Pituitary hormone deficiency, combined, 1

Summary

Pituitary hormone deficiency, combined, 1 (MONDO:0024464) is a disease caused by POU1F1 (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Causal gene: POU1F1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 65
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pituitary hormone deficiency, combined, 1
Mondo ID	MONDO:0024464
MeSH	C567803
OMIM	613038
DOID	DOID:0061019
UMLS	C2751608
MedGen	414421
GARD	0010601
Is cancer (heuristic)	no

Also known as: combined pituitary hormone deficiencies, genetic form caused by mutation in POU1F1 · CPHD1 · pituitary hormone deficiency, combined 1 · pituitary hormone deficiency, combined or isolated, 1 · pituitary hormone deficiency, combined, 1 · POU1F1 combined pituitary hormone deficiencies, genetic form

Data availability: 65 ClinVar variants · 7 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 › pituitary hormone deficiency, combined, 1

Related subtypes (8): isolated congenital growth hormone deficiency, septooptic dysplasia, congenital isolated adrenocorticotropic hormone deficiency, non-acquired combined pituitary hormone deficiency with spine abnormalities, short stature-pituitary and cerebellar defects-small sella turcica syndrome, pituitary hormone deficiency, combined, 6, panhypopituitarism, 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

65 retrieved; paginated sample, class counts are floors:

18 pathogenic, 17 uncertain significance, 13 conflicting classifications of pathogenicity, 8 likely pathogenic, 3 pathogenic/likely pathogenic, 3 benign/likely benign, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
492848	NM_003865.3(HESX1):c.240del (p.Glu81fs)	HESX1	Pathogenic	no assertion criteria provided
126542	NM_000306.4(POU1F1):c.665+1G>T	POU1F1	Pathogenic	no assertion criteria provided
1285381	NM_000306.4(POU1F1):c.143-69T>G	POU1F1	Pathogenic	no assertion criteria provided
1285382	NM_000306.4(POU1F1):c.143-66T>G	POU1F1	Pathogenic	no assertion criteria provided
1285384	NM_000306.4(POU1F1):c.143-71T>G	POU1F1	Pathogenic	no assertion criteria provided
1285385	NM_000306.4(POU1F1):c.143-68T>A	POU1F1	Pathogenic	no assertion criteria provided
13602	NM_000306.4(POU1F1):c.514C>T (p.Arg172Ter)	POU1F1	Pathogenic	criteria provided, single submitter
13604	NM_000306.4(POU1F1):c.472G>C (p.Ala158Pro)	POU1F1	Pathogenic	criteria provided, multiple submitters, no conflicts
13606	NM_000306.4(POU1F1):c.428G>A (p.Arg143Gln)	POU1F1	Pathogenic	criteria provided, single submitter
13607	NM_000306.4(POU1F1):c.748G>T (p.Glu250Ter)	POU1F1	Pathogenic	no assertion criteria provided
13608	NM_000306.4(POU1F1):c.404T>G (p.Phe135Cys)	POU1F1	Pathogenic	no assertion criteria provided
13609	NM_000306.4(POU1F1):c.715C>T (p.Pro239Ser)	POU1F1	Pathogenic	no assertion criteria provided
13611	NM_000306.4(POU1F1):c.577T>C (p.Trp193Arg)	POU1F1	Pathogenic	no assertion criteria provided
13612	NM_000306.4(POU1F1):c.433A>T (p.Lys145Ter)	POU1F1	Pathogenic	no assertion criteria provided
13613	NM_000306.4(POU1F1):c.688G>A (p.Glu230Lys)	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13614	NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13615	NM_000306.4(POU1F1):c.775dup (p.Arg259fs)	POU1F1	Pathogenic	no assertion criteria provided
13616	NM_000306.4(POU1F1):c.537C>G (p.Ser179Arg)	POU1F1	Pathogenic	no assertion criteria provided
2258706	NM_000306.4(POU1F1):c.427C>T (p.Arg143Ter)	POU1F1	Pathogenic	criteria provided, multiple submitters, no conflicts
3340314	NM_000306.4(POU1F1):c.143-83A>G	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292029	NM_000306.4(POU1F1):c.562_565del (p.Ala188fs)	POU1F1	Pathogenic	criteria provided, single submitter
492849	NM_003865.3(HESX1):c.308T>A (p.Leu103Ter)	HESX1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1183964	NM_000306.4(POU1F1):c.662T>C (p.Ile221Thr)	POU1F1	Likely pathogenic	criteria provided, single submitter
13605	NM_000306.4(POU1F1):c.71C>T (p.Pro24Leu)	POU1F1	Likely pathogenic	criteria provided, single submitter
13610	NM_000306.4(POU1F1):c.747del (p.Glu250fs)	POU1F1	Likely pathogenic	criteria provided, single submitter
161432	NC_000003.12:g.87310484C>T	POU1F1	Likely pathogenic	no assertion criteria provided
254175	NM_000306.4(POU1F1):c.638_642del (p.Arg213fs)	POU1F1	Likely pathogenic	criteria provided, single submitter
254176	NM_000306.4(POU1F1):c.215-3C>G	POU1F1	Likely pathogenic	no assertion criteria provided
560655	NM_000306.4(POU1F1):c.500A>C (p.Gln167Pro)	POU1F1	Likely pathogenic	criteria provided, single submitter
267733	NM_003865.3(HESX1):c.385G>A (p.Val129Ile)	HESX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 14 · 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
POU1F1	Definitive	Semidominant	pituitary hormone deficiency, combined, 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POU1F1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
POU1F1	Orphanet:231679	Isolated growth hormone deficiency type II
POU1F1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
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
HESX1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
HESX1	Orphanet:3157	Septo-optic dysplasia spectrum
HESX1	Orphanet:478	Kallmann syndrome
HESX1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
HESX1	Orphanet:95496	Pituitary stalk interruption syndrome
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

