Hyperparathyroidism 2 with jaw tumors

Summary

Hyperparathyroidism 2 with jaw tumors (MONDO:0007768) is a disease caused by CDC73 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CDC73 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 203
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0002897	Parathyroid adenoma	Obligate (100%)
HP:0003072	Hypercalcemia	Obligate (100%)
HP:0008200	Primary hyperparathyroidism	Obligate (100%)
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0002150	Hypercalciuria	Very frequent (80-99%)
HP:0003165	Elevated circulating parathyroid hormone level	Very frequent (80-99%)
HP:0011766	Abnormality of the parathyroid morphology	Very frequent (80-99%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0000131	Uterine leiomyoma	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001959	Polydipsia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0010614	Fibroma	Frequent (30-79%)
HP:0012232	Shortened QT interval	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0000934	Chondrocalcinosis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0002017	Nausea and vomiting	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002574	Episodic abdominal pain	Occasional (5-29%)
HP:0002653	Bone pain	Occasional (5-29%)
HP:0004398	Peptic ulcer	Occasional (5-29%)
HP:0008696	Renal hamartoma	Occasional (5-29%)
HP:0200025	Mandibular pain	Occasional (5-29%)
HP:0002667	Nephroblastoma	Very rare (<1-4%)
HP:0002890	Thyroid carcinoma	Very rare (<1-4%)
HP:0006725	Pancreatic adenocarcinoma	Very rare (<1-4%)
HP:0010788	Testicular neoplasm	Very rare (<1-4%)
HP:0012032	Lipoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperparathyroidism 2 with jaw tumors
Mondo ID	MONDO:0007768
OMIM	145001
Orphanet	99880
NCIT	C48287
SNOMED CT	702378002
UMLS	C1704981
MedGen	310065
GARD	0010829
Is cancer (heuristic)	no

Also known as: familial primary hyperparathyroidism with multiple ossifying jaw fibromas · hereditary hyperparathyroidism-jaw tumor syndrome · hereditary hyperparathyroidism-jaw tumour syndrome · HPT-JT · HRPT2 · hyperparathyroidism 2 · hyperparathyroidism 2 with jaw tumors · hyperparathyroidism type 2 · hyperparathyroidism-2 · hyperparathyroidism-jaw tumor syndrome · hyperparathyroidism-jaw tumour syndrome · hyperparathyroidism-jaw tumour syndrome, hereditary · parathyroid adenoma with cystic changes

Data availability: 203 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › hyperparathyroidism 2 with jaw tumors

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, 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, familial isolated hyperparathyroidism, 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

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

203 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 30 conflicting classifications of pathogenicity, 19 benign/likely benign, 15 pathogenic, 13 likely benign, 6 benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
560081	Single allele	B3GALT2	Pathogenic	criteria provided, single submitter
1074700	NM_024529.5(CDC73):c.415C>T (p.Arg139Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
1076788	NM_024529.5(CDC73):c.687_688del (p.Arg229fs)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
1194275	NM_024529.5(CDC73):c.802C>T (p.Arg268Ter)	CDC73	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449272	NM_024529.5(CDC73):c.1195C>T (p.Arg399Ter)	CDC73	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21687	NM_024529.5(CDC73):c.766_767del (p.Val256fs)	CDC73	Pathogenic	no assertion criteria provided
241496	NM_024529.5(CDC73):c.687_688dup (p.Val230fs)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
2691855	NM_024529.5(CDC73):c.131+1del	CDC73	Pathogenic	criteria provided, single submitter
279741	NM_024529.5(CDC73):c.226C>T (p.Arg76Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
3267	NM_024529.5(CDC73):c.3G>A (p.Met1Ile)	CDC73	Pathogenic	criteria provided, single submitter
3268	NM_024529.5(CDC73):c.25C>T (p.Arg9Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
3269	CDC73, 41-BP DUP/INS	CDC73	Pathogenic	no assertion criteria provided
3270	NM_024529.5(CDC73):c.679_680insAG (p.Arg227fs)	CDC73	Pathogenic	no assertion criteria provided
3276	NM_024529.5(CDC73):c.131+1G>A	CDC73	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3279	NM_024529.5(CDC73):c.238-1G>A	CDC73	Pathogenic	no assertion criteria provided
4056154	NM_024529.5(CDC73):c.100A>T (p.Lys34Ter)	CDC73	Pathogenic	criteria provided, single submitter
658835	NM_024529.5(CDC73):c.664C>T (p.Arg222Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
846304	NM_024529.5(CDC73):c.271C>T (p.Arg91Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
1704640	NM_024529.5(CDC73):c.584del (p.Ser195fs)	CDC73	Likely pathogenic	criteria provided, single submitter
2771148	NM_024529.5(CDC73):c.513-1G>A	CDC73	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382714	NM_024529.5(CDC73):c.127dup (p.Trp43fs)	CDC73	Likely pathogenic	criteria provided, single submitter
3574849	NM_024529.5(CDC73):c.512+1del	CDC73	Likely pathogenic	criteria provided, single submitter
3574863	NM_024529.5(CDC73):c.549del (p.Ala184fs)	CDC73	Likely pathogenic	criteria provided, single submitter
1054916	NM_024529.5(CDC73):c.116A>G (p.Asn39Ser)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133841	NM_024529.5(CDC73):c.1149C>A (p.Asp383Glu)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2070736	NM_024529.5(CDC73):c.973-18A>G	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21680	NM_024529.5(CDC73):c.-11G>A	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241494	NM_024529.5(CDC73):c.1333G>A (p.Val445Ile)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286328	NM_024529.5(CDC73):c.-4dup	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294410	NM_024529.5(CDC73):c.156A>G (p.Arg52=)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDC73	Orphanet:143	Parathyroid carcinoma
CDC73	Orphanet:99879	Familial isolated hyperparathyroidism
CDC73	Orphanet:99880	Hyperparathyroidism-jaw tumor 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
CDC73	HGNC:16783	ENSG00000134371	Q6P1J9	Parafibromin	gencc,clinvar
B3GALT2	HGNC:917	ENSG00000162630	O43825	Beta-1,3-galactosyltransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDC73	Parafibromin	Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways.
B3GALT2	Beta-1,3-galactosyltransferase 2	Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-N-acetylglucosamine (beta-GlcNAc) residue.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDC73	Other/Unknown	no		Cdc73/Parafibromin, CDC73_C, Cdc73_N
B3GALT2	Enzyme (other)	yes	2.4.1.62	Glyco_trans_31, B3GT2_N

