The correct answer is 4. It seems to me to be more of an endocrine question than a pediatric question. Proto-oncogene carriers usually have early thyroid tumors so radical thyroidectomy is usually recommended before the age of 5 years. Obviously I had to look this up...it is not very common in our routine practice.

[HIDDEN] It seems to me to be more of an endocrine question than a pediatric question. Proto-oncogene carriers usually have early thyroid tumors so radical thyroidectomy is usually recommended before the age of 5 years. Obviously I had to look this up...it is not very common, in our routine practice.

A 5-year-old girl, completely asymptomatic, who comes to the pediatrician for a regular check-up. She consults because her mother was operated on for a thyroid tumor and a grandmother died 10 years ago from a pheochromocytoma. The priority therapeutic attitude we will adopt will be:

Exhaustive physical examination with blood pressure control to assess whether the child may have a familial disease.

Biochemical analysis with calcitonin. If it is normal, no further control is necessary at this age.

Annual monitoring of calcitonin levels with pentagastrin stimulation and, if elevated, indication of prophylactic thyroidectomy.

Genetic study of the RET c634 proto-oncogene mutation, and if positive, prophylactic radical thyroidectomy will be performed at this age.

Genetic study of the RET c634 proto-oncogene mutation, calcitonin levels and FNA (fine needle aspiration) and if positive, radical thyroidectomy will be performed.

Late-onset medullary carcinoma of the thyroid: need for genetic testing and prophylactic thyroidectomy in adult family members.

Sporadic late-onset medullary carcinoma of the thyroid is quite rare. Usually, the patient presents with a thyroid mass or neck node metastasis along with high levels of calcitonin and preoperative fine needle aspiration biopsy suggestive of medullary carcinoma of the thyroid. The role of genetic testing in such individuals, along with testing of other family members, remains somewhat unclear at this stage, especially in patients presenting with familial medullary thyroid carcinoma. Genetic testing with RET proto-oncogene mutational studies is very popular in familial medullary thyroid carcinoma, especially in children, with routine prophylactic thyroidectomy. However, its indications in adults remain unclear at this time. Recently, a 69-year-old woman presented with a thyroid mass and underwent total thyroidectomy and central compartment dissection. She was found to have medullary carcinoma of the thyroid. The patient had four children, three of whom were found to have a RET mutation similar to their mother's, V804M. In view of the RET mutation, the three children were offered prophylactic thyroidectomy at ages 42, 45, and 47. The patient's son was noted to have extensive C-cell hyperplasia in both lobes of the thyroid. The other two individuals had benign pathology with no evidence of C-cell hyperplasia. There is no definite consensus of opinion about the need for prophylactic total thyroidectomy in adults with RET mutation. The rarely reported 804 mutation is, however, a predictor of medullary carcinoma of the thyroid. One individual in this group had extensive C-cell hyperplasia, suggesting that he would have developed medullary carcinoma of the thyroid in the future. Prophylactic thyroidectomy should be recommended in patients with RET mutation and a family history of medullary carcinoma of the thyroid; however, its role in adult family members needs to be evaluated with larger registry of prophylactic thyroidectomy. Whether these adults with rare 804-mutation could be observed and followed with serial calcitonin, ultrasound, or calcitonin stimulation tests remains to be studied.

[Prophylactic thyroidectomy in children and young people with hereditary medullary thyroid carcinoma: a Chilean experience].

