INTRODUCTION
Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome with a worldwide incidence of 1 in 35000 and 1 in 30000 to 50000 in the United States. We can classify MEN2 into 2A (MEN2A) and 2B. Furthermore, we can divide MEN2A into MEN2A, Hirschsprung sickness, familial medullary thyroid cancer (MTC), and MEN2A with cutaneous lichen amyloidosis[1]. The pathogenesis of MEN2A involves rearranged during transfection (RET) proto-oncogenes on chromosome 10. When the DNA sequence changes, it can also change the protein sequence in one copy of the gene[2]. This is called autosomal dominant inheritance. In MEN2A-type endocrine tumors, RET protooncogenes are highly expressed. In MEN2A and familial MEN2A patients, the risk of developing tumors is greater in the thyroid, parathyroid, and adrenal glands, which significantly reduces life expectancy and survival. The superb prognosis for MTC diagnosed at its earliest stage underscores the importance of early analysis for sporadic and hereditary MTC[2]. Identifying RET mutations in coding regions, particularly exons 10 and 11, in MEN2 patients is critical because it aids in clinical decision-making. In the future, we can use whole-genome sequencing and next-generation sequencing (NGS) to investigate and understand the pathogenesis of MEN2.
PATHOGENESIS OF MEN2A
RET, a protooncogene, is involved in the pathogenesis of MEN2A. RET encodes a tyrosine kinase receptor that plays an important role in signal transduction. Receptor tyrosine kinases are transmembrane proteins with extracellular and intracellular domains. The extracellular domain has a cadherin-like domain and a cysteine-rich domain. The encoded protein interacts with the glial-derived neurotrophic factor (GDNF) family through the GDNF family receptor. This leads to autophosphorylation and kinase activation of RET and intracellular signaling. The mitogen-activated protein kinase signaling cascades are set off by the RET tyrosine kinase intracellular domain. The activation of tyrosine kinase variants plays an important role in the development of MEN2[3]. The extracellular domain was the most common pathogenic variant identified in RET oncogenes. These variants include codons 609, 611, 618, and 620 in exon 10, as well as codons 630 and 634 in exon 11. Researchers have linked these variants to familial MEN2A and familial medullary thyroid carcinoma (MTC). In 98% of families with MEN2A, exons 10 and 11 genetic variants have been detected[4]. Familial MEN2A also contains other codons, including 631, 768, 790, 804, 844, and 891, as well as those in exons 5, 8, 10, 11, and 13–16[5]. Different types of RET genes have also been linked to aggressive MTC, pheochromocytoma, and hyperparathyroidism[6]. Familial MTC exhibits a pathogenic variant at codons 620 and 912[7].
ANALYSIS AND ASSESSMENT OF MEN2
A variety of factors lead to the diagnosis of MEN2. We have to assess the suspected instances of MEN2 for classical clinical features, family history, and genetic testing. We need to screen for MEN2 in younger patients with MTC or pheochromocytoma when more than one family member has this condition. If a suspected patient has one or two features, mutational evaluation of the RET gene is important for determining MEN2's specific prognosis. If mutation evaluation is not possible, the clinical features of MEN2 in close relatives and children should be evaluated to diagnose MEN2[8]. If there may be no familial inheritance or RET mutation, at least two clinical features of MEN2A are required to diagnose MEN2. We should evaluate RET mutations in MEN2 patients and initiate family screening for early diagnosis. We must perform RET mutation analysis on all exons. Exons 10 and 11 are the most commonly analyzed regions for the RET mutation. If there are no mutations in exons 10 and 11, we can screen other exons[9]. If the family does not have germline mutations, we must perform sequencing of the entire RET coding region. RET mutation analysis in first- and second-degree family individuals is needed for MEN2 patients with germline RET mutations. We must also screen patients with sporadic MTC for germline RET mutations, as germline RET gene mutations were detected in 6% of sporadic cases[10].
