Multiple Endocrine Neoplasia (MEN) Syndrome in Childhood: Diagnosis and Management — Overview, Diagnosis & Treatment Options | MyMedicPlus

Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant hereditary disorders predisposing to tumors of multiple endocrine glands. Three main types are clinically recognized. MEN1 is caused by germline loss-of-function mutations in the MEN1 tumor suppressor gene (chromosome 11q13) — encoding menin — and is characterized by the triad of parathyroid adenoma (primary hyperparathyroidism, >95% penetrance by age 50), pancreatic/duodenal neuroendocrine tumors (~70% penetrance: gastrinoma, insulinoma, non-functional NETs), and anterior pituitary adenoma (prolactinoma most common, ~40% penetrance). MEN2A is caused by activating germline mutations in the RET proto-oncogene — most commonly at codon 634 — and is defined by medullary thyroid carcinoma (MTC) in virtually all carriers, pheochromocytoma in ~50%, and primary hyperparathyroidism in 20–30%. MEN2B is the most severe subtype, usually caused by the RET M918T mutation, characterized by MTC (presenting in infancy), pheochromocytoma, mucosal neuromas (lips, tongue, eyelids), Marfanoid habitus, and intestinal ganglioneuromatosis. In childhood, MEN2 is particularly important as prophylactic thyroidectomy based on RET codon stratification can prevent — or cure — MTC.

MEN1 is caused by heterozygous germline mutations in the MEN1 gene (over 1,000 distinct pathogenic variants identified) with autosomal dominant inheritance and near-complete penetrance by age 50. Somatic 'second hit' loss of the wild-type allele (Knudson's two-hit model) leads to tumor formation. MEN2 is caused by gain-of-function mutations in the RET receptor tyrosine kinase gene — specific codons of RET are pathogenic. The RET M918T mutation (codon 918, exon 16) causes MEN2B with the earliest and most aggressive MTC onset (frequently in the first year of life). Codon 634 mutations (exon 11) cause classic MEN2A with high penetrance of pheochromocytoma and hyperparathyroidism. Codons 609, 611, 618, 620 (exon 10) cause MEN2A/FMTC with lower penetrance. Sporadic MTC (non-familial) accounts for 75% of MTC but lacks germline RET mutations; however, all newly diagnosed MTC patients require germline RET testing. de novo RET mutations causing MEN2B account for approximately 50% of MEN2B cases — meaning parents without the disease can have an affected child.

MEN1 in childhood: primary hyperparathyroidism (asymptomatic hypercalcaemia on biochemical screening; rarely nephrolithiasis or bone pain in adolescents); insulinoma causes symptomatic fasting hypoglycaemia — sweating, tremor, confusion; gastrinoma causes peptic ulcer disease and diarrhoea (Zollinger-Ellison syndrome); pituitary adenomas cause headache, visual field defects, amenorrhoea (prolactinoma), or acromegaly (GH-secreting). MEN2A in childhood: MTC presents as a thyroid nodule or cervical lymphadenopathy; calcitonin elevation is the diagnostic marker. Pheochromocytoma causes episodic hypertension, headache, palpitations, and sweating — always exclude before thyroid surgery. MEN2B in infancy/early childhood: unique manifestations include mucosal neuromas on the tongue, lips, and eyelids (present from birth), megacolon from intestinal ganglioneuromatosis causing chronic constipation and failure to thrive, and marfanoid body habitus with joint laxity. MTC in MEN2B arises in the first year of life — often as microscopic C-cell hyperplasia — and is very aggressive.

Genetic testing forms the backbone of MEN diagnosis and surveillance. Germline RET sequencing identifies MEN2 mutations in all carriers and determines the specific codon for risk stratification and timing of prophylactic surgery. Germline MEN1 sequencing is offered to all first-degree relatives of MEN1 patients; if a familial mutation is known, targeted mutation testing is appropriate. Biochemical screening in known MEN1 carriers (from age 5 per Endocrine Society guidelines): annual serum calcium, PTH, fasting glucose, prolactin, and IGF-1; annual chromogranin A and pancreatic polypeptide from age 5; fasting gastrin from age 20. Imaging: MRI abdomen every 1–2 years from age 10 for pancreatic NETs; MRI pituitary every 3 years from age 5. For MEN2 carriers: annual calcitonin from RET mutation identification; annual plasma metanephrines (pheochromocytoma screening) from age 11 (earlier for MEN2B, from age 3); neck ultrasound for thyroid surveillance. Calcium and PTH screening from puberty for MEN2A carriers.

