Familial isolated hyperparathyroidism

Summary

Familial isolated hyperparathyroidism (MONDO:0015027) is a disease with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000121	Nephrocalcinosis	Very frequent (80-99%)
HP:0000934	Chondrocalcinosis	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0002150	Hypercalciuria	Very frequent (80-99%)
HP:0002897	Parathyroid adenoma	Very frequent (80-99%)
HP:0003072	Hypercalcemia	Very frequent (80-99%)
HP:0003109	Hyperphosphaturia	Very frequent (80-99%)
HP:0003165	Elevated circulating parathyroid hormone level	Very frequent (80-99%)
HP:0008200	Primary hyperparathyroidism	Very frequent (80-99%)
HP:0040160	Generalized osteoporosis	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0011458	Abdominal symptom	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial isolated hyperparathyroidism
Mondo ID	MONDO:0015027
Orphanet	99879
ICD-11	1799621215
NCIT	C94830
UMLS	C4551961
MedGen	1643161
GARD	0016923
Is cancer (heuristic)	no

Also known as: familial isolated hyperparathyroidism · FIHP · FIHPT

Data availability: 1 ClinVar variant · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › familial isolated hyperparathyroidism

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Subtypes (3): hyperparathyroidism 1, hyperparathyroidism 3, hyperparathyroidism 4

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 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
585285	NM_001370259.2(MEN1):c.1341T>G (p.Phe447Leu)	MEN1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 12 · 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
CDC73	Definitive	Autosomal dominant	hyperparathyroidism 2 with jaw tumors	8
GCM2	Strong	Autosomal recessive	hypoparathyroidism, familial isolated, 2	5
MEN1	Supportive	Autosomal dominant	familial isolated hyperparathyroidism	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEN1	Orphanet:2965	Prolactinoma
MEN1	Orphanet:314786	Silent pituitary adenoma
MEN1	Orphanet:314790	Null pituitary adenoma
MEN1	Orphanet:652	Multiple endocrine neoplasia type 1
MEN1	Orphanet:97279	Insulinoma
MEN1	Orphanet:99725	Pituitary gigantism
MEN1	Orphanet:99879	Familial isolated hyperparathyroidism
CDC73	Orphanet:143	Parathyroid carcinoma
CDC73	Orphanet:99879	Familial isolated hyperparathyroidism
CDC73	Orphanet:99880	Hyperparathyroidism-jaw tumor syndrome
GCM2	Orphanet:2239	Familial isolated hypoparathyroidism due to agenesis of parathyroid gland
GCM2	Orphanet:99879	Familial isolated hyperparathyroidism

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	gencc,clinvar
CDC73	HGNC:16783	ENSG00000134371	Q6P1J9	Parafibromin	gencc
GCM2	HGNC:4198	ENSG00000124827	O75603	Chorion-specific transcription factor GCMb	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
CDC73	Parafibromin	Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways.
GCM2	Chorion-specific transcription factor GCMb	Transcription factor that binds specific sequences on gene promoters and activate their transcription.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MEN1	Other/Unknown	no		Menin
CDC73	Other/Unknown	no		Cdc73/Parafibromin, CDC73_C, Cdc73_N
GCM2	Other/Unknown	no		Tscrpt_reg_GCM, GCM_dom_sf, GCM

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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lower esophagus mucosa	1
right hemisphere of cerebellum	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
ileal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
CDC73	271	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
GCM2	9	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MEN1	5,226
CDC73	4,592
GCM2	892

