Endocrine: Multiple Endocrine Neoplasia (MEN) Syndrome

Multiple Endocrine Neoplasia (MEN) Syndromes

MEN I (Wermer Syndrome)

Mutation: MENIN Gene (Tumor Suppressor Gene on Chromosome 11) Mn
- Autosomal Dominant
Primary Associations: Mn
- Primary Hyperparathyroidism (90-100% – Most Common Manifestation)
  - Usually Affects Multiple Glands (Asynchronous & Asymmetric)
  - Each Gland is Considered a Monoclonal Lesion – Hyperplastic or Adenomatous
- Pancreatic Islet Cell Tumors (60-70%)
  - Most Common Functional Tumor: Gastrinoma
  - Gastrinoma & Nonfunctional Tumors Have Similar Prevalence
- Pituitary Adenoma (15-42%)
  - Most Common: Lactotroph/Prolactinoma
Other Associations:
- Adrenocortical Tumors
- Carcinoid Tumors (Most Common Site in MEN I: Thymus)
- Lipoma
- Leiomyoma
- Meningioma
- Angiofibroma
- Spinal Cord Ependymomas
- Pheochromocytoma or Paraganglioma – Very Rare & Much More Common in MEN II

MEN IIA (MEN II/Sipple Syndrome)

Much More Common Than Type 2B (90% of MEN II Cases)
Mutation: RET (Proto-Oncogene on Chromosome 10)
- Autosomal Dominant
Primary Associations:
- Medullary Thyroid Carcinoma (Almost 100% – Most Common Manifestation)
- Pheochromocytoma (40-50%)
- Parathyroid Hyperplasia (10-25%)
Other Associations:
- Cutaneous Lichen Amyloidosis – Pruritic, Scaly & Pigmented Lesions on Extensor Surfaces or Intrascapular Region
- Hirschsprung Disease
Subtypes:
- Classical MEN 2A – Only the 3 Primary Associations
- MEN 2A with Cutaneous Lichen Amyloidosis
- MEN 2A with Hirschsprung Disease
- Familial Medullary Thyroid Carcinoma – High-Risk for MTC but Not the Other Manifestations

MEN IIB (MEN III)

Mutation: RET (Proto-Oncogene on Chromosome 10)
- Autosomal Dominant
Primary Associations:
- Medullary Thyroid Carcinoma (Almost 100% – Most Common Manifestation)
- Pheochromocytoma (40-50%)
Other Associations:
- Mucosal Neuromas – Involving Lips & Tongue
- Marfan Habitus – Tall Stature, Long Limbs & Hyperlaxity
  - No Aortic Abnormalities Which are Seen in Marfan Syndrome
- Intestinal Autonomic Ganglion Dysfunction – Leads to Megacolon

MEN IV (MEN X)

Mutation: CDNK1B (Tumor Suppressor Gene)
- Autosomal Dominant
Primary Associations:
- Primary Hyperparathyroidism
- Pituitary Adenoma
Other Associations:
- Adrenal Tumors
- Kidney Tumors
- Reproductive Organ Tumors (Testicular Cancer or Cervical Neuroendocrine Tumors)

MEN Syndromes ¹

Most Common Initial Manifestation

Most Common Cause of Death

MEN I: Nonfunctional Pancreatic Tumor Malignancy
MEN IIA/IIB: Medullary Thyroid Carcinoma
- MEN IIA Risk: 9.7%
- MEN IIB Risk: 50%

Screening Tests

Indications:
- All Diagnosed Patients Should be Screened for Other Associated Tumors
- All First/Second Degree Family Members Should be Screened for Other Associated Tumors & Gene Mutations
MEN I:
- Metabolic Panel (Including Calcium)
- Gastrin Level
- Prolactin Level
MEN IIA/IIB:
- Metabolic Panel (Including Calcium) – Not Needed for Type IIB
- Calcitonin Level & Thyroid US
- Plasma Metanephrines

First Manifestation to Surgically Correct if Multiple are Concurrent

Prophylactic Thyroidectomy in MEN IIA/IIB

MEN IIA:
- Low/Moderate-Risk Mutations: Start Clinical Monitoring by 3-5 Years of Age
- High-Risk Mutations: Thyroidectomy Before Age 5 Years
MEN IIB: Thyroidectomy in First Year of Life Mn

MEN I Mutation & Chromosome

MEN Disease Associations

P’s (3>2>1) & M’s (0>1>2-3) to Total 3 for Each
- I: 3 P’s & 0 M’s (Total 3)
- IIA: 2 P’s & 1 M (Total 3)
- IIB: 1 P & 2-3 M’s (Total 3)
When Differentiating the P’s
- I P’s: Close to Midline (Pituitary, Pancreas & Parathyroid)
- II P’s: Have 2 Sides (Parathyroid & Pheochromocytoma/Adrenals)

Prophylactic Thyroidectomy in MEN IIA/IIB