Panhypopituitarism

Summary

Panhypopituitarism (MONDO:0019591) is a disease with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include somatropin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 27
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		41	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0040075	Hypopituitarism	Obligate (100%)
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000141	Amenorrhea	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000789	Infertility	Frequent (30-79%)
HP:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002920	Decreased circulating ACTH level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008245	Pituitary hypothyroidism	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0009888	Abnormality of secondary sexual hair	Frequent (30-79%)
HP:0010311	Aplasia/Hypoplasia of the breasts	Frequent (30-79%)
HP:0010627	Anterior pituitary hypoplasia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0040086	Abnormal prolactin level	Frequent (30-79%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000839	Pituitary dwarfism	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0005625	Osteoporosis of vertebrae	Occasional (5-29%)
HP:0008187	Absence of secondary sex characteristics	Occasional (5-29%)
HP:0011755	Ectopic posterior pituitary	Very rare (<1-4%)
HP:0012731	Ectopic anterior pituitary gland	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	panhypopituitarism
Mondo ID	MONDO:0019591
Orphanet	90695
DOID	DOID:9410
ICD-11	1576287890
NCIT	C110940
SNOMED CT	32390006
UMLS	C0242343
MedGen	69171
GARD	0015020
MedDRA	10033662
Is cancer (heuristic)	no

Also known as: complete hypopituitarism

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records · 5 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › panhypopituitarism

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, pituitary hormone deficiency, combined, 1, pituitary hormone deficiency, combined or isolated, 8

Subtypes (2): pituitary hormone deficiency, combined, 2, panhypopituitarism, X-linked

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267830	46;X;t(X;5)(q24;q13)dn		Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 8 · 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
SOX3	Definitive	X-linked	intellectual disability, X-linked, with panhypopituitarism	13
PROP1	Supportive	Autosomal recessive	panhypopituitarism	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX3	Orphanet:3157	Septo-optic dysplasia spectrum
SOX3	Orphanet:393	46,XX testicular difference of sex development
SOX3	Orphanet:67045	X-linked intellectual disability with isolated growth hormone deficiency
SOX3	Orphanet:79495	X-linked congenital generalized hypertrichosis
SOX3	Orphanet:90695	Non-acquired panhypopituitarism
PROP1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
PROP1	Orphanet:90695	Non-acquired panhypopituitarism
PROP1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX3	HGNC:11199	ENSG00000134595	P41225	Transcription factor SOX-3	gencc
PROP1	HGNC:9455	ENSG00000175325	O75360	Homeobox protein prophet of Pit-1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX3	Transcription factor SOX-3	Transcription factor required during the formation of the hypothalamo-pituitary axis.
PROP1	Homeobox protein prophet of Pit-1	Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX3	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
PROP1	Transcription factor	no		HTH_motif, HD, 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)	1
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
ganglionic eminence	1
ventricular zone	1
adenohypophysis	1
bone marrow cell	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX3	72	broad	marker	ventricular zone, ganglionic eminence, embryo
PROP1	4		yes	pituitary gland, adenohypophysis, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROP1	1,160
SOX3	47

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROP1	O75360	70.74
SOX3	P41225	58.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Deactivation of the beta-catenin transactivating complex	1	233.1×	0.012	SOX3
TCF dependent signaling in response to WNT	1	117.7×	0.012	SOX3
Signaling by WNT	1	112.0×	0.012	SOX3
Signal Transduction	1	10.2×	0.098	SOX3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
central nervous system development	2	115.4×	0.001	SOX3, PROP1
hypophysis morphogenesis	1	4213.0×	0.002	PROP1
somatotropin secreting cell differentiation	1	2106.5×	0.003	PROP1
hypothalamus cell differentiation	1	1685.2×	0.003	PROP1
sex determination	1	842.6×	0.005	SOX3
hypothalamus development	1	526.6×	0.006	SOX3
face development	1	401.2×	0.007	SOX3
sensory organ development	1	337.0×	0.007	SOX3
pituitary gland development	1	324.1×	0.007	SOX3
dorsal/ventral pattern formation	1	210.7×	0.009	PROP1
blood vessel development	1	187.2×	0.010	PROP1
negative regulation of neuron differentiation	1	135.9×	0.012	SOX3
neuron differentiation	1	50.1×	0.031	SOX3
brain development	1	39.8×	0.036	SOX3
cell migration	1	30.8×	0.043	PROP1
negative regulation of apoptotic process	1	17.4×	0.071	PROP1
apoptotic process	1	14.3×	0.081	PROP1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.122	SOX3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	SOX3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	PROP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
SOX3	0	0
PROP1	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	2	SOX3, PROP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX3	0	—
PROP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	4
Not specified	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00144391	PHASE4	COMPLETED	Testosterone Gel Applied to Women With Pituitary Gland Problems
NCT00373386	PHASE4	COMPLETED	Growth Hormone and Endothelial Function in Children
NCT04897802	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (GLP1 Study)
NCT04902235	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (CRH Study)
NCT06217848	EARLY_PHASE1	UNKNOWN	The Effect of GLP-1 Agonist in Patients With Hypothalamic Obesity: Prospective, Pilot Study
NCT00001595	Not specified	RECRUITING	An Investigation of Pituitary Tumors and Related Hypothalmic Disorders
NCT00144404	Not specified	WITHDRAWN	Baseline Sexual Function, Cognitive Function, Body Composition and Muscle Parameters and Pharmacokinetics of Transdermal Testosterone Gel in Women With Hypopituitarism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOMATROPIN	4	1