Multiple endocrine neoplasia type 2

Summary

Multiple endocrine neoplasia type 2 (MONDO:0019003) is a disease with 1 cohort gene and 4 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3,225
• Phenotypes (HPO): 48
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.9	Europe	Validated
Point prevalence	1-9 / 100 000	1.25	Germany	Validated

Signs & symptoms

Clinical features (HPO)

48 HPO clinical features (Orphanet curated; top 48 by frequency):

HPO ID	Term	Frequency
HP:0002865	Medullary thyroid carcinoma	Very frequent (80-99%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002640	Hypertension associated with pheochromocytoma	Frequent (30-79%)
HP:0002666	Pheochromocytoma	Frequent (30-79%)
HP:0003345	Elevated urinary norepinephrine	Frequent (30-79%)
HP:0003528	Elevated calcitonin	Frequent (30-79%)
HP:0003639	Elevated urinary epinephrine	Frequent (30-79%)
HP:0008208	Parathyroid hyperplasia	Frequent (30-79%)
HP:0011781	Thyroid C cell hyperplasia	Frequent (30-79%)
HP:0011976	Elevated urinary catecholamines	Frequent (30-79%)
HP:0011978	Elevated urinary vanillylmandelic acid	Frequent (30-79%)
HP:0025388	Thyroid nodule	Frequent (30-79%)
HP:0032241	Cervical neoplasm	Frequent (30-79%)
HP:0100735	Hypertensive crisis	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002864	Paraganglioma of head and neck	Occasional (5-29%)
HP:0002896	Neoplasm of the liver	Occasional (5-29%)
HP:0002897	Parathyroid adenoma	Occasional (5-29%)
HP:0003072	Hypercalcemia	Occasional (5-29%)
HP:0003165	Elevated circulating parathyroid hormone level	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0008200	Primary hyperparathyroidism	Occasional (5-29%)
HP:0010622	Neoplasm of the skeletal system	Occasional (5-29%)
HP:0010726	Prominent corneal nerve fibers	Occasional (5-29%)
HP:0012471	Thick vermilion border	Occasional (5-29%)
HP:0025151	Ganglioneuromatosis	Occasional (5-29%)
HP:0025289	Cervical lymphadenopathy	Occasional (5-29%)
HP:0030430	Neuroma	Occasional (5-29%)
HP:0030809	Abnormal tongue morphology	Occasional (5-29%)
HP:0030833	Neck pain	Occasional (5-29%)
HP:0031023	Multiple mucosal neuromas	Occasional (5-29%)
HP:0032346	Cutaneous lichen amyloidosis	Occasional (5-29%)
HP:0100526	Neoplasm of the lung	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001519	Disproportionate tall stature	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002150	Hypercalciuria	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0003758	Reduced subcutaneous adipose tissue	Very rare (<1-4%)
HP:0007126	Proximal amyotrophy	Very rare (<1-4%)
HP:0001382	Joint hypermobility	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple endocrine neoplasia type 2
Mondo ID	MONDO:0019003
Orphanet	653
ICD-11	1837913809
NCIT	C123329
SNOMED CT	61808009
UMLS	C4048306
MedGen	887211
GARD	0003830
MedDRA	10028191
NORD	1467
Is cancer (heuristic)	no

Also known as: MEN2 · multiple endocrine neoplasia type 2

Data availability: 3,225 ClinVar variants · 9 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › endocrine gland neoplasm › thyroid tumor › thyroid cancer › thyroid gland carcinoma › multiple endocrine neoplasia type 2

Related subtypes (10): thyroid gland spindle cell tumor with thymus-like differentiation, thyroid gland squamous cell carcinoma, thyroid gland undifferentiated (anaplastic) carcinoma, differentiated thyroid carcinoma, familial nonmedullary thyroid carcinoma, thyroid gland adenocarcinoma, intrathyroid thymic carcinoma, thyroid gland cribriform morular carcinoma, thyroid gland mixed medullary and follicular cell-derived carcinoma, thyroid gland mucinous carcinoma

Subtypes (3): familial medullary thyroid carcinoma, multiple endocrine neoplasia type 2B, multiple endocrine neoplasia type 2A

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

600 retrieved; paginated sample, class counts are floors:

