submitter |
| 7507 | NM_033343.4(LHX4):c.628G>C (p.Ala210Pro) | ACBD6 | Pathogenic | no assertion criteria provided |
| 18444 | NM_033343.4(LHX4):c.293dup (p.Thr99fs) | LHX4 | Pathogenic | no assertion criteria provided |
| 7506 | NM_033343.4(LHX4):c.607-1G>C | LHX4-AS1 | Pathogenic | no assertion criteria provided |
| 7509 | NM_033343.4(LHX4):c.569T>G (p.Leu190Arg) | LHX4-AS1 | Pathogenic | no assertion criteria provided |
| 7510 | NM_033343.4(LHX4):c.1162C>A (p.Pro388Thr) | LHX4-AS1 | Pathogenic | no assertion criteria provided |
| 4056579 | NM_033343.4(LHX4):c.461_462del (p.Glu154fs) | ACBD6 | Likely pathogenic | criteria provided, single submitter |
| 293857 | NM_033343.4(LHX4):c.37G>A (p.Val13Ile) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 293861 | NM_033343.4(LHX4):c.146A>G (p.His49Arg) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 7508 | NM_033343.4(LHX4):c.250C>T (p.Arg84Cys) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 801583 | NM_033343.4(LHX4):c.704G>A (p.Arg235Gln) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 801584 | NM_033343.4(LHX4):c.776G>A (p.Arg259Gln) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 874814 | NM_033343.4(LHX4):c.1007G>A (p.Ser336Asn) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 876697 | NM_033343.4(LHX4):c.378G>A (p.Thr126=) | LHX4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1710224 | NM_033343.4(LHX4):c.822T>A (p.Tyr274Ter) | ACBD6 | Uncertain significance | no assertion criteria provided |
| 2433430 | NM_033343.4(LHX4):c.1087A>T (p.Ile363Phe) | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 3238840 | NM_033343.4(LHX4):c.694A>G (p.Lys232Glu) | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 874818 | NM_033343.4(LHX4):c.*17C>T | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 875752 | NM_033343.4(LHX4):c.*154A>G | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 875753 | NM_033343.4(LHX4):c.*221G>T | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 876749 | NM_033343.4(LHX4):c.*280T>C | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 876750 | NM_033343.4(LHX4):c.*460G>C | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 976050 | NM_033343.4(LHX4):c.602T>C (p.Val201Ala) | ACBD6 | Uncertain significance | criteria provided, single submitter |
| 1213718 | NM_033343.4(LHX4):c.464C>T (p.Ala155Val) | LHX4 | Uncertain significance | criteria provided, single submitter |
| 1705660 | NM_033343.4(LHX4):c.569T>C (p.Leu190Pro) | LHX4 | Uncertain significance | criteria provided, single submitter |
| 2433432 | NM_033343.4(LHX4):c.37_39del (p.Val13del) | LHX4 | Uncertain significance | criteria provided, single submitter |
| 2573040 | NM_033343.4(LHX4):c.451G>C (p.Asp151His) | LHX4 | Uncertain significance | criteria provided, single submitter |
| 2627082 | NM_033343.4(LHX4):c.364C>T (p.Arg122Trp) | LHX4 | Uncertain significance | criteria provided, single submitter |
| 293853 | NM_033343.4(LHX4):c.-172A>G | LHX4 | Uncertain significance | criteria provided, single submitter |
| 293854 | NM_033343.4(LHX4):c.-134G>C | LHX4 | Uncertain significance | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 8 · 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 |
|---|---|---|---|---|
| LHX4 | Definitive | Autosomal dominant | short stature-pituitary and cerebellar defects-small sella turcica syndrome | 8 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| LHX4 | Orphanet:226307 | Hypothyroidism due to deficient transcription factors involved in pituitary development or function |
| LHX4 | Orphanet:85442 | Short stature-pituitary and cerebellar defects-small sella turcica syndrome |
| LHX4 | Orphanet:95494 | Combined pituitary hormone deficiencies, genetic forms |
| LHX4 | Orphanet:95496 | Pituitary stalk interruption syndrome |