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POU1F1	HGNC:9210	ENSG00000064835	P28069	Pituitary-specific positive transcription factor 1	gencc,clinvar
LHX4	HGNC:21734	ENSG00000121454	Q969G2	LIM/homeobox protein Lhx4	clinvar
HESX1	HGNC:4877	ENSG00000163666	Q9UBX0	Homeobox expressed in ES cells 1	clinvar
LHX3	HGNC:6595	ENSG00000107187	Q9UBR4	LIM/homeobox protein Lhx3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POU1F1	Pituitary-specific positive transcription factor 1	Transcription factor involved in the specification of the lactotrope, somatotrope, and thyrotrope phenotypes in the developing anterior pituitary.
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.
HESX1	Homeobox expressed in ES cells 1	Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland.
LHX3	LIM/homeobox protein Lhx3	Transcription factor.

Protein-family classification

Druggable: 0 · Difficult: 4 · 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	4	8.3×	2e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POU1F1	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
LHX4	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
HESX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
LHX3	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	2
pituitary gland	2
buccal mucosa cell	2
decidua	1
pancreatic ductal cell	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
diaphragm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POU1F1	73	tissue_specific	yes	pituitary gland, adenohypophysis, decidua
LHX4	166	tissue_specific	yes	buccal mucosa cell, sperm, pancreatic ductal cell
HESX1	167	broad	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
LHX3	22	tissue_specific	yes	pituitary gland, diaphragm, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LHX3	1,661
LHX4	1,566
POU1F1	1,170
HESX1	888

Intra-cohort edges

A	B	Sources
HESX1	POU1F1	string_interaction
LHX3	LHX4	intact
LHX3	POU1F1	string_interaction
LHX4	POU1F1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POU1F1	P28069	1
LHX4	Q969G2	1
HESX1	Q9UBX0	1

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 4 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
Signaling by ROBO receptors	2	124.1×	3e-04	LHX4, LHX3
Regulation of expression of SLITs and ROBOs	2	69.2×	5e-04	LHX4, LHX3
Axon guidance	2	45.1×	7e-04	LHX4, LHX3
Nervous system development	2	42.9×	7e-04	LHX4, LHX3
Developmental Biology	2	14.5×	0.005	LHX4, 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 4 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	2	4213.0×	2e-06	LHX4, LHX3
motor neuron axon guidance	2	351.1×	2e-04	LHX4, LHX3
placenta development	2	221.7×	4e-04	LHX4, LHX3
regulation of transcription by RNA polymerase II	4	11.7×	5e-04	POU1F1, LHX4, HESX1, LHX3
animal organ morphogenesis	2	95.8×	0.001	LHX4, LHX3
prolactin secreting cell differentiation	1	2106.5×	0.003	LHX3
neuron differentiation	2	50.1×	0.003	LHX4, LHX3
leukemia inhibitory factor signaling pathway	1	1053.2×	0.004	HESX1
somatotropin secreting cell differentiation	1	1053.2×	0.004	LHX3
positive regulation of transcription by RNA polymerase II	3	11.2×	0.004	POU1F1, LHX4, LHX3
ventral spinal cord interneuron specification	1	702.2×	0.005	LHX3
thyroid-stimulating hormone-secreting cell differentiation	1	702.2×	0.005	LHX3
adenohypophysis development	1	601.9×	0.005	POU1F1
nose development	1	601.9×	0.005	HESX1
otic vesicle formation	1	526.6×	0.005	HESX1
spinal cord motor neuron cell fate specification	1	383.0×	0.006	LHX3
forebrain morphogenesis	1	351.1×	0.007	HESX1
spinal cord association neuron differentiation	1	324.1×	0.007	LHX3
gonad development	1	280.9×	0.007	HESX1
negative regulation of apoptotic process	2	17.4×	0.009	LHX4, LHX3
cellular response to cadmium ion	1	191.5×	0.010	HESX1
pituitary gland development	1	162.0×	0.011	HESX1
apoptotic process	2	14.3×	0.012	LHX4, LHX3
thyroid gland development	1	135.9×	0.012	HESX1
stem cell population maintenance	1	105.3×	0.015	HESX1
inner ear development	1	93.6×	0.016	LHX3
camera-type eye development	1	89.6×	0.016	HESX1
regulation of embryonic development	1	82.6×	0.017	HESX1
ERK1 and ERK2 cascade	1	79.5×	0.017	HESX1
stem cell differentiation	1	75.2×	0.017	HESX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 0 of 4 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
POU1F1	0	0
LHX4	0	0
HESX1	0	0
LHX3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	POU1F1, LHX4, HESX1, LHX3

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
POU1F1	0	—
LHX4	0	—
HESX1	0	—
LHX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns