|Ahead of print
A rare RET mutation in an Indian pedigree with familial medullary thyroid carcinoma
Roopa Vijayan, Vasantha Nair, Usha Menon, Harish Kumar
Department of Endocrinology, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
|Date of Submission||17-Jul-2019|
|Date of Decision||27-Aug-2019|
|Date of Acceptance||30-Aug-2019|
|Date of Web Publication||14-Sep-2020|
Department of Endocrinology, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
Familial medullary thyroid carcinoma (FMTC) is a variant of multiple endocrine neoplasia type 2 (MEN2) associated with the RET gene mutation. We report a rare RET mutation of c.2671T>G; p.Ser891Ala in Exon 15 of the RET gene in an Indian pedigree where seven family members out of 14 screened were found to be positive for the same. RET genetic analysis should be considered as an early approach in the diagnosis of medullary thyroid carcinoma (MTC) since it improves the prognosis and permits surveillance of other family members.
Keywords: Familial medullary thyroid carcinoma, genetic counseling, rare RET gene mutation
| » Introduction|| |
Familial Medullary Thyroid Carcinoma (FMTC), a subtype of multiple endocrine neoplasia type 2 (MEN2) accounts for less than 15% of all reported cases.,RET mutation of Ser891Ala accounts for less than 5% cases among FMTC. The present case report describes an Indian FMTC family with rare RET mutation. The aim of our case report is to evaluate the importance and advantages of genetic counseling and analysis in the diagnosis of medullary thyroid carcinoma (MTC).
| » Case Report|| |
A 44-year-old woman was incidentally detected to have a neck swelling 11.5 months prior to her visit to our hospital. She was evaluated externally wherein ultrasound of thyroid showed a hypoechoic nodule with calcifications and therefore fine-needle aspiration cytology was suggestive of MTC. She did not have any history of renal stones, bone fractures, paroxysmal events, hypertension, or similar illness in her family members.
Her preoperative calcitonin (Ctn) was 447 pg/mL (normal: ≤5 pg/mL) and carcinoembryonic antigen (CEA) 91.79 ng/mL (normal: ≤5 ng/mL). Computed tomography (CT) of the chest showed no evidence of metastasis. Pheochromocytoma and primary hyperparathyroidism (PHPT) was ruled out prior to surgery by appropriate testing. She underwent total thyroidectomy with central compartment neck dissection. Histopathology showed multifocal MTC involving both lobes; tumor measuring 3.2 × 1.7 × 1.5 cm with extra-thyroid extension and lymphovascular emboli with no evidence of perineural invasion. Three out of six levels of lymph nodes I–VI showed tumor deposits with extra-nodal spread and the largest node measured about 1 cm. Postoperatively, she was started on thyroxine and calcium supplements. At present, she is on follow-up and her calcitonin levels at 3 months and 6 months were 3 and 2 ng/mL respectively, during the postoperative period.
After obtaining her informed consent, RET genetic screening by DNA PCR (Polymerase Chain Reaction) sequencing was carried out for Exons 8, 10, 11, 13,14,15,16 in a central molecular laboratory offering RET mutational testing. Genetic analysis showed a rare c.2671T>G; p. Ser891Ala mutation in Exon 15 of the RET gene. In view of her positive genetic screening, all her five siblings were screened and her four female siblings were found to carry the same mutation. The at-risk members of next-generation except two, who were not available for testing, were also screened. Out of eight screened, two were positive for the same [Figure 1]. Hence out of the 14 family members screened, six turned out to be carriers of similar mutation. Though all the four sisters did not have any suspicious nodules, they had elevated calcitonin levels and hence all underwent total thyroidectomy after ruling out pheochromocytoma and PHPT. Histopathology studies revealed MTC which was confirmed by immunohistochemistry for calcitonin. Postoperative calcitonin levels at 3 months follow-up for all four sisters was observed to be <2 pg/mL [Table 1].
| » Discussion|| |
MTC arises from the parafollicular C cells of the thyroid and occurs in a sporadic or inherited pattern. About 75% occurs sporadically whereas the rest (25%) is inherited as either a component of MEN2 syndrome or FMTC. Inherited forms are due to mutations in RET proto-oncogene, which is mapped on chromosome 10q11.2 and contains 21 exons. RET gene encodes a tyrosine kinase transmembrane receptor with three domains, namely, extracellular, transmembrane, and intracellular domains.,
FMTC is recognized as a variant of MEN2A and includes families with only MTC. FMTC is currently defined as the presence of a RET germline mutation in families with MTC, or single individuals with MTC and no family history of MTC, who develop neither pheochromocytoma nor PHPT. It is commonly associated with mutations in codons 609, 611, 618, and 620 in exon 10, codon 768 in exon 13, codon 804 in exon 14, codon 891 in exon 15, and codon 912 in exon 16., Moreover, Ser891Ala mutation accounts for less than 5% patients with RET mutation and is considered as a moderate risk category as per American Thyroid Association (ATA) 2015 MTC guidelines.,
To our knowledge, this affected family is probably the first reported Indian pedigree with c.2671T>G; p. Ser891Ala mutation in Exon 15 of the RET gene. Previous studies have reported similar mutations in 3 of 141 German RET mutation families (2.1%) and 17 of 356 European RET mutation families (4.8%)., Although this mutation was originally considered as FMTC type, recent reports have shown that other MEN2A features can develop in these patients such as pheochromocytoma. Blom et al., in a study conducted among 85 carriers of S891A mutation, reported that MTC had predominant manifestation comprising of 72.9% (62/85), out of which 3.5% (3/85) had pheochromocytoma and an equal number (3/85) had PHPT. The mean age of MTC diagnosis in that group was 42.3 years. In this family, the mean age was 47.1 years ranging from 20–63 years. Five out of seven mutation carriers had MTC with no evidence of pheochromocytoma or PHPT. Similar to this pedigree, FMTC was reported from a four-generation Chinese Han family who had six mutation carriers out of 14 screened and had only MTC features. Their four patients had lymph node metastasis whereas only our index case had extra thyroidal spread.
The penetrance of MTC arising in cases with this mutation is variable but usually MTC develops at a later stage. Presently, the recommended treatment is early total thyroidectomy with central compartment neck dissection though there is no consensus on the age for performing total thyroidectomy in this moderate-risk group. The two younger members of this reported family are on follow-up with serial ultrasound and tumor markers now, as Ctn is not yet raised. Hence screening for RET mutations and calcitonin levels in mutation carriers are good screening tools for detecting MTC. Since p. Ser891Ala mutation is considered as a moderate risk category with a milder form of disease, asymptomatic adult mutation carriers can be followed up with an annual calcitonin testing. However, surgery should be undertaken before long, as age-related penetrance is high nearly 100% by 60 years of age with steady increase from 20 years onwards. Post total thyroidectomy, calcitonin is done at 3 months to see adequacy of procedure and then at appropriate intervals along with imaging as per the latest ATA guidelines for MTC.
| » Conclusion|| |
Our case emphasizes the importance of screening of MTC patients at the onset whatever may be the age of patients with appropriate genetic counseling. Although this mutation carries only moderate risk, early detection, and prompt surgery were possible because of the willingness of the family for testing, which is often avoided in view of expense involved in testing and other anxiety issues. Proper surveillance of mutation carriers enables early detection and prevention of complications.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Dr. Rekha Pai and team, Molecular Pathology Lab, Department Of Pathology, Christian Medical College, Vellore: 632004, Tamil Nadu.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al
. Revised American thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25:567-610.
Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: An update. J Clin Endocrinol Metab 2013;98:3149-64.
Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al
. Medullary thyroid cancer: Management guidelines of the American thyroid association. Thyroid 2009;19:565-612.
Qi X-P, Zhao J-Q, Chen Z-G, Cao J-L, Du J, Liu N-F, et al
. RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR
variant p.G513D. Oncotarget 2015;6:33993-4003.
Schulte KM, Machens A, Fugazzola L, McGregor A, Diaz-Cano S, Izatt L, et al
. The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A. J Clin Endocrinol Metab 2010;95:E92-7.
Machens A, Dralle H. Familial prevalence and age of RET germline mutations: Implications for screening. Clin Endocrinol 2008;69:81-7.
Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: Clinical opportunities. J Intern Med 2009;266:114-25.
Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, et al
. Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: Report of a case. Surg Today 2014;44:2195-200.
Blom CB, Ceolin L, Romitti M, Siqueira D, Maia AL. The rare intracellular RET mutation p. Ser891Ala in an apparently sporadic medullary thyroid carcinoma: A case report and review of the literature. Arq Bras Endocrinol Metabol 2012;56:586-91.
Qi XP, Zhang RX, Cao JL, Chen ZG, Jin HY, Yang RR. The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma. J Biosci 2014;39:505-12.
Qi XP, Zhao JQ, Du ZF, Yang RR, Ma JM, Fei J, et al
. Prophylactic thyroidectomy for MEN 2- related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China. Eur J Surg Oncol 2013;39:1007-12.