MEN1 treatment is guided by the specific manifestation. Primary hyperparathyroidism requires 3.5-gland parathyroidectomy with autotransplantation; subtotal parathyroidectomy risks recurrence given the multiglandular disease typical of MEN1. Insulinoma is managed by surgical enucleation or distal pancreatectomy. Gastrinoma: high-dose PPI therapy for ZES symptom control; surgical resection for non-metastatic gastrinoma. Non-functional pancreatic NETs ≥2 cm require surgical resection; smaller tumors are observed. Pituitary adenomas: prolactinoma responds to cabergoline; GH-secreting adenomas require transsphenoidal surgery. MEN2 treatment centers on prophylactic total thyroidectomy, the timing of which depends on RET codon risk stratification per ATA 2015 MTC guidelines: MEN2B/M918T — highest risk — ideally in the first 6 months of life; codon 634 — high risk — before age 5; codons 609/611/618/620 — moderate risk — before age 5. Post-thyroidectomy: lifelong thyroid hormone replacement and calcitonin monitoring. Pheochromocytoma requires laparoscopic adrenalectomy (cortex-sparing where possible to preserve adrenal function). Cabozantinib and vandetanib are approved for advanced progressive MTC.

Prognosis for MEN syndromes depends on the specific subtype, timeliness of diagnosis, and completeness of tumor treatment and surveillance. In MEN2B, MTC arising in the first year of life without prophylactic thyroidectomy is potentially fatal by adolescence if left untreated; prophylactic thyroidectomy within the first 6 months of life in M918T mutation carriers results in cure in over 95% of cases as C-cell hyperplasia is excised before progression to invasive MTC. MEN2A with codon 634 mutations, if prophylactic thyroidectomy is performed before age 5 with calcitonin monitoring, achieves surgical cure in the majority of patients. Advanced or metastatic MTC (nodal or distant metastases) at time of thyroidectomy reduces cure rates to 50–70% for nodal disease and below 25% for distant metastases. Pheochromocytomas in MEN2, when treated by laparoscopic adrenalectomy before hypertensive crisis, are biochemically cured in >90% of cases. MEN1-related primary hyperparathyroidism recurs in 40–60% at 10 years after parathyroidectomy due to multiglandular disease. MEN1-related pancreatic NETs are the major cause of MEN1 disease-related mortality — nonfunctional NETs ≥2 cm carry significant malignant transformation risk requiring resection. Long-term, MEN1 patients face multiple sequential operative procedures and chronic hormonal management, but modern multidisciplinary surveillance has substantially improved quality-adjusted life expectancy. Genetic counselling and cascade testing of first-degree relatives are essential to identify carriers before disease expression and to enable prophylactic intervention.

Prophylactic thyroidectomy based on RET codon risk stratification is the cornerstone of MTC prevention in MEN2 and is curative if performed before C-cell hyperplasia progresses to invasive MTC. In MEN2B/M918T, surgery before 6 months of age is required to prevent MTC — making neonatal genetic testing imperative when a parent has MEN2B. All first-degree relatives of MEN1 and MEN2 patients must be offered genetic testing from birth (MEN2B) or from early childhood (MEN1, MEN2A). Clinical surveillance (biochemical and imaging) in confirmed carriers enables early detection and curative management of developing tumors before they cause irreversible complications. MEN1 carriers should avoid chronic proton pump inhibitor use without documented indication, as it may mask gastrin-related symptoms of gastrinoma. Pre-conception genetic counselling is essential for carriers of MEN1 or MEN2 mutations planning a family, as each child has a 50% chance of inheriting the mutation.

Any child of a parent with MEN1 or MEN2 should be offered genetic testing in infancy (MEN2B) or early childhood (MEN2A, MEN1) — not deferred until symptoms develop, as MTC in MEN2B can be fatal by adolescence if prophylactic surgery is delayed. Pediatricians should consider MEN2B in any infant with: mucosal neuromas on the lips or tongue, constipation from ganglioneuromatosis, marfanoid habitus, or a thyroid nodule. Any child with hypercalcaemia, nephrolithiasis, or a pancreatic mass should have MEN1 germline testing. Episodic hypertension with headache, palpitations, and sweating in a child or adolescent with a MEN2 family history requires immediate plasma metanephrine measurement to exclude pheochromocytoma — pheochromocytoma must be treated before any operative procedure. A multidisciplinary team including pediatric endocrinology, genetics, oncology, and surgery is essential for MEN syndrome management.