With the availability of the RET proto-oncogene genetic testing, it is possible to perform prophylactic total thyroidectomy among carriers of RET mutation. To evaluate the histological findings and the effects of the prophylactic total thyroidectomy in first-degree relatives of Chilean patients with multiple endocrine neoplasia type 2 (MEN 2) based on the Ret proto-oncogene analysis. Nineteen patients belonging to 11 MEN 2 families underwent total thyroidectomy. Of these, 16 either with C cell hyperplasia (CCH) or microscopic medullary thyroid carcinoma (MTC) were selected for the final analysis. The age at the moment of thyroidectomy ranged from 3 to 24 years (median 9.5). The most common mutation was located in codon 634 (69%) followed by codon 620 (25%). Histopathology revealed MTC in 13 patients (81%, youngest 3 years, oldest ones 19 and 24 years) and CCH in 3. A significant correlation was observed between basal preoperative serum calcitonin/tumor size (r = 0.53, P < 0.05) and age/tumor size (r = 0.56, P < 0.03), but not between basal preoperative serum calcitonin and age. Stimulated preoperative calcitonin levels were confounding and not useful for differentiating CCH from MTC. None of patients in whom cervical dissection was done (9/16) presented lymph node metastases, including the oldest ones. All patients but the older ones were biochemically cured after a mean of 5 years of follow-up. Prophylactic total thyroidectomy should be done early in life because there is an age-dependent progression from HCC to MTC. MTC often precedes biochemical detection of the disease.

Prophylactic thyroidectomy in MEN IIA: does the calcitonin level correlate with tumor spread?

The fate of patients with multiple endocrine neoplasia of type II A (MEN II A) is determined by medullary thyroid carcinoma, which occurs in all cases. This has led to the therapeutic concept of prophylactic thyroidectomy in affected family members with the goal of removing the thyroid before the manifestation of carcinoma. We investigated a prophylactically thyroidectomized MEN II A population to determine whether the highly specific and sensitive tumor marker calcitonin correlates with tumor spread. Fifteen patients with MEN II A (aged 4-24 years) who had undergone prophylactic thyroidectomy since 1990 were included in the study. Baseline and pentagastrin-stimulated calcitonin levels were preoperatively determined in all cases. The indication for surgery was established on the basis of pathologic calcitonin levels in the first seven patients and on the basis of detected RET proto-oncogene mutation in the other eight patients. Bilateral central lymphadenectomy was performed in all patients in addition to thyroidectomy. Histology demonstrated C-cell hyperplasia in five patients (aged 4-13 years), unilateral medullary microcarcinoma in six (aged 9-17 years) and a bilateral medullary microcarcinoma in three cases (aged 17-24 years). One 9-year-old boy with bilateral microcarcinoma already had a lymph node metastasis. The mean baseline calcitonin level correlated with the histologic findings (r=0.71, P=0.003) but there was no correlation between pentagastrin-stimulated calcitonin levels and histology (r=0.21, P=0.47). In MEN II A patients undergoing prophylactic thyroidectomy, baseline but not stimulated calcitonin levels already correlate with the histologic tumor stage at the stage of clinically occult C-cell hyperplasia or medullary microcarcinoma. However, biochemical screening cannot reliably discriminate the transition from C-cell hyperplasia to invasive microcarcinoma. Individuals with MEN IIA should therefore undergo early prophylactic thyroidectomy once the diagnosis is confirmed by molecular genetic testing.

When is prophylactic thyroidectomy indicated for patients with the RET codon 609 mutation?

Mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN2A), and prophylactic thyroidectomy has generally been recommended before the age of 5 years. Patients with codon 609 mutations develop MTC at a later age and therefore the timing of prophylactic thyroidectomy is less clear. We report a three-generation family with C609Y RET mutation where members having prophylactic or therapeutic thyroidectomy call the current recommendations for age at thyroidectomy into question. Sixteen family members underwent thyroidectomy, for which clinical, laboratory, and pathological data were analyzed. A literature review of RET codon 609 mutations was carried out. Data were collected from 16 patients from this 38-member kindred. None of these affected members had pheochromocytoma, and one had a parathyroid adenoma. Nine of 16 patients had MTC (mean age 44.7 years, range 29-59 years) and elevated basal calcitonin levels; 6 of these 9 had lymph node metastases. Two patients had C-cell hyperplasia (CCH) at ages 18 and 37 years, and five patients had normal thyroid pathology (mean age 16 years, range 5-37 years). In the literature, a family with C609Y mutation was reported, with 15 members having MTC (mean age 42 years, range 21-59 years), and 6 with CCH (mean age 24 years, range 15-37 years). The youngest patient with C609Y RET mutation and MTC was 21 years old, and the youngest patient with CCH was 15 years old at diagnosis. These data suggest that patients with RET C609Y mutations can delay thyroidectomy until 10-15 years of age, with annual calcitonin screening prior to thyroidectomy.

Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of international guidelines for MEN type 2 in a single centre.

Genetic diagnosis available since 1993 established germinal mutations of the RET proto-oncogene at codon 634 as the main cause of inherited medullary thyroid carcinoma (MTC). International guidelines established in 1999 recommend that children with such mutations undergo a total thyroidectomy before age 5, with unspecified cervical neck dissection. Since 1993, only 41 of 275 thyroidectomies reported in RET 634 children were performed before age 5 (15%). The aim of this study was to evaluate the implementation of these guidelines in a single centre. Genetic diagnosis was proposed to the parents of all eight children born after 1992 from two RET 634 families. Total thyroidectomy was proposed before age 5 if the child carried a mutation. Genetic diagnosis was performed in all the children (aged 1-3) and thyroidectomy in the five who carried a mutation (aged 2-5). Cervical lymph node dissection varied from lymphadenectomy of central and lateral compartments in the eldest child to pickings in the youngest. There was no permanent hypoparathyroidism or recurrent nerve paralysis. C-cell hyperplasia, medullary thyroid carcinoma and lymph node metastasis were present in 5/5, 3/5 and 0/5, respectively. Undetectable pentagastrin-stimulated CT levels were achieved and maintained postoperatively in all five children (average follow-up 3.6 years). MEN 2 guidelines on thyroidectomy can be efficiently and safely implemented by a multidisciplinary team operating in a single centre. The lack of guidelines on cervical neck dissection remains a problem; this could be solved by determining an age under which this procedure would be deemed unnecessary.

[Clinical diagnosis and treatment of familial medullary thyroid carcinoma caused by a p.C618Y RET proto-oncogene mutation in a Chinese pedigree].

To explore the clinical characteristics, therapeutic and clinical significance for RET proto-oncogene screening in a pedigree with familial medullary thyroid carcinoma. Comprehensive medical history was obtained from 19 members in a 4-generate southern Chinese family. Systemic clinical investigations including biochemical testing, imaging examinations and germline RET screening. RET screening showed heterozygous missense mutations of TGC to TAC at codon 618 on exon 10 in 8 cases (p.C618Y) completely consistent with the clinical manifestations. The clinical data of 7 patients with medullary thyroid carcinoma (MTC) and 2 carriers of asymptomatic RET mutation from were analyzed. Single/bilateral multi-centric MTC with lymph node metastases was confirmed in 6 cases by histopathology and 1 case by clinical examination. There were 1 male and 6 females with an initial mean diagnostic age was 49.6 years (range: 24 - 78). All had palpable neck masses. And the mean maximum diameter of MTC was 2.6 cm (range 1.4 - 4.4). Seven patients underwent thyroidectomy except a 78-year-old female patient: right total and left subtotal thyroidectomy (n = 1), right total thyroidectomy (previous left total thyroidectomy for benign mass) (n = 1) and total thyroidectomy (n = 4) were performed. All procedures were accompanied by at least bilateral level VI lymph node dissection and/or with modified single/bilateral neck dissection. After the first operation, 6 patients still presented a high value of calcitonin: 1 patient died of metastasis 64 months postoperatively; 3 patients underwent reoperation at 6 months after initial operation, the calcitonin levels dropped to normal in 2/3 cases and stayed higher in 1 case; another two cases presented bilateral thyroid gland residua, local lymph node enlargement on imaging examination and elevated levels of calcitonin at 214 and 60 months postoperation respectively. However, 1/2 asymptomatic with elevated pre-operative calcitonin subjects underwent total thyroidectomy and histopathological examination showed bilateral C cell hyperplasia. The other carriers, without surgery, with normal neck images, close monitoring and a 10-month follow-up, still presented undetectable calcitonin. Based on family survey, integrated RET screening and serum levels of calcitonin facilitate an early diagnosis and normalize surgery to improve the prognosis. For asymptomatic RET mutation carriers, their levels of calcitonin shall guide the individualized regimen of prophylactic thyroidectomy or strict monitoring and follow-ups.

