Non-acquired combined pituitary hormone deficiency with spine abnormalities

Summary

Non-acquired combined pituitary hormone deficiency with spine abnormalities (MONDO:0009091) is a disease caused by LHX3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LHX3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 161
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000824	Decreased response to growth hormone stimulation test	Very frequent (80-99%)
HP:0003423	Thoracolumbar kyphoscoliosis	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008213	Gonadotropin deficiency	Very frequent (80-99%)
HP:0008245	Pituitary hypothyroidism	Very frequent (80-99%)
HP:0010627	Anterior pituitary hypoplasia	Very frequent (80-99%)
HP:0012287	Hypothalamic luteinizing hormone-releasing hormone deficiency	Very frequent (80-99%)
HP:0011748	Adrenocorticotropic hormone deficiency	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	non-acquired combined pituitary hormone deficiency with spine abnormalities
Mondo ID	MONDO:0009091
MeSH	C536710
OMIM	221750
Orphanet	231720
DOID	DOID:0061021
UMLS	C3489787
MedGen	483740
GARD	0010603
Is cancer (heuristic)	no

Also known as: CPHD3 · Deafness, sensorineural with pituitary dwarfism · non-acquired combined pituitary hormone deficiency with spine abnormalities · non-acquired combined pituitary hormone deficiency-deafness-rigid cervical spine syndrome · Pituitary hormone deficiency, combined with rigid cervical spine · pituitary hormone deficiency, combined, 3 · pituitary hormone deficiency, combined, type 3 · Winkelmann-Bethge-Pfeiffer syndrome

Data availability: 161 ClinVar variants · 4 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 › non-acquired combined pituitary hormone deficiency with spine abnormalities

Related subtypes (8): isolated congenital growth hormone deficiency, septooptic dysplasia, congenital isolated adrenocorticotropic hormone deficiency, short stature-pituitary and cerebellar defects-small sella turcica syndrome, 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

161 retrieved; paginated sample, class counts are floors:

