Pseudohypoparathyroidism

Summary

Pseudohypoparathyroidism (MONDO:0019992) is a disease (an umbrella term covering 5 Mondo subtypes) with 2 cohort genes and 11 clinical trials. Top therapeutic interventions include theophylline anhydrous.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 36
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.67	Italy	Validated
Point prevalence	1-9 / 1 000 000	0.34	Japan	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoparathyroidism
Mondo ID	MONDO:0019992
MeSH	D011547
Orphanet	97593
DOID	DOID:4184
ICD-10-CM	E20.1
ICD-11	1225154856
NCIT	C99027
SNOMED CT	58976002
UMLS	C0033806
MedGen	46178
GARD	0010758
MedDRA	10037126
NORD	1627
Is cancer (heuristic)	no

Data availability: 36 ClinVar variants.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › pseudohypoparathyroidism

Related subtypes (8): familial periodic paralysis, hereditary hemochromatosis, acrodermatitis enteropathica, atransferrinemia, Wilson disease, Menkes disease, familial primary hypomagnesemia, sulfite oxidase deficiency due to molybdenum cofactor deficiency

Subtypes (5): pseudohypoparathyroidism type 1A, pseudohypoparathyroidism type 2, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudopseudohypoparathyroidism

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

36 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033065	NM_000516.7(GNAS):c.1107_1108del (p.Asn371fs)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1354948	NM_000516.7(GNAS):c.348del (p.Val117fs)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15927	NM_000516.7(GNAS):c.1A>G (p.Met1Val)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15928	NM_000516.7(GNAS):c.839+1G>C	GNAS	Pathogenic	no assertion criteria provided
15929	NM_000516.7(GNAS):c.725del (p.Thr242fs)	GNAS	Pathogenic	no assertion criteria provided
15930	GNAS, IVS3AS, A-G, -12	GNAS	Pathogenic	no assertion criteria provided
15931	NM_000516.7(GNAS):c.296T>C (p.Leu99Pro)	GNAS	Pathogenic	no assertion criteria provided
15932	NM_000516.7(GNAS):c.493C>T (p.Arg165Cys)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15938	NM_000516.7(GNAS):c.565_568del (p.Asp189fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15939	NM_000516.7(GNAS):c.750C>G (p.Ser250Arg)	GNAS	Pathogenic	no assertion criteria provided
15940	NM_000516.7(GNAS):c.119_139+17del	GNAS	Pathogenic	no assertion criteria provided
15946	NM_000516.7(GNAS):c.692G>A (p.Arg231His)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15947	NM_000516.7(GNAS):c.617_618del (p.Gly206fs)	GNAS	Pathogenic	no assertion criteria provided
15948	NM_000516.7(GNAS):c.302_303del (p.Glu101fs)	GNAS	Pathogenic	no assertion criteria provided
15950	NM_000516.7(GNAS):c.112del (p.Arg38fs)	GNAS	Pathogenic	no assertion criteria provided
15951	NM_000516.7(GNAS):c.860_861del (p.Val287fs)	GNAS	Pathogenic	criteria provided, single submitter
15953	NM_000516.7(GNAS):c.344C>T (p.Pro115Leu)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15957	NM_000516.7(GNAS):c.254dup (p.Asp85fs)	GNAS	Pathogenic	no assertion criteria provided
15958	NM_000516.7(GNAS):c.1097_1108dup (p.Thr369_Glu370insAlaValAspThr)	GNAS	Pathogenic	no assertion criteria provided
209158	NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
216937	NM_000516.7(GNAS):c.880C>T (p.Gln294Ter)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374113	NM_000516.7(GNAS):c.85C>T (p.Gln29Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
635558	NM_000516.7(GNAS):c.277C>T (p.Gln93Ter)	GNAS	Pathogenic	criteria provided, single submitter
691981	NM_000516.7(GNAS):c.271A>T (p.Lys91Ter)	GNAS	Pathogenic	criteria provided, single submitter
816649	NM_000516.7(GNAS):c.530+1G>T	GNAS	Pathogenic	criteria provided, single submitter
816910	NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976346	NM_080425.4(GNAS):c.754_761del (p.Ser252fs)	GNAS	Likely pathogenic	criteria provided, single submitter
981517	NM_000516.7(GNAS):c.212+3_212+6del	GNAS	Likely pathogenic	criteria provided, single submitter
1301904	NM_000316.3(PTH1R):c.723C>G (p.Asp241Glu)	PTH1R	Likely pathogenic	criteria provided, single submitter
431104	NM_080425.4(GNAS):c.475G>A (p.Glu159Lys)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B
PTH1R	Orphanet:296	Ollier disease
PTH1R	Orphanet:33067	Metaphyseal chondrodysplasia, Jansen type
PTH1R	Orphanet:412206	Primary failure of tooth eruption
PTH1R	Orphanet:50945	Blomstrand lethal chondrodysplasia
PTH1R	Orphanet:79106	Eiken syndrome

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
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	clinvar
PTH1R	HGNC:9608	ENSG00000160801	Q03431	Parathyroid hormone/parathyroid hormone-related peptide receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTH1R	Parathyroid hormone/parathyroid hormone-related peptide receptor	G-protein-coupled receptor for parathyroid hormone (PTH) and for parathyroid hormone-related peptide (PTHLH).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
PTH1R	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_parathyroid_rcpt