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN-2A) or type 2B or familial medullary thyroid carcinoma. We sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with MEN-2A who had a mutated allele of the RET proto-oncogene could prevent or cure medullary thyroid carcinoma. A total of 50 patients 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutation characteristic of MEN-2A underwent total thyroidectomy. Five to 10 years after the surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents. In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay (proportion, 0.88; 95 percent confidence interval, 0.76 to 0.95). Two patients had basal and stimulated plasma calcitonin levels above the normal range. Stimulated plasma calcitonin levels had increased but remained within the normal range in four patients. The data suggest that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before eight years of age and in children in whom there were no metastases to cervical lymph nodes. In this study, young patients identified by direct DNA analysis as carriers of a RET mutation characteristic of MEN-2A had no evidence of persistent or recurrent medullary thyroid carcinoma five or more years after total thyroidectomy. A longer period of evaluation will be necessary to confirm that they are cured.

Child with RET proto-oncogene codon 634 mutation.

İnce D, Demirağ B, Ataseven E, Oymak Y, Tuhan H, Karakuş OZ, Hazan F, Abacı A, Özer E, Mutafoglu K, Olgun N. Child with RET proto-oncogene codon 634 mutation. Turk J Pediatr 2017; 59: 590-593. Herein we reported a 7-year-old child with RET proto-oncogene c634 mutation. Her mother had been diagnosed with medullary thyroid carcinoma (MTC), and treated six years ago. Heterozygous mutation of the RET proto-oncogene at c634 had been detected in her mother. Genetic analysis showed the presence of the same mutation in our patient. Thyroid functions were normal. Serum calcitonin level was found mildly elevated. Parathormone (PTH) and carcinoembrionic antigen (CEA) levels were normal. Prophylactic thyroidectomy and sampling of cervical lymph nodes were performed. Histopathologic examination revealed hyperplasia in thyroid C cells, and reactive lymphadenopathy. The risk of MTC has been reported 100% through the life of patients with RET proto-oncogene mutation. It has been reported that particularly patients with c634 mutation have more risk of occurence of metastatic and progressive/recurrent MTC. Prophylactic `thyroidectomy, cervical lymph node dissection` before 5-years-of-age should be considered for these patients.

Long-term outcome of "prophylactic therapy" for familial medullary thyroid cancer.

About one quarter of all medullary thyroid cancers (MTC) are determined genetically due to a mutation in the RET proto-oncogene. The most common site of mutation is in codon 634. Therapeutic approaches toward patients at risk for the development of MTC identified by family screening programs range from total thyroidectomy to total thyroidectomy with lymphadenectomy of all 4 compartments. We report 17 patients (median age, 13 years; range, 4-36) carrying a mutation in codon 634 of the RET proto-oncogene who were operated on prophylactically at our department. All patients underwent thyroidectomy with bilateral cervicocentral lymphadenectomy. Current calcitonin level, overall survival, and disease-free survival were analyzed by contacting general practitioners and patients. Tumor classification was as follows: C-cell hyperplasia, 18% (n = 3); T1 (<1 cm), 71% (n = 12); and T1 (>1 cm), 12% (n = 2). Only 2 patients had lymph node metastases (12%). These patients developed recurrent disease (median observation time, 147 months; range, 90-181). In 1 patient, the calcitonin level normalized after unilateral cervicolateral lymphadenectomy. The other patient (9 years old at primary operation) still has a persistently increased serum calcitonin level after 140 months of follow-up despite several operations for MTC. Total thyroidectomy with bilateral cervicocentral lymphadenectomy is sufficient as routine "prophylactic therapy" for patients with mutations in codon 634 of the RET proto-oncogene. Cervicolateral lymphadenectomy is indicated if calcitonin remains elevated after primary surgery. Prophylactic thyroidectomy should be performed before the development of lymph node metastases.