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
cortical plate	1
endothelial cell	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDC73	271	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
B3GALT2	200	broad	yes	cortical plate, heart right ventricle, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDC73	4,592
B3GALT2	632

Intra-cohort edges

A	B	Sources
B3GALT2	CDC73	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDC73	Q6P1J9	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALT2	O43825	78.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Blood group systems biosynthesis	1	571.0×	0.021	B3GALT2
Protein ubiquitination	1	407.9×	0.021	CDC73
Lewis blood group biosynthesis	1	335.9×	0.021	B3GALT2
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.026	CDC73
Formation of RNA Pol II elongation complex	1	96.8×	0.026	CDC73
RNA Polymerase II Transcription Elongation	1	96.8×	0.026	CDC73
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.026	CDC73
Signaling by Hedgehog	1	92.1×	0.026	CDC73
Hedgehog ‘on’ state	1	79.3×	0.026	CDC73
RNA Polymerase II Pre-transcription Events	1	68.8×	0.026	CDC73
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.026	CDC73
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.026	B3GALT2
TCF dependent signaling in response to WNT	1	58.9×	0.026	CDC73
Signaling by WNT	1	56.0×	0.026	CDC73
CHD1 and CHD2 subfamily	1	54.4×	0.026	CDC73
RNA Polymerase II Transcription	1	11.3×	0.114	CDC73
Post-translational protein modification	1	9.6×	0.125	CDC73
Gene expression (Transcription)	1	8.9×	0.127	CDC73
Metabolism of proteins	1	6.2×	0.171	CDC73
Metabolism	1	5.8×	0.173	B3GALT2
Signal Transduction	1	5.1×	0.187	CDC73

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
glucosylceramide metabolic process	1	2808.7×	0.006	B3GALT2
positive regulation of mRNA 3’-end processing	1	1685.2×	0.006	CDC73
endodermal cell fate commitment	1	1404.3×	0.006	CDC73
positive regulation of cell cycle G1/S phase transition	1	561.7×	0.010	CDC73
negative regulation of myeloid cell differentiation	1	468.1×	0.010	CDC73
oligosaccharide biosynthetic process	1	324.1×	0.010	B3GALT2
mRNA 3’-end processing	1	280.9×	0.010	CDC73
negative regulation of fibroblast proliferation	1	247.8×	0.010	CDC73
transcription elongation by RNA polymerase II	1	221.7×	0.010	CDC73
stem cell population maintenance	1	210.7×	0.010	CDC73
positive regulation of Wnt signaling pathway	1	191.5×	0.010	CDC73
negative regulation of G1/S transition of mitotic cell cycle	1	179.3×	0.010	CDC73
glycoprotein biosynthetic process	1	168.5×	0.010	B3GALT2
positive regulation of transcription elongation by RNA polymerase II	1	150.5×	0.010	CDC73
protein destabilization	1	145.3×	0.010	CDC73
negative regulation of epithelial cell proliferation	1	145.3×	0.010	CDC73
protein O-linked glycosylation	1	112.3×	0.012	B3GALT2
regulation of cell growth	1	110.9×	0.012	CDC73
Wnt signaling pathway	1	49.9×	0.024	CDC73
cellular response to lipopolysaccharide	1	49.0×	0.024	CDC73
negative regulation of cell population proliferation	1	21.1×	0.054	CDC73
negative regulation of apoptotic process	1	17.4×	0.062	CDC73
negative regulation of transcription by RNA polymerase II	1	8.9×	0.114	CDC73
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	CDC73

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDC73	1	2
B3GALT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	CDC73

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDC73	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALT2	2.4.1.62	ganglioside galactosyltransferase

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

1 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)
MOLIBRESIB	2	CDC73

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	1	CDC73
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	B3GALT2
E	Difficult family or no structure, no drug	0

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)
B3GALT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.