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Multiple-endocrine-neoplasia.svg

Image: “Multiple endocrine neoplasia” by Mikael Häggström. License: CC0 BY 1.0


MEN-1 Syndrome (Wermer Syndrome)

MEN-1 syndrome belongs to the multiple endocrine syndromes and is inherited in an autosomal dominant manner.

Etiology of MEN-1 syndrome

The cause of MEN-1 syndrome is a mutation of the menin gene. This gene is located on the long arm of chromosome 11 (11q13).

The menin gene is a tumor suppressor gene. Proteins that regulate the cell cycle as well as apoptosis, belong to this group. The risk of neoplasias is increased due to the mutation of a tumor suppressor gene.

Note: MEN-1 syndrome is caused by a mutation of the menin gene.

Diseases of MEN-1 syndrome

The signature disease of MEN-1 syndrome is primary hyperparathyroidism (95% of cases). Here, an increased level of parathormone occurs due to parathyroid hyperfunction.

Note: The signature disease of MEN-1 syndrome is primary hyperparathyroidism.

Tumors of MEN-1 syndrome

Pancreatic-insulinoma

Image: Histopathology of a pancreatic endocrine tumor (insulinoma). By KGH, License: CC BY-SA 3.0

The possible tumors that can evolve from a MEN-1 syndrome are tumors of the pancreas like gastrinoma and insulinoma. These 2 tumors belong to the spectrum of endocrine pancreatic tumors and appear in 50% of the cases. Tumors of the hypophysis are rarer (about 30–50% of the cases) but are still common in MEN-1 syndrome.

MEN-2 Syndrome

MEN-2 syndrome also displays an autosomal dominant inheritance pattern and can further be divided into Sipple syndrome (2a), Gorlin syndrome (2b), and FMTC-only (familial medullary thyroid carcinoma).

Medullary_thyroid_carcinoma

Image: Medullary thyroid carcinoma. By Nephron, License: CC BY-SA 3.0

FMTC-only is a special form of MEN-2 syndrome since only medullary thyroid carcinomas appear. That is why it is also called a non-MEN syndrome because no multiple endocrine tumors are present.

Etiology of MEN-2 syndrome

The etiology of the 3 subgroups of MEN-2 syndrome is identical. All 3 are caused by a mutation of the Ret-proto-oncogene that codes for a transmembranous tyrosine kinase. The locus of the mutation is on the long arm of chromosome 10 (10q11.2).

Clinical presentation of MEN-2a syndrome (Sipple syndrome)

Sipple syndrome, comprising 70% of MEN-2 cases, is notably more common than Gorlin syndrome (about 10% of all cases).

Diseases of MEN-2a syndrome
Phaeochromocytoma (approx. 50% of cases) and primary hyperparathyroidism (20% of cases) occur as a part of Sipple syndrome.

Note: Primary hyperparathyroidism can be part of MEN-1 syndrome and MEN-2a syndrome.

Tumors of MEN-2a syndrome
The most common tumor and signature disease of MEN-2a syndrome is medullary thyroid carcinoma (C cell carcinoma). This occurs in almost 100% of the cases.

Note: The signature disease of Sipple syndrome is medullary thyroid carcinoma.

Clinical presentation of MEN-2b syndrome (Gorlin syndrome)

Gorlin syndrome is the least often occurring subgroup of MEN-2 syndrome, accounting for 10% of the cases. In about 60% of the cases, Gorlin syndrome evolves as part of a new mutation, which means that it is not inherited in an autosomal dominant fashion. These cases are called sporadic cases.

Diseases of MEN-2b syndrome
Similar to Sipple syndrome, a phaeochromocytoma also occurs in 50% of Gorlin syndrome cases.

Note: In contrast, primary hyperparathyroidism does not occur in Gorlin syndrome.

Other clinical characteristics that appear as a part of Gorlin syndrome, are mucosal neurinomas, ganglioneuromatoses in organs like the tongue or intestine, as well as marfanoid habitus. Characteristics of marfanoid habitus are a lean, tall body shape with long extremities and hyperextension of joints.

Tumors of MEN-2b syndrome
Similar to Sipple syndrome, medullary thyroid carcinoma is also the signature disease of Gorlin syndrome (about 100% of the cases).

Clinical presentation of FMTC-only syndrome (non-MEN syndrome)

As mentioned above, an FMTC-only syndrome is a special form as only medullary thyroid carcinomas occur.

Note: Always think of a MEN-2 syndrome as comprising familial medullary thyroid carcinomas. With a molecular genetic diagnosis, ‘unaffected’ family members can also be tested for the mutation so a prophylactic thyroidectomy can be considered.
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