Surgical strategy in a kindred with a rare RET protooncogene mutation of variable penetrance with regard to multiple endocrine neoplasia.

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.

Early, Prophylactic Thyroidectomy in Hereditary Medullary Thyroid Carcinoma: A 26-year Monoinstitutional Experience.

Prophylactic thyroidectomy has been encouraged for children with REarranged during Transfection (RET) germline mutations to prevent the onset, persistence, or recurrence of medullary thyroid carcinoma (MTC). The American Thyroid Association (ATA) recently published guidelines on the timing of prophylactic thyroidectomy. Our aim here was to seek information on the optimal timing of surgery for carriers of RET gene mutations with no clinical evidence of disease, bearing in mind the ATA recommendations. From 1986 to 2012, total thyroidectomy was performed at our institute on 31 carriers of RET gene mutations, 28 of them found on family screening in the post-RET era, and the other 3 under 20 years of age and classified as "early cases" in the pre-RET era. The following parameters were studied: age at surgery, MTC risk, basal calcitonin (bCT) and pentagastrin-stimulated calcitonin (sCT), surgery outcomes, and persistence of disease. By family, the most prevalent mutation was codon 634 (30%) RET mutation. The youngest MTC patient was 5 years old. Overall, MTC was found in 68% of cases; 52% of the sample had a normal bCT and 25% had an sCT unresponsive to pentagastrin. The only factor predicting the risk of MTC at final histology was an ATA-RET risk level C. On receiver oparating curves analysis, a cutoff at age over 24 years predicted (P=0.06) a yield of MTC in the resected specimen. Interestingly, none of the patients with MTC had nodal involvement (0/21 patients with MTC). Yet, none of the patients had permanent nerve palsy, and only 1 patient had permanent hypocalcemia. bCT was normal postoperatively and during the follow-up in all but 3 patients. It is noteworthy that the yield of cancer in removed thyroid was 100% for codon 634 (9/9 patients, 5 families) and for codons 891 and 768 (2/2 patients in each of the 2 families with those codon mutations), followed by 67% for codon 609 (4/6 patients, 1 family), and 60% for codon 618 (3/5 patients in 4 families) RET mutation. In cases of ATA-RET levels B and C, waiting for an increase in bCT and/or sCT may not guarantee that prophylactic surgery is performed before MTC develops (which would assure patients a life free of diseases and a less-invasive surgical procedure, without any need for central lymph-node dissection).

The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center.

Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-producing C-cell tumor. In hereditary cases, a germline RET mutation is found in 98% of families. Because MTC is cured only if intrathyroidal, prophylactic thyroidectomy is recommended in the gene carrier (GC). The aim was to determine whether thyroidectomy performed when stimulated CT becomes detectable is as safe as prophylactic thyroidectomy and to identify the serum CT cutoff able to distinguish intrathyroidal from extrathyroidal MTC. Eighty-four GC were prospectively enrolled; 53 of the 84 underwent total thyroidectomy, one refused surgery, and 30 with normal basal and stimulated CT were under surveillance. The follow-up ranged from 2 to 18 yr. GC operated on for elevated stimulated CT included 27 GC with a positive peak CT at the screening and four cases who became positive after 4 yr. All of them had intrathyroidal MTC and no node metastases; all were cured after a mean follow-up of 7.5 yr. Among those operated on for detectable basal CT, intrathyroidal tumors were found when CT was below 60 pg/ml, whereas either node metastases or larger tumors were observed when CT was above 60 pg/ml. No correlation among serum CT, age, and type of RET mutation was observed. Thirty GC were still biochemically negative at the annual control. The time of thyroidectomy in GC with negative CT could be personalized and safely planned when stimulated CT becomes positive, independent of the type of RET mutation and patient's age. In this series, a basal CT below 60 pg/ml was always associated to an intrathyroidal localization of MTC.

