Multiple Endocrine Neoplasia, Type IIA

Alternative Names

  • MEN2A
  • Pheochromocytoma and Amyloid-Producing Medullary Thyroid Carcinoma
  • PTC Syndrome
  • Sipple Syndrome
  • Thyroid Carcinoma, Familial Medullary
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WHO-ICD-10 version:2010

Neoplasms

Malignant neoplasms

OMIM Number

171400

Mode of Inheritance

Autosomal dominant

Gene Map Locus

10q11.21

Description

Medullary thyroid cancers (MTC) are rare tumors of neuroendocrine origin that arise from parafollicular C cells which secrete calcitonin and other peptides and hormones.  Sporadic MTC accounts for 75% of cases, and inherited MTC constitutes the rest.  Inherited MTC occurs in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but non-MEN familial MTC also occurs.

Multiple Endocrine Neoplasia Type II (MEN2) is a rare hereditary cancer disease expressing a variety of aggressive endocrine and non-endocrine tumors.  MEN2 can be classified into three forms: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).  MEN2 has been reported in approximately 500-1000 families worldwide and its prevalence has been estimated at approximately 1:30,000.

MEN2A accounts for more than 70-80% of all MEN2 cases.  MEN2A is characterized by the presence of medullary thyroid carcinoma (MTC), which occurs in all patients with MEN2, unilateral or bilateral pheochromocytoma (PHEO; in more than 50% of cases) and primary hyperparathyroidism (PHPT) resulting from parathyroid cells hyperplasia or adenoma (15-30% of cases).  Affected individuals with FMTC develop only MTC, without other clinical manifestations of MEN2.  MTC is generally the first clinical manifestation of MEN2A and is the principal cause of morbidity and mortality.  In MEN2A families, the biochemical manifestations of MTC appear between 5 and 25 years of age.  Rare variants of MEN2A can be associated with paraneoplastic syndromes such as cutaneous lichen amyloidosis or excessive production of corticotrophin.  The lichenoid skin lesions are usually located over the upper portion of the back and may appear before the onset of MTC.  In addition, some patients with MEN2A develop Hirschsprung's disease (HD).

The diagnosis of MTC is based on history, physical exam, calcitonin and CEA levels, imaging, and fine needle aspiration biopsy.  MEN2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives.  Genetic testing is also implemented for this disease.  This test offers the opportunity for early detection of presymptomatic gene carriers in order to reduce morbidity and mortality though early intervention.

At the present time, surgical treatment offers the only chance for cure.  A prophylactic thyroidectomy is recommended for all patients with an identified RET mutation between the ages of 2-5.  Also lifelong thyroid hormone supplementation is needed.  The prognosis of MTC depends on the stage at which it is diagnosed and the quality of initial surgical treatment.

Like other MEN2 subtypes, MEN2A is inherited in an autosomal dominant manner.  However, some cases result from de novo gene mutations.

The c-RET proto-oncogene is the only gene known to be associated with MEN2.  This gene is located on the pericentromeric region of chromosome 10 at 10q11.2.  It consists of 21 exons and encodes a membrane tyrosine kinase receptor protein named RET.  The RET protein is a subunit of a multimolecular complex that binds growth factors of the glial derived neurotrophic factor (GDNF) family.

Mutations responsible for MEN2 result in an overactive RET protein which can transmit signals without first attaching to growth factors outside the cell.  The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine system and other tissues.  More than 25 mutations in the RET gene are known to cause MEN2.  Most of these mutations are missense type.  The most common mutation responsible for MEN2A is Cys634Arg, strictly associated with the occurrence of PHEO and/or PHPT.  About 98% of individuals with MEN 2A are identifiable through RET testing and 85% of MEN2A patients have the Cys634Arg mutation.

Epidemiology in the Arab World

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Other Reports

Morocco

Peretz et al. (1997) demonstrated that the Cys618Arg mutation in the RET gene cosegregates with familial medullary thyroid carcinoma and Hirschsprung disease in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A single haplotype shared by chromosomes bearing the Cys618Arg mutation in both families strongly suggested a founder effect for this mutation.

Benazzouz et al. (2006) identified the first RET mutation underlying multiple endocrine neoplasia type IIA (NEM2A) in Morocco. The C634Y mutation was present in the heterozygous state in a Moroccan family with MEN2A. Genetic screening showed that six asymptomatic members of this family were not C364Y carriers.

Qatar

Zirie et al. (2001) studied the pattern of multiple endocrine neoplasia type IIA (MEN2A) and described the clinical features and results of genetic testing and treatment in 21 members of the first reported family with MEN2A in Qatar. Ten members in this kindred (6 adults and 4 children) were affected with MEN2A. The proband was a 27-year old Qatari female, who presented with a 3-4 year history of goiter. Her grandfather had had multiple tumors removed from the neck and abdomen. Thyroidectomy was recommended. She was found to have extremely elevated calcitonin (2,800 pg/ml) and CEA level (79 ng/ml). DNA analysis revealed a RET proto-oncogene mutation in codon 634 (TGC-GGC), which was also seen in her mother. All 21 family members of the proband were screened with genetic testing for the RET proto-oncogene mutation. Those subjects with the mutation were further assessed for pheochromocytoma by measurement of the 24-hour urinary vanillylmandelic acid, metanephrines, and catecholamines, and those with high levels underwent a metaiodobenzylguanidine scan and adrenalectomy. The serum calcium was measured as an effort to detect hyperparathyroidism. Those family members who had the mutation and were eligible for surgical treatment underwent total thyroidectomy and central compartment dissection. In those patients with high postoperative calcitonin levels, residual disease was sought with radiologic imaging, and follow-up was done with pentagastrin stimulation tests. Of the 21 family members screened, 10 were found to have the RET proto-oncogene mutation (codon 634, TGC->GGC; 5 females and 5 males; 6 adults and 4 children). Zirie et al. (2001) found that all the adults had bilateral medullary thyroid carcinoma (MTC); four of them had lymph node metastatic lesions, and one had metastatic involvement of the liver. Two adults had pheochromocytomas. Two family members were reported to have parathyroid hyperplasia, although both were normocalcemic. Zirie et al. (2001) concluded that this family with MEN2A showed classic Mendelian autosomal dominant inheritance.

Saudi Arabia

Abu-Amero et al. (2006) sequenced the entire coding region of mitochondrial DNA for 26 MTC patients and 119 normal population controls.  Of the MTC patients, 13 were sporadic, nine had MEN 2A, one had MEN 2B, and three had FMTC.  In 20 MTC samples, 41 nonsynonymous mutations were detected; nine were from sporadic MTC and 11 were from familial MTC and MEN2.  Also, 15 synonymous mtDNA sequence variants were found in MTC samples, seven of them were novel.  Twenty seven mutations were transversions; 22 nonsynonymous and six synonymous.  These transversion variants were only detected in FMTC/MEN2 and transition variants were mainly in sporadic MTC.  None of these mutations were present in the normal controls, suggesting that mtDNA mutations may be involved in MTC tumorigensis and progression.

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