SCREENING FOR MEN2-RELATED TUMORS AND FAMILY INDIVIDUALS
To mitigate earlier analysis, we must screen patients with multiple endocrine neoplasias and their family members for MEN2-related tumors. Plasma fractionated metanephrines and serum calcium should be monitored. The presence of MTC in patients with MEN2 who had pheochromocytoma, serum calcitonin, and thyroid levels should be assessed, and neck ultrasound sonography should be performed. Patient screening for pheochromocytoma is mandatory in all patients with inherited MTC. If we find pheochromocytoma, we should eliminate the tumor before performing a thyroidectomy. For pheochromocytoma and hyperthyroidism patients, we should monitor plasma-fractionated metanephrines and calcium levels. If patients with familial MTC have plasma levels of fractioned metanephrines multiple times the upper limit of normal, we can use adrenal computed tomography (CT) or magnetic resonance imaging (MRI). If a pheochromocytoma is not present, we may conduct an observational assessment. Patients should have their serum calcium and parathyroid hormone (PTH) levels monitored. Patients with hyperthyroidism present elevated serum PTH concentrations and calcium levels. We should perform a follow-up evaluation every year to assess hyperparathyroidism if the serum calcium levels are within normal ranges. Genetic screening of MEN2 prevents disorder-related morbidity and mortality[11,12]. RET mutation detection is critical for diagnosing MEN2 syndrome. RET mutations can predict the onset, aggression, and risk of developing endocrine neoplasms in MTC. As a result, it facilitates MEN2 surveillance and control. Researchers have used pentagastrin and calcium stimulation exams to diagnose MTC in family members. However, we currently do not use RET mutation screening, which aids in better diagnosing MEN2. Genetic testing has advantages over pentagastrin or calcium tests. The significance of the RET genotype lies in its ability to predict the initial diagnosis of MTC, and those who do not harbor the MEN2 mutation should avoid further biochemical evaluations. It prevents thyroidectomy in genetically normal individuals in the MEN2 family because of false-positive pentagastrin tests. However, biochemical analysis can still be beneficial for families without a mutation in the coding region of the RET gene or for families who refuse genetic testing. All MEN2 patients should undergo screening if their first-degree and second-degree relatives' RET mutation status is unknown. Families with RET mutations are scheduled for prophylactic thyroidectomy based on the mutation in the RET and its location. The availability of thyroid hormone substitutes and the lower morbidity of thyroidectomy present a better acceptance of thyroidectomy in familial MEN2 patients[13]. Zhang et al[14] reported that the assessment of the C634Y mutation in the family members of MEN2A patients revealed the C634Y mutation in three family members. The clinical features of two patients confirmed the presence of pheochromocytomas and bilateral MTC. This study emphasizes the importance of earlier screening in familial members of patients diagnosed with MEN2A.
SCREENING FOR MEN2-RELATED TUMORS IN YOUNGSTERS
For children with RET mutations, early diagnosis of MTC is critical. Therefore, children with RET mutations should undergo prophylactic thyroidectomy before MTC develops or localizes to the thyroid gland. We should perform thyroidectomy in advance for children with high-risk RET mutations (codon 918). We should monitor children with excessive-risk mutations (codons 634 and 883) and high-risk mutations for 3–5 years[9]. The assessment consists of a physical examination, neck ultrasound, and monitoring of serum calcitonin. Elevated serum calcitonin can be indicative of thyroidectomy. Children at high risk and moderate risk should begin screening for pheochromocytoma at 11–16 years of age[9]. We monitor patients for fractionated metanephrines or a combination of metanephrines and normetanephrines. Adrenal CT or MRI should be performed. There may be considerable variability in the RET gene, and germline mutation penetrance in pheochromocytoma varies with mutations in different codons. Screening for pheochromocytomas can help younger people identify the disease earlier than when signs and symptoms are observed. Hyperparathyroidism in MEN2 patients is typically mild and asymptomatic. Reports have indicated that children as young as 2 years old can receive a diagnosis[15,16]. High- and moderate-risk individuals should begin biochemical screening for hyperparathyroidism at 11–16 years of age. Serum calcium and PTH concentrations must be monitored to determine the prognosis of hyperparathyroidism patients. For MTC in children, either pentagastrin or calcium stimulation can be used. If the risk of C-cell hyperplasia is high, we can initiate plans for thyroidectomy[17,18].
PENTAGASTRIN AND CALCIUM STIMULATION TESTS
The tests involve administering pentagastrin (0.5 mcg/kg body weight) intravenously for 3 min and collecting blood samples for checking calcitonin levels at baseline and 30 min[19,20]. A PCT value of ≥ 200 pg/mL suggests thyroidectomy and lymphadenectomy. If the values are less than 100 pg/mL, the risk of MTC is minimal, and we typically recommend a follow-up assessment if reports indicate 100–200 pg/mL calcitonin levels in C-cell hyperplasia or micro-MTC. If the risk is greater, we may initiate a surgical operation or opt for a follow-up every year. For the calcium stimulation tests, calcium gluconate (2.5 mg elemental calcium/kg) is administered, and blood samples are collected at baseline and at fixed intervals. Calcitonin levels above 32.6 pg/mL (women) and 192 pg/mL (men) are indicative of C-cell hyperplasia or MTC[21].
CONCLUSION
Understanding the pathogenesis of MEN2 and associated subtypes has led to a paradigm shift in disease management and improved survival rates. By looking at the RET mutation, age penetrance, and inheritance of familial MEN2A, it is possible to guess whether an individual will develop endocrine cancer. Prophylactic surgery involving thyroidectomy and adrenalectomy can improve survival rates, possibly because of the predictive potential of RET mutations. RET pathogenic mutations can be identified, and the levels of PTH, calcium, thyroid hormones, calcitonin, fractionated metanephrines, or metanephrines and normetanephrines can be monitored, as these findings can aid in the early detection of pheochromocytoma, MTC, and hyperthyroidism. Furthermore, patients and family members with MEN2 should receive MEN2 awareness and counseling. Patients and family members with MEN2 should receive psychological support. The NGS of RET oncogenes or whole-genome sequencing can provide alternative diagnostic approaches in addition to traditional methods, provide multimodal treatment options, and improve disease outcomes.
Provenance and peer review: Invited article; Externally peer reviewed.
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Specialty type: Medicine, research and experimental
Country of origin: India
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P-Reviewer: He L S-Editor: Luo ML L-Editor: Wang TQ P-Editor: Zhang XD