Prophylactic thyroidectomy for asymptomatic 3-year-old boy with positive multiple endocrine neoplasia type 2A mutation (codon 634).

The multiple endocrine neoplasia type 2A (MEN 2A) syndrome, comprising medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism (PHPT) is most frequently caused by codon 634 activating mutations of the RET (rearranged during transfection) proto-oncogene on chromosome 10. For this codon-mutation carriers, earlier thyroidectomy (before the age of 5 years) would be advantageous in limiting the potential for the development of MTC as well as parathyroid adenomas. This is a case report of 3-year-old boy from the MEN 2A family (the boy's father and grandmother and paternal aunt) in which cysteine substitutes for phenylalanine at codon 634 in exon 11 of the RET proto-oncogene, who underwent thyroidectomy solely on the basis of genetic information. A boy had no thyromegaly, thyroidal irregularities or lymphadenopathy and no abnormality on the neck ultrasound examination. The pathology finding of thyroid gland was negative for MTC. Two years after total thyroidectomy, 5-year-old boy is healthy with permanent thyroxine replacement. His serum calcitonin level is < 2 pg/ml (normal < 13 pg/ml), has normal serum calcium and parathyroid hormone levels and negative urinary catecholamines. Long-term follow-up of this patient is required to determine whether very early thyroidectomy improves the long-term outcome of PHPT. Children with familial antecedents of MEN 2A should be genetically studied for the purpose of determining the risk of MTC and assessing the possibilities of making prophylactic thyroidectomy before the age of 5 years.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Early thyroidectomy in multiple endocrine neoplasia: a four decade experience.

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9-24). The median duration of follow-up at the time of examination was 40 years (range 21-43) with a median current age of 52 years (range 34-65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.

[Prophylactic thyroidectomy in multiple endocrine neoplasia syndrome].

Multiple endocrine neoplasia (MEN) 2a consists on medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The identification of the RET proto-oncogene in 1993 has changed the prognosis of the disease. We have retrospectively studied the patients diagnosed of MEN 2a in our centre for the last 7 years in order to establish the most adequate age to undergo surgery. We present ten patients diagnosed with MEN 2a, whose ages ranged from 1.5 to 11 years old. Mean age at time of operation: 6,4 years An ultrasound study, calcitonin determinations and cathecholamines and urinary metanephrine levels were obtained before surgery. The surgical treatment is based on total total thyroidectomy, in selected cases lymph node resection in the central zone lf the neck. The most frequent RET mutation is the one affecting codon 634 (exon 10), which was found in children. Both of them had an alteration in codon 611 (exon11). No complications appeared after surgery and hospital discharge took place in the 2nd-4th day after surgery. Pathological findings were medullary thyroid microcarcinoma (MTMC) in 3 out of 10 patients, calcitonin preoperative tests were high in one of them. No tumoral cells were found in the lymph nodes. During the follow up period, 9 out of 10 from the operated patients, maintained normal calcitonin, CEA, PTH, calcium, cathecholamines and urinary metanephrine levels. Since there are 3 cases of MTC in patients between 3 and 6 years old, and diagnostic test data are not conclusive, we thoroughly recommend prophyilactic thyroidectomy at early ages, from 3 to 4 years old.

Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers.

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and > or = 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (> or = 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r = 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.

RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed?

To describe a kindred with a rare RET germline mutation in codon 791 and discuss potential management strategies. We present clinical and biochemical data as well as results of mutation analysis in our study subjects and provide an overview of related published reports. Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia or adenoma. Germline mutations in RET are responsible for this autosomal dominant syndrome. Familial MTC is a variant of MEN 2A and can be caused by RET mutations in codon 791. Deaths from gene carriers with mutations in these codons have not yet been reported. In general, gene carriers with these RET mutations have late-onset MTC. Because only a few kindreds with this specific mutation have been identified and no long-term follow-up data are available, management of these patients can be a challenge. We illustrate the difficulties with decisions about not only when to perform thyroidectomy in these patients but also whether thyroidectomy should even be considered in such gene carriers with a benign course. Our reported kindred included four carriers with a codon 791 RET germline mutation, one of whom had the rare concomitant occurrence of acromegaly and MEN 2A. The 70-year-old mother had acromegaly and hyperparathyroidism but normal serum calcitonin levels and normal findings on thyroid ultrasound examination. She refused pentagastrin testing and any surgical intervention. The 37-year-old daughter had hypothyroidism, a small thyroid gland, and negative results of pentagastrin stimulation testing of calcitonin. The 18-year-old grandson also had a negative pentagastrin test result and normal thyroid ultrasound findings. The 5-year-old granddaughter had normal results of thyroid ultrasonography. In all patients, we recommended thyroidectomy. Prospective studies are needed to clarify which patients with codon 791 RET germline mutation should undergo thyroidectomy.