90 uncertain significance, 18 conflicting classifications of pathogenicity, 17 likely pathogenic, 12 pathogenic, 10 likely benign, 8 benign, 4 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070291	NM_178138.6(LHX3):c.80-2A>G	LHX3	Pathogenic	criteria provided, single submitter
1073213	NM_178138.6(LHX3):c.214C>T (p.Arg72Ter)	LHX3	Pathogenic	criteria provided, multiple submitters, no conflicts
1451723	NM_178138.6(LHX3):c.572C>A (p.Ser191Ter)	LHX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2115867	NM_178138.6(LHX3):c.93C>A (p.Cys31Ter)	LHX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2128359	NM_178138.6(LHX3):c.152G>A (p.Trp51Ter)	LHX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444147	NM_178138.6(LHX3):c.354C>A (p.Cys118Ter)	LHX3	Pathogenic	criteria provided, single submitter
4069850	NM_178138.6(LHX3):c.451C>T (p.Arg151Ter)	LHX3	Pathogenic	criteria provided, single submitter
4772503	NM_178138.6(LHX3):c.562G>T (p.Glu188Ter)	LHX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9021	NM_178138.6(LHX3):c.332A>G (p.Tyr111Cys)	LHX3	Pathogenic	no assertion criteria provided
9022	NM_178138.6(LHX3):c.452_454+20del	LHX3	Pathogenic	no assertion criteria provided
9023	NM_178138.6(LHX3):c.96del (p.Gly33fs)	LHX3	Pathogenic	criteria provided, single submitter
9025	NM_178138.6(LHX3):c.287_288delinsTCCT (p.Gly96fs)	LHX3	Pathogenic	no assertion criteria provided
9026	NC_000009.12:g.(?136197325)(136205012_?)del	LHX3	Pathogenic	no assertion criteria provided
9027	NM_178138.6(LHX3):c.672G>A (p.Trp224Ter)	LHX3	Pathogenic	no assertion criteria provided
9028	NM_178138.6(LHX3):c.80-530_776-454del	LHX3	Pathogenic	no assertion criteria provided
9029	NM_178138.6(LHX3):c.133A>T (p.Lys45Ter)	LHX3	Pathogenic	no assertion criteria provided
1067231	NM_178138.6(LHX3):c.607-3_630del	LHX3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324663	NM_178138.6(LHX3):c.280C>T (p.Gln94Ter)	LHX3	Likely pathogenic	criteria provided, single submitter
1341562	NM_178138.6(LHX3):c.581C>G (p.Thr194Arg)	LHX3	Likely pathogenic	no assertion criteria provided
3596759	NM_178138.6(LHX3):c.963dup (p.Ala322fs)	LHX3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596760	NM_178138.6(LHX3):c.908_909del (p.Pro303fs)	LHX3	Likely pathogenic	criteria provided, single submitter
3596761	NM_178138.6(LHX3):c.79+1989G>C	LHX3	Likely pathogenic	criteria provided, single submitter
4069835	NM_178138.6(LHX3):c.956del (p.Pro319fs)	LHX3	Likely pathogenic	criteria provided, single submitter
4069845	NM_178138.6(LHX3):c.191del (p.Pro64fs)	LHX3	Likely pathogenic	criteria provided, single submitter
4815722	NM_178138.6(LHX3):c.160A>T (p.Lys54Ter)	LHX3	Likely pathogenic	criteria provided, single submitter
4815723	NM_178138.6(LHX3):c.448C>T (p.Gln150Ter)	LHX3	Likely pathogenic	criteria provided, single submitter
4815724	NM_178138.6(LHX3):c.79+1949_79+1950delinsA	LHX3	Likely pathogenic	criteria provided, single submitter
4815725	NM_178138.6(LHX3):c.607-2A>T	LHX3	Likely pathogenic	criteria provided, single submitter
4815726	NM_178138.6(LHX3):c.679dup (p.Tyr227fs)	LHX3	Likely pathogenic	criteria provided, single submitter
4815727	NM_178138.6(LHX3):c.775+1G>A	LHX3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
LHX3	Definitive	Autosomal recessive	non-acquired combined pituitary hormone deficiency with spine abnormalities	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LHX3	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
LHX3	Orphanet:231720	Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities 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
LHX3	HGNC:6595	ENSG00000107187	Q9UBR4	LIM/homeobox protein Lhx3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LHX3	LIM/homeobox protein Lhx3	Transcription factor.

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)
LHX3	Transcription factor	no		HD, Znf_LIM, 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
adenohypophysis	1
diaphragm	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LHX3	22	tissue_specific	yes	pituitary gland, diaphragm, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LHX3	1,661

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LHX3	Q9UBR4	68.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Signaling by ROBO receptors	1	124.1×	0.029	LHX3
Regulation of expression of SLITs and ROBOs	1	69.2×	0.029	LHX3
Axon guidance	1	45.1×	0.029	LHX3
Nervous system development	1	42.9×	0.029	LHX3
Developmental Biology	1	14.5×	0.069	LHX3

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	LHX3
prolactin secreting cell differentiation	1	8426.0×	0.001	LHX3
somatotropin secreting cell differentiation	1	4213.0×	0.001	LHX3
ventral spinal cord interneuron specification	1	2808.7×	0.001	LHX3
thyroid-stimulating hormone-secreting cell differentiation	1	2808.7×	0.001	LHX3
spinal cord motor neuron cell fate specification	1	1532.0×	0.002	LHX3
spinal cord association neuron differentiation	1	1296.3×	0.002	LHX3
motor neuron axon guidance	1	702.2×	0.003	LHX3
placenta development	1	443.5×	0.005	LHX3
inner ear development	1	374.5×	0.005	LHX3
lung development	1	198.3×	0.008	LHX3
animal organ morphogenesis	1	191.5×	0.008	LHX3
neuron differentiation	1	100.3×	0.014	LHX3
negative regulation of apoptotic process	1	34.8×	0.037	LHX3
apoptotic process	1	28.7×	0.040	LHX3
positive regulation of DNA-templated transcription	1	27.9×	0.040	LHX3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	LHX3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	LHX3

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
LHX3	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	LHX3

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)
LHX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.