Multiple endocrine neoplasia type 2: A review

Mathiesen, Jes Sloth; Effraimidis, Grigoris; Rossing, Maria; Rasmussen, Åse Krogh; Hoejberg, Lise; Bastholt, Lars; Godballe, Christian; Oturai, Peter; Feldt‐Rasmussen, Ulla

doi:10.1016/j.semcancer.2021.03.035

Cited by 51 publications

(47 citation statements)

References 245 publications

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“…The frequent findings of the variant in these studies indicate that Leu56Met is a common variant in the general population. Indeed, it has been reported in gnomAD with an allele frequency of 0.48% in the non-Finnish European population, including one individual homozygous for the variant 1 . In comparison, two of the known pathogenic variants causative of MEN 2, p.Cys634Tyr and p.Met918Thr ( 6) are both reported in gnomAD with allele frequencies below 0.001%.…”

Section: Discussionmentioning

confidence: 97%

“…The RET protein, which is encoded by the RET gene on chromosome 10, is composed of three functional domains. These include an intracellular tyrosine kinase domain, a transmembrane domain and an extracellular ligand binding domain, containing cadherin-like domains and a cysteine-rich domain important for receptor dimerization ( 1 ). Germline loss-of-function variants in RET cause Hirschsprung’s disease (HSCR), a congenital intestinal malformation ( 2 ), while activating variants cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

“…Germline loss-of-function variants in RET cause Hirschsprung’s disease (HSCR), a congenital intestinal malformation ( 2 ), while activating variants cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome ( 3 , 4 ). The MEN 2A subtype is characterized by medullary thyroid cancer (MTC) with pheochromocytoma, primary hyperparathyroidism (PHPT) and in some cases, cutaneous lichen amyloidosis and HSCR, while MEN2B is characterized by MTC, pheochromocytoma, gastrointestinal and/or mucosal neuromas and a marfanoid habitus ( 1 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

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Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2

et al. 2021

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Activating variants in the receptor tyrosine kinase REarranged during Transfection (RET) cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome. The variant c.166C>A, p.Leu56Met in RET was recently reported in two patients with medullary thyroid cancer (MTC). The presence of a pheochromocytoma in one of the patients, suggested a possible pathogenic role of the variant in MEN 2A. Here, we present clinical follow up of a Danish RET Leu56Met cohort. Patients were evaluated for signs of MEN 2 according to a set of predefined criteria. None of the seven patients in our cohort exhibited evidence of MEN 2. Furthermore, we found the Leu56Met variant in our in-house diagnostic cohort with an allele frequency of 0.59%, suggesting that it is a common variant in the population. Additionally, none of the patients who harbored the allele were listed in the Danish MTC and MEN 2 registries. In conclusion, our findings do not support a pathogenic role of the Leu56Met variant in MEN 2.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2

et al. 2021

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“…According to genetic and clinical characteristics of each hereditary disease, several approaches may be proposed: prophylactic surgery of involved organ, regular biochemical and/or morphological screening to promptly identify an arising neoplasia, and chemoprevention to hinder cancer development [ 16 ]. In MEN2, the suggested approach swings between the prophylactic surgery (in case of highest and very high risk RET mutations) and the regular follow-up (in case of moderate risk RET mutations), while chemoprevention has not gained space so far [ 8 , 17 ]. If the surgical approach must be proposed before 1 year of age in patients harboring RET M918T , in case of other RET mutations a personalized approach should be persuaded [ 8 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia

Prete

Matrone

Gambale

et al. 2021

Cancers

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Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

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“…Patients with MEN 2B may also have gastrointestinal (GI) dysmotility and abnormal dilation of the GI tract such as megacolon or megaesophagus. Skeletal deformities such as slipped capital femoral epiphysis (SCFE), scoliosis, pectus, and foot abnormalities may also be associated with MEN 2B [ 4 , 5 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Psychosocial Characteristics and Experiences in Patients with Multiple Endocrine Neoplasia Type 2 (MEN2) and Medullary Thyroid Carcinoma (MTC)

et al. 2022

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Multiple Endocrine Neoplasia type 2 (MEN2) is a genetic cancer syndrome for which there are limited data pertaining to the quality of life and psychosocial experiences of persons affected. Medullary thyroid carcinoma (MTC) is a rare disease of the thyroid gland often associated with MEN2. MTC often progresses slowly and may present with a myriad of physical symptoms including hair loss, sleep disturbance, fatigue, weight changes, heart palpitations, and constipation or diarrhea. Like other cancers or rare, inheritable illnesses, patients with MEN2 and MTC may be at risk for psychosocial stressors. The current, cross-sectional study administered a structured psychosocial interview and The Distress Thermometer/Problem Checklist to 63 patients with MEN2 and MTC and their caregivers. Despite reports of overall good health, 46% of adults and 44% of youth reported that pain interferes with their daily life; 53% of adults and 59% of youth reported that pain interferes with their mood. Pediatric patients frequently reported experiencing attention challenges (50%) and difficulty concentrating (65%). Parents reported that mood shifts and becoming upset easily were the most prevalent concerns for their children. The most frequent need for services included education about MTC, treatment and research participation, and the opportunity to meet others with MTC.

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Multiple endocrine neoplasia type 2: A review

Cited by 51 publications

References 245 publications

Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2

Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2

Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia

Psychosocial Characteristics and Experiences in Patients with Multiple Endocrine Neoplasia Type 2 (MEN2) and Medullary Thyroid Carcinoma (MTC)

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