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Cancer syndrome ยท EndocrineRET (10q11.21)

Multiple endocrine neoplasia type 2B

MEN 2B; multiple mucosal neuroma syndrome; "Wagenmann-Froboese" syndrome (older eponym); MEN 3 (older designation)

Multiple endocrine neoplasia type 2B is a rare and aggressive autosomal dominant cancer-predisposition syndrome caused, in >95% of cases, by a single germline activating mutation of the RET proto-oncogene โ€” M918T on chromosome 10q11.21. The syndrome combines a near-universal lifetime risk of medullary thyroid carcinoma (MTC) developing in early childhood (median age <5 years), a 50% lifetime risk of phaeochromocytoma developing from adolescence, and a distinctive constellation of mucocutaneous and skeletal features that the dermatologist or paediatrician often recognises first โ€” multiple mucosal neuromas of the lips, tongue, conjunctiva and oral mucosa, marfanoid habitus, intestinal ganglioneuromatosis (with chronic constipation and megacolon from birth), and characteristic facial features (thickened lips, "blubbery" lips, prominent corneal nerves). Recognition of the mucosal neuromas in an infant or child mandates urgent germline RET testing โ€” early prophylactic thyroidectomy in the first months of life dramatically improves survival from what was historically a uniformly fatal disease. Selpercatinib and pralsetinib (highly selective RET inhibitors) have transformed the prognosis of advanced disease.

CurrentLast reviewed 26 April 2026

Genetics

  • Autosomal dominant; ~50% sporadic / de novo, ~50% inherited.
  • Caused in >95% of cases by a single germline activating mutation: RET M918T on chromosome 10q11.21.
  • The same RET gene also causes:
    • MEN 2A โ€” multiple distinct RET mutations; MTC + phaeochromocytoma + primary hyperparathyroidism; cutaneous lichen amyloidosis as a marker.
    • Familial medullary thyroid carcinoma (FMTC) โ€” MTC only.
    • Hirschsprung disease โ€” RET inactivating mutations.
  • Confirm by germline RET sequencing.

Mucocutaneous & physical features

  • Mucosal neuromas โ€” multiple small soft pink-to-flesh-coloured papules on:
    • Lips (especially upper) โ€” produces a "blubbery" / thickened lip appearance.
    • Anterior tongue tip โ€” multiple small papules.
    • Buccal mucosa, gingiva, palate.
    • Conjunctiva (and prominent corneal nerves on slit-lamp).
    • Anus, urethra, female genitalia.
    • Develop in infancy / childhood โ€” the diagnostic clue that should prompt urgent RET testing.
  • Marfanoid habitus โ€” tall, slim, long limbs and digits, joint hyperextensibility, scoliosis, pectus excavatum / carinatum; resembles Marfan syndrome but without aortic root dilation, lens dislocation or cardiac valve disease.
  • Intestinal ganglioneuromatosis โ€” diffuse infiltration of intestinal wall by neuromatous tissue; chronic constipation and megacolon from infancy; misdiagnosed as functional constipation.
  • "Long face" + prominent corneal nerves + thickened lips โ€” characteristic facial gestalt.

Cancer risk

  • Medullary thyroid carcinoma (MTC) โ€” near-universal lifetime risk; develops in early childhood (median age <5 years); aggressive in MEN 2B with early metastasis to cervical lymph nodes; overall MTC mortality the leading cause of death.
  • Phaeochromocytoma โ€” ~50% lifetime risk; bilateral in many; develops from adolescence; produces hypertension, palpitations, sweating, headache.
  • Primary hyperparathyroidism โ€” typically NOT a feature of MEN 2B (vs MEN 2A where it is part of the triad).
  • Other malignancies โ€” minimal additional cancer burden.

Surveillance & management

  • Multidisciplinary care โ€” paediatric endocrinology, endocrine surgery, gastroenterology, ophthalmology, dermatology, clinical genetics; lifelong; specialist endocrine MDT.
  • Prophylactic total thyroidectomy โ€” performed in the first months of life for MEN 2B and certainly before age 1 (ATA highest-risk category). The single most important intervention; dramatically improves survival from historical uniform mortality.
  • Calcitonin and CEA monitoring from infancy after thyroidectomy โ€” track for residual / recurrent MTC.
  • Phaeochromocytoma surveillance โ€” annual plasma / urinary metanephrines from age 11; abdominal MRI as needed.
  • Cutaneous / oral surveillance โ€” mucosal neuromas are benign and require no removal unless cosmetically intrusive or functionally problematic; reassurance.
  • Surgical management of MTC:
    • Prophylactic thyroidectomy in infancy.
    • Compartment-oriented neck dissection if disease present.
    • Adjuvant external-beam radiotherapy for high-risk disease.
    • Selective RET inhibitors — selpercatinib (Retsevmo) and pralsetinib (Gavreto) — for advanced / metastatic RET-mutant MTC; highly effective with response rates >70%. NHS commissioning is via the endocrine MDT and specialist thyroid-cancer service; confirm the current NICE / NHS England access route at the time of prescribing.
    • Cabozantinib, vandetanib โ€” older multikinase inhibitors with broader toxicity.
  • Phaeochromocytoma management โ€” ฮฑ- then ฮฒ-blockade pre-operatively; laparoscopic adrenalectomy.
  • Genetic counselling, cascade testing of relatives, prenatal / preimplantation genetic diagnosis.

References

  1. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid; 2015.
  2. Wirth LJ et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med; 2020.

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