Intra-cohort edges

A	B	Sources
CDC73	GCM2	string_interaction
CDC73	MEN1	string_interaction
GCM2	MEN1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MEN1	O00255	69
CDC73	Q6P1J9	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GCM2	O75603	58.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. 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
Formation of the beta-catenin:TCF transactivating complex	2	120.2×	9e-04	MEN1, CDC73
TCF dependent signaling in response to WNT	2	117.7×	9e-04	MEN1, CDC73
Signaling by WNT	2	112.0×	9e-04	MEN1, CDC73
Protein ubiquitination	1	407.9×	0.015	CDC73
RNA Polymerase II Transcription	2	22.5×	0.015	MEN1, CDC73
Post-translational protein modification	2	19.2×	0.015	MEN1, CDC73
Gene expression (Transcription)	2	17.8×	0.015	MEN1, CDC73
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	184.2×	0.018	MEN1
RHO GTPases activate IQGAPs	1	173.0×	0.018	MEN1
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.018	CDC73
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	154.3×	0.018	MEN1
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.018	MEN1
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.018	MEN1
Signaling by TGF-beta Receptor Complex	1	100.2×	0.018	MEN1
Formation of RNA Pol II elongation complex	1	96.8×	0.018	CDC73
RNA Polymerase II Transcription Elongation	1	96.8×	0.018	CDC73
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.018	CDC73
Signaling by Hedgehog	1	92.1×	0.018	CDC73
Metabolism of proteins	2	12.4×	0.018	MEN1, CDC73
Signal Transduction	2	10.2×	0.018	MEN1, CDC73
Hedgehog ‘on’ state	1	79.3×	0.019	CDC73
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.019	MEN1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.020	MEN1
RNA Polymerase II Pre-transcription Events	1	68.8×	0.020	CDC73
Signaling by TGFB family members	1	57.7×	0.023	MEN1
CHD1 and CHD2 subfamily	1	54.4×	0.023	CDC73
Post-translational protein phosphorylation	1	50.1×	0.024	MEN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.027	MEN1
Epigenetic regulation of gene expression	1	35.7×	0.032	MEN1
RHO GTPase Effectors	1	34.0×	0.032	MEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of mRNA 3’-end processing	1	1123.5×	0.010	CDC73
endodermal cell fate commitment	1	936.2×	0.010	CDC73
gliogenesis	1	936.2×	0.010	GCM2
parathyroid gland development	1	802.5×	0.010	GCM2
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	702.2×	0.010	MEN1
T-helper 2 cell differentiation	1	624.1×	0.010	MEN1
negative regulation of cell population proliferation	2	28.1×	0.010	MEN1, CDC73
intracellular phosphate ion homeostasis	1	510.7×	0.010	GCM2
positive regulation of cell cycle G1/S phase transition	1	374.5×	0.012	CDC73
osteoblast development	1	330.4×	0.012	MEN1
negative regulation of myeloid cell differentiation	1	312.1×	0.012	CDC73
obsolete negative regulation of DNA-binding transcription factor activity	1	244.2×	0.014	MEN1
negative regulation of protein phosphorylation	1	193.7×	0.014	MEN1
response to gamma radiation	1	193.7×	0.014	MEN1
mRNA 3’-end processing	1	187.2×	0.014	CDC73
negative regulation of JNK cascade	1	187.2×	0.014	MEN1
positive regulation of transforming growth factor beta receptor signaling pathway	1	175.5×	0.014	MEN1
negative regulation of fibroblast proliferation	1	165.2×	0.014	CDC73
transcription elongation by RNA polymerase II	1	147.8×	0.014	CDC73
stem cell population maintenance	1	140.4×	0.014	CDC73
positive regulation of Wnt signaling pathway	1	127.7×	0.014	CDC73
transcription initiation-coupled chromatin remodeling	1	127.7×	0.014	MEN1
response to UV	1	122.1×	0.014	MEN1
negative regulation of G1/S transition of mitotic cell cycle	1	119.5×	0.014	CDC73
positive regulation of transcription elongation by RNA polymerase II	1	100.3×	0.014	CDC73
negative regulation of osteoblast differentiation	1	98.5×	0.014	MEN1
protein destabilization	1	96.8×	0.014	CDC73
negative regulation of cell cycle	1	96.8×	0.014	MEN1
negative regulation of epithelial cell proliferation	1	96.8×	0.014	CDC73
negative regulation of transcription by RNA polymerase II	2	11.8×	0.014	MEN1, CDC73

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
MEN1	LOPERAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
CDC73	1	2
GCM2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MEN1	93	Binding:86, Functional:7
CDC73	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MEN1
B	Phased (≥1) drug, not yet approved	1	CDC73
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GCM2

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)
GCM2	0	CDC73

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
NCT01369953	Not specified	COMPLETED	Informed Consent for Whole Genome Sequencing: Ideals and Norms Referenced by Early Participants