323 uncertain significance, 132 likely benign, 64 conflicting classifications of pathogenicity, 43 benign/likely benign, 28 pathogenic, 4 likely pathogenic, 4 pathogenic/likely pathogenic, 1 benign, 1 benign; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069381	NM_020975.6(RET):c.229C>T (p.Arg77Cys)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069637	NM_020975.6(RET):c.318G>A (p.Trp106Ter)	RET	Pathogenic	criteria provided, single submitter
1372611	NM_020975.6(RET):c.1826G>C (p.Cys609Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13908	NM_020975.6(RET):c.1900T>G (p.Cys634Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13909	NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13910	NM_020975.6(RET):c.1901G>C (p.Cys634Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13911	NM_020975.6(RET):c.1901G>T (p.Cys634Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13913	NM_020975.6(RET):c.1833C>G (p.Cys611Trp)	RET	Pathogenic	criteria provided, single submitter
13914	NM_020975.6(RET):c.1853G>C (p.Cys618Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13915	NM_020975.6(RET):c.1858T>C (p.Cys620Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13917	NM_020975.6(RET):c.1900T>C (p.Cys634Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13918	NM_020975.6(RET):c.1902C>G (p.Cys634Trp)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13919	NM_020975.6(RET):c.2753T>C (p.Met918Thr)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13925	NM_020975.6(RET):c.538C>T (p.Arg180Ter)	RET	Pathogenic	criteria provided, single submitter
13928	NM_020975.6(RET):c.1859G>T (p.Cys620Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13929	NM_020975.6(RET):c.1852T>C (p.Cys618Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13931	NM_020975.6(RET):c.2304G>C (p.Glu768Asp)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13933	NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13934	NM_020975.6(RET):c.1860C>G (p.Cys620Trp)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13935	NM_020975.6(RET):c.2370G>C (p.Leu790Phe)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13943	NM_020975.6(RET):c.1859G>C (p.Cys620Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13944	NM_020975.6(RET):c.1825T>C (p.Cys609Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13946	NM_020975.6(RET):c.2410G>T (p.Val804Leu)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13950	NM_020975.6(RET):c.1597G>T (p.Gly533Cys)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13951	NM_020975.6(RET):c.2671T>G (p.Ser891Ala)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
1403312	NM_020975.6(RET):c.1252C>T (p.Arg418Ter)	RET	Pathogenic	criteria provided, single submitter
1405715	NM_020975.6(RET):c.317G>A (p.Trp106Ter)	RET	Pathogenic	criteria provided, single submitter
1406541	NM_020975.6(RET):c.2427C>A (p.Tyr809Ter)	RET	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 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
Formation of the nephric duct	1	634.4×	0.003	RET
NPAS4 regulates expression of target genes	1	496.5×	0.003	RET
Formation of the ureteric bud	1	496.5×	0.003	RET
RET signaling	1	259.6×	0.005	RET
RAF/MAP kinase cascade	1	61.1×	0.016	RET

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic epithelial tube formation	1	8426.0×	0.001	RET
posterior midgut development	1	8426.0×	0.001	RET
positive regulation of metanephric glomerulus development	1	5617.3×	0.001	RET
ureter maturation	1	4213.0×	0.001	RET
Peyer’s patch morphogenesis	1	4213.0×	0.001	RET
GDF15-GFRAL signaling pathway	1	4213.0×	0.001	RET
lymphocyte migration into lymphoid organs	1	1872.4×	0.002	RET
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	1532.0×	0.002	RET
positive regulation of cell size	1	1296.3×	0.002	RET
glial cell-derived neurotrophic factor receptor signaling pathway	1	1203.7×	0.002	RET
membrane protein proteolysis	1	1053.2×	0.002	RET
positive regulation of cell adhesion mediated by integrin	1	1053.2×	0.002	RET
neuron cell-cell adhesion	1	991.3×	0.002	RET
enteric nervous system development	1	991.3×	0.002	RET
response to pain	1	887.0×	0.002	RET
regulation of axonogenesis	1	887.0×	0.002	RET
neuron maturation	1	802.5×	0.002	RET
ureteric bud development	1	455.5×	0.004	RET
neural crest cell migration	1	337.0×	0.005	RET
regulation of cell adhesion	1	306.4×	0.005	RET
cellular response to retinoic acid	1	234.1×	0.007	RET
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.008	RET
MAPK cascade	1	153.2×	0.009	RET
homophilic cell-cell adhesion	1	140.4×	0.009	RET
positive regulation of neuron projection development	1	137.0×	0.009	RET
axon guidance	1	90.6×	0.014	RET
positive regulation of MAPK cascade	1	80.6×	0.015	RET
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.015	RET
positive regulation of cell migration	1	61.7×	0.018	RET
positive regulation of gene expression	1	38.7×	0.028	RET

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT01424878	Not specified	COMPLETED	Study of Molecular Pathways in Medullary Thyroid Carcinoma and Correlation of Molecular Data With Clinical Behavior of the MTC in Individuals Patients