STEPTRACKERENDOCRINE + ONCOLOGY | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

MEN & Hereditary Endocrine Syndromes

Inherited syndromes that build endocrine tumors in sets — know the gene, the trio, and the tumor that shows up first.

FOCUS ON
MEN1 (menin, tumor suppressor): parathyroid, pituitary, pancreas (gastrinoma, insulinoma). MEN2A (RET gain of function): medullary thyroid, pheo, parathyroid. MEN2B (RET): medullary thyroid, pheo, mucosal neuromas, marfanoid habitus. Also VHL, NF1, Carney complex, McCune-Albright, and the autoimmune polyglandular syndromes.
SYNDROME
GENE · INHERITANCE
TUMORS · FEATURES
CLUE
MEN1
MEN1 (menin, chr 11) — tumor suppressor, AD
Parathyroid hyperplasia (most common, earliest), pituitary adenoma (prolactinoma), pancreatic/duodenal NETs (gastrinoma, insulinoma); also foregut carcinoids, adrenal adenomas, facial angiofibromas, lipomas
"3 Ps" · kidney stones + ulcers
MEN2A
RET proto-oncogene gain of function, AD
Medullary thyroid carcinoma (nearly all), pheochromocytoma, parathyroid hyperplasia; cutaneous lichen amyloidosis
Hirschsprung disease association
MEN2B
RET (often M918T), AD
Aggressive early MTC, pheochromocytoma, mucosal neuromas (lips, tongue, eyelids), marfanoid habitus, intestinal ganglioneuromatosis
No hyperparathyroidism
RET carrier management
MTC is nearly certain
Prophylactic thyroidectomy: MEN2B in the first year, MEN2A in childhood (by ~5)
Screen for pheo before any surgery
Von Hippel-Lindau
VHL (chr 3p) tumor suppressor, AD → HIF stabilization
Retinal and cerebellar hemangioblastomas, bilateral clear cell RCC, pheochromocytoma, pancreatic NETs and serous cysts
Polycythemia from EPO
Neurofibromatosis type 1
NF1 (neurofibromin, RAS-GAP, chr 17), AD
Café-au-lait spots, neurofibromas, Lisch nodules, axillary freckling; pheochromocytoma; duodenal carcinoid, GIST
HTN in NF1 → pheo or renal artery stenosis
Carney complex
PRKAR1A, AD
Cardiac myxomas, spotty skin pigmentation, primary pigmented nodular adrenal disease (Cushing), GH adenomas, Sertoli tumors
Atrial myxoma + freckles
McCune-Albright syndrome
Somatic mosaic GNAS activation (Gsα always on)
Polyostotic fibrous dysplasia, café-au-lait spots with jagged "coast of Maine" borders, precocious puberty; hyperthyroidism, acromegaly, Cushing
Not inherited (lethal if germline)
APS type 1
AIRE defect, AR → failed thymic negative selection
Chronic mucocutaneous candidiasis, hypoparathyroidism, Addison disease (in childhood)
Antibodies to IL-17 / IL-22
APS type 2
Polygenic, HLA-DR3/DR4
Addison disease + autoimmune thyroid disease ± type 1 diabetes (adults)
More common than APS-1
Functional islet tumors (recap)
Insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma
Whipple triad · refractory ulcers · necrolytic migratory erythema · watery diarrhea + low K⁺ · gallstones + DM
Full detail: 11.02

Mechanism — two kinds of genes

MEN1, VHL, NF1Tumor suppressors
→
One germline hit
→
Second somatic hitTumor in that cell
RETProto-oncogene
→
One activating mutation
→
Constant signalingC-cell hyperplasia → MTC

Because one RET mutation is enough, MTC develops in nearly every carrier — the basis for prophylactic thyroidectomy.

MEN syndromes side by side

FEATURE
MEN1
MEN2A
MEN2B
Gene
MEN1 (menin)
RET
RET
Parathyroid
✓
✓
—
Pituitary
✓
—
—
Pancreas
✓
—
—
Medullary thyroid
—
✓
✓
Pheochromocytoma
—
✓
✓
Other
Angiofibromas
Lichen amyloidosis
Neuromas, marfanoid

How it's tested

COMMON CONFUSIONMEN2A and MEN2B share MTC and pheo. Hyperparathyroidism = 2A; mucosal neuromas and marfanoid body = 2B.
THE TRAPTwo endocrine tumors in one patient (e.g., a prolactinoma plus hypercalcemia) are a syndrome until proven otherwise — screen relatives and look for the third tumor.
YOUR APPROACHList the tumors → match to the trio → gene → inheritance → screen family → anticipate the next tumor (and pheo before surgery).

If you see… think…

Hypercalcemia + prolactinoma + recurrent jejunal ulcers → MEN1
First manifestation of MEN1 → primary hyperparathyroidism
Medullary thyroid cancer + pheo + hypercalcemia → MEN2A
Bumpy lips and tongue, tall thin body, MTC → MEN2B
Child carrying a RET mutation → prophylactic thyroidectomy
Cerebellar hemangioblastoma + bilateral RCC → von Hippel-Lindau
Café-au-lait spots, neurofibromas, and paroxysmal hypertension → NF1 + pheochromocytoma
Atrial myxoma + spotty lip pigmentation + Cushing → Carney complex
Precocious puberty + irregular café-au-lait + bone fibrous dysplasia → McCune-Albright
Child with thrush, tetany and adrenal insufficiency → APS-1 (AIRE)