Cohort genes → proteins
3 cohort genes, 2 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 3 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| LHX4 | HGNC:21734 | ENSG00000121454 | Q969G2 | LIM/homeobox protein Lhx4 | gencc,clinvar |
| ACBD6 | HGNC:23339 | ENSG00000230124 | Q9BR61 | Acyl-CoA-binding domain-containing protein 6 | clinvar |
| LHX4-AS1 | HGNC:40982 | LHX4 antisense RNA 1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| LHX4 | LIM/homeobox protein Lhx4 | May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. |
| ACBD6 | Acyl-CoA-binding domain-containing protein 6 | Binds long-chain acyl-coenzyme A molecules with a strong preference for unsaturated C18:1-CoA, lower affinity for unsaturated C20:4-CoA, and very weak affinity for saturated C16:0-CoA. |
Protein-family classification
Druggable: 0 · Difficult: 2 · 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 |
|---|---|---|---|
| Scaffold/PPI | 1 | 5.8× | 0.482 |
| Transcription factor | 1 | 2.8× | 0.482 |
| Other/Unknown | 1 | 0.6× | 0.914 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| LHX4 | Transcription factor | no | HD, Znf_LIM, Homeodomain-like_sf | |
| ACBD6 | Scaffold/PPI | no | Acyl-CoA-binding_protein, Ankyrin_rpt, FERM/acyl-CoA-bd_prot_sf | |
| LHX4-AS1 | Other/Unknown | no |
Expression context
Cohort genes with no expression data: 1.
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) | 2 |
| unknown | 1 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| buccal mucosa cell | 1 |
| pancreatic ductal cell | 1 |
| sperm | 1 |
| cortical plate | 1 |
| ganglionic eminence | 1 |
| left testis | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| LHX4 | 166 | tissue_specific | yes | buccal mucosa cell, sperm, pancreatic ductal cell |
| ACBD6 | 231 | ubiquitous | marker | cortical plate, ganglionic eminence, left testis |
| LHX4-AS1 |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| LHX4 | 1,566 |
| ACBD6 | 1,486 |
| LHX4-AS1 | 0 |
Structural data
PDB: 2 · AlphaFold-only: 0 · No structure: 1
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| LHX4 | Q969G2 | 1 |
| ACBD6 | Q9BR61 | 1 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Mitochondrial Fatty Acid Beta-Oxidation | 1 | 190.3× | 0.047 | ACBD6 |
| Fatty acid metabolism | 1 | 65.6× | 0.048 | ACBD6 |
| Signaling by ROBO receptors | 1 | 62.1× | 0.048 | LHX4 |
| Regulation of expression of SLITs and ROBOs | 1 | 34.6× | 0.065 | LHX4 |
| Axon guidance | 1 | 22.6× | 0.069 | LHX4 |
| Nervous system development | 1 | 21.5× | 0.069 | LHX4 |
| Metabolism of lipids | 1 | 15.8× | 0.080 | ACBD6 |
| Developmental Biology | 1 | 7.2× | 0.150 | LHX4 |
| Metabolism | 1 | 5.8× | 0.165 | ACBD6 |
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 |
|---|---|---|---|---|
| medial motor column neuron differentiation | 1 | 8426.0× | 0.001 | LHX4 |
| motor neuron axon guidance | 1 | 702.2× | 0.006 | LHX4 |
| placenta development | 1 | 443.5× | 0.007 | LHX4 |
| animal organ morphogenesis | 1 | 191.5× | 0.012 | LHX4 |
| neuron differentiation | 1 | 100.3× | 0.018 | LHX4 |
| negative regulation of apoptotic process | 1 | 34.8× | 0.043 | LHX4 |
| apoptotic process | 1 | 28.7× | 0.045 | LHX4 |
| positive regulation of transcription by RNA polymerase II | 1 | 14.9× | 0.076 | LHX4 |
| regulation of transcription by RNA polymerase II | 1 | 11.7× | 0.086 | LHX4 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3
Druggability breadth: 0 of 3 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 |
|---|---|---|
| LHX4 | 0 | 0 |
| ACBD6 | 0 | 0 |
| LHX4-AS1 | 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 | 3 | LHX4, ACBD6, LHX4-AS1 |
Undrugged target profiles
3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| LHX4 | 0 | — |
| ACBD6 | 0 | — |
| LHX4-AS1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.