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1
adult mammalian kidney	1
metanephros cortex	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
PTH1R	219	broad	marker	adult mammalian kidney, metanephros cortex, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTH1R	1,633
GNAS	410

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
PTH1R	Q03431	48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 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
G alpha (s) signalling events	2	73.2×	0.003	GNAS, PTH1R
PKA activation in glucagon signalling	1	335.9×	0.012	GNAS
Prostacyclin signalling through prostacyclin receptor	1	300.5×	0.012	GNAS
Glucagon signaling in metabolic regulation	1	173.0×	0.012	GNAS
Glucagon-type ligand receptors	1	173.0×	0.012	GNAS
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.012	GNAS
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.012	GNAS
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.012	GNAS
GPER1 signaling	1	124.1×	0.012	GNAS
G alpha (z) signalling events	1	116.5×	0.012	GNAS
Class B/2 (Secretin family receptors)	1	95.2×	0.013	PTH1R
Hedgehog ‘off’ state	1	89.2×	0.013	GNAS
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.013	GNAS
G alpha (i) signalling events	1	19.5×	0.051	GNAS

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
adenylate cyclase-activating G protein-coupled receptor signaling pathway	2	113.1×	0.004	GNAS, PTH1R
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	2808.7×	0.005	GNAS
response to parathyroid hormone	1	2106.5×	0.005	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	1685.2×	0.005	GNAS
hair follicle placode formation	1	1685.2×	0.005	GNAS
regulation of skeletal muscle contraction	1	1404.3×	0.005	GNAS
positive regulation of inositol phosphate biosynthetic process	1	1203.7×	0.005	PTH1R
cellular response to catecholamine stimulus	1	1203.7×	0.005	GNAS
G protein-coupled receptor signaling pathway	2	36.2×	0.005	GNAS, PTH1R
adenylate cyclase-activating dopamine receptor signaling pathway	1	766.0×	0.005	GNAS
intracellular transport	1	766.0×	0.005	GNAS
response to prostaglandin E	1	702.2×	0.005	GNAS
adenylate cyclase-activating adrenergic receptor signaling pathway	1	601.9×	0.005	GNAS
activation of adenylate cyclase activity	1	561.7×	0.005	GNAS
sensory perception of chemical stimulus	1	561.7×	0.005	GNAS
negative regulation of multicellular organism growth	1	561.7×	0.005	GNAS
osteoblast development	1	495.6×	0.006	PTH1R
cellular response to glucagon stimulus	1	421.3×	0.006	GNAS
cellular response to prostaglandin E stimulus	1	421.3×	0.006	GNAS
developmental growth	1	366.4×	0.006	GNAS
cellular response to acidic pH	1	366.4×	0.006	GNAS
vascular endothelial cell response to laminar fluid shear stress	1	366.4×	0.006	GNAS
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.007	GNAS
intracellular glucose homeostasis	1	290.6×	0.007	GNAS
bone resorption	1	290.6×	0.007	PTH1R
renal water homeostasis	1	255.3×	0.007	GNAS
cell maturation	1	221.7×	0.008	PTH1R
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.009	GNAS
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.010	PTH1R
platelet aggregation	1	168.5×	0.010	GNAS

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Somatropin.

Drug target analysis

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

Druggability breadth: 2 of 2 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
PTH1R	ABALOPARATIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTH1R	3	4
GNAS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABALOPARATIDE	4	PTH1R
TERIPARATIDE	4	PTH1R
PCO-371	1	PTH1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PTH1R	59	Functional:42, Binding:17

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

3 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)
ABALOPARATIDE	4	PTH1R
TERIPARATIDE	4	PTH1R
PCO-371	1	PTH1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTH1R
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	GNAS

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)
GNAS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03029429	PHASE2	ACTIVE_NOT_RECRUITING	Theophylline Treatment for Pseudohypoparathyroidism
NCT04240821	PHASE2	ENROLLING_BY_INVITATION	Theophylline for Treatment of Pseudohypoparathyroidism
NCT04551170	PHASE2	ACTIVE_NOT_RECRUITING	Theophylline Treatment for Pseudohypoparathyroidism - Children 2-12 Years Old
NCT04969926	Not specified	RECRUITING	Natural History Study of Parathyroid Disorders
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT00001242	Not specified	COMPLETED	Studies of States With Resistance to Vitamin D and Parathyroid Hormone
NCT00004661	Not specified	COMPLETED	Study of the Regulation of Parathyroid Hormone Secretion in Pseudohypoparathyroidism
NCT00497484	Not specified	UNKNOWN	Evaluation of rhGH Replacement Therapy in Patients With Pseudohypoparathyroidism Type Ia (PHP Ia)
NCT02411461	Not specified	COMPLETED	Early-onset Obesity and Cognitive Impairment in Children With Pseudohypoparathyroidism
NCT02551120	Not specified	UNKNOWN	Characterization of Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism
NCT03761290	Not specified	TERMINATED	Glucose Homeostasis in Pseudohypoparathyroidism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
THEOPHYLLINE ANHYDROUS	4	6