Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management (original) (raw)
Related papers
Update on Multiple Endocrine Neoplasia Type 2: Focus on Medullary Thyroid Carcinoma
Journal of the Endocrine Society, 2018
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations in the RET proto-oncogene on chromosome 10. Specific RET mutations can predispose toward a particular phenotype and clinical course, with strong genotype-phenotype correlations. MEN2 is highly penetrant in medullary thyroid carcinoma (MTC), and it can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Two different clinical variants of MEN2 are known: MEN2A, which includes the familial subtype, and MEN2B. Treatment includes early thyroidectomy. Recommendations on the timing and extent of surgery are based on the RET mutation risk categories (moderate-, high-, or highest-risk) regarding the age of MTC onset. Early identification of patients with hereditary MTC has improved treatment outcomes. Previously, MTC was diagnosed based on clinical tumors; in contrast, with genetic screening, MTC can be diagnosed at preclinical disease states. This approach has resulted in a high cure rate and a much better prognosis for MTC. However, classification into one of the three RET mutation risk groups for predicting aggressiveness and prognosis has had limited impact. Increasing evidence has shown that patients with RET mutations in different risk classifications exhibit a broad spectrum of MTC aggressiveness during follow-up, with no relevant difference in survival. The specific germline activating mutation of the RET proto-oncogene appears to be the first determinant of the age of MTC onset, but, presumably, different regulatory events determine long-term tumor behavior.
Thyroid, 2011
Background: Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. Summary: The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy. Conclusion: A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.
Journal of Internal Medicine, 1995
Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.
Update multiple endocrine neoplasia type 2
Familial Cancer, 2010
Multiple endocrine neoplasia type 2 (MEN2) is a autosomal dominat inherited tumour-syndrome caused by germline activating mutations of the RET proto-oncogene on chromosome 10. It is clinically characterized by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: the classical MEN 2A, MEN 2B, an association of MTC, pheochromocytoma and mucosal neuroma, (FMTC) familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.
Multiple Endocrine Neoplasia Type 2
Archives of Surgery, 2003
Hypothesis: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. Design: Review of endocrine surgery database from 1951 through 2002. Setting: Tertiary referral center. Patients: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). Main Outcome Measures: Stage of MTC at diagno-sis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.
European Journal of Endocrinology, 2008
Introduction: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene (RET), mainly in exons 10-15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. Patients-methods: We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7-19 and 21, following standard procedures. Results: The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. Conclusion: Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome.
Thyroid, 2005
Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype-phenotype correlations to stratify mutations into three risk levels.
Pediatric surgery international, 2003
The diagnosis and treatment of multiple endocrine neoplasias type 2A (MEN 2A) requires interdisciplinary management. The association of RET proto-oncogene mutations and medullary thyroid carcinoma (MTC) in children is well-known, but the optimal timing for elective surgery is controversial. Besides the risk of MTC, associated anomalies like hyperparathyroidism have to be considered. We report the results of molecular genetic investigations, the pentagastrin stimulation test, pre- and postoperative staging, and histologic examinations of four children who had a positive family history for MEN 2A. Histologic specimens of the removed thyroid glands showed MTC in all four cases. The patients had an uneventful postoperative clinical course. In view of the recent literature and our patients' results, we suggest a concept for diagnostic strategy and timing of the elective thyroidectomy.
The Journal of Clinical Endocrinology & Metabolism, 1998
Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent
The Journal of clinical endocrinology and metabolism, 2017
High-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) and presumed increased aggressiveness compared with moderate-risk RET mutations. To determine if high-risk RET mutations are more aggressive Retrospective cohort study utilizing institutional MEN2 registry A tertiary cancer care center Those with MTC and moderate- or high-risk germline RET mutation. None (observational study) Proxies for aggressiveness were: overall survival (OS) and time to distant metastatic disease (DMD) 127 moderate-risk and 135 high-risk patients were included (n=262). Median age of diagnosis for moderate-risk mutations was 42.3 years (range 6.4-86.4; mean 41.6) and 23.0 years (range 3.7-66.8; mean 25.6) for high-risk (P<0.0001). Moderate-risk patients had more T3/T4 tumors at diagnosis (P=0.03), but there was no significant difference for N or M stage and no significant difference in OS (P=0.40). From multivariable analysis for OS, increasing age...