Preventive thyroidectomy in patients with hereditary medullary thyroid carcinoma found heterozygote for mutant RET proto-oncogene.

The currently available genetic tests for identification of the RET proto-oncogene mutation offer the possibility of prospective successful therapy before the hyperplasia of C-cells evolve to Medullary Thyroid Carcinoma. We present our experience regarding the preventive thyroidectomy of family members with history of Medullary Thyroid Carcinoma, who were found to be heterozygote for mutant RET proto-oncogene. We have retrospectively reviewed 19 members of 6 families with history of Medullary Thyroid Carcinoma, who were heterozygote for mutant RET protooncogene and underwent prophylactic thyroidectomy. All patients included in this series were below twenty years of age. The Medullary Thyroid Carcinoma was asymptomatic and the mutation of RET protooncogene has been also documented pre-operatively in all of them. All patients had undergone total thyroidectomy, while 1 with pheochromocytoma had undergone also left epinephridectomy. Fourteen patients (73.68%) had undergone lymph-nodes resection (in 10 of them the resection was central, in 3 unilateral and in 1 bilateral). Although none of our patients suffered from hyperparathyroidism, 7 parathyroid glands have been also resected from 3 patients, while auto-transfusion has been performed in one. In all patients, preoperative measurement of the calcitonin blood levels before and after stimulation with pentagastrin has been performed.

[Is immediate prophylactic thyroidectomy indispensable in familiar medullary thyroid carcinoma?].

To emphasize the importance of genetic studies in family members and early prophylactic thyroidectomy in oncogene mutation carriers in the management of familiar medullary thyroid carcinoma. A retrospective review of families with familiar medullary thyroid carcinoma treated at our center in the last 7 years was performed. We identified a total of 7 families who has isolated prevalences with thyroid malignancies. Forty members of the 7 families were screened for gene RET mutations. Prophylactic total thyroidectomy was performed in every RET mutation gene carriers. In all families the index case were patients with medullary thyroid carcinoma presenting at a mean age of 37.25 years (range 23-42). The RET oncogen mutation was in codon 634 in exon 11 (multiple endocrine neoplasia type 2A) in all these patients. Fourteen gene carriers were identified with a mean age of 20 years (range 7-37), eleven of whom had medullary thyroid carcinoma at the time of surgery. Five of the gene carriers were children, with a mean age of 11 years (range 7-16), four of whom had microcarcinoma and one had metastatic carcinoma at the time of surgery. After surgery no hypoparathyroidism or recurrent nerve paralysis were documented. No pediatric patient has presented with phaeochromocytoma or hypoparathyroidism to date Four of the five children have normal calcitonin levels (< 2 pg/ml) and they are free of disease. The one who presented metastatic carcinoma has recurrent disease and is awaiting surgical treatment. Genetic studies of family members related to patients with familiar medullary thyroid carcinoma and RET mutations is indispensable. The RET mutation in codon 634 exon 11 was found to be the most frequent association. Prophylactic thyroidectomy is the only curative treatment and has minimal complications when performed by expert surgeons. Early thyroidectomy is recommended since distant metastatic spread can occur at early age.

Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated?

RET proto-oncogene mutations are associated with medullary thyroid carcinomas usually requiring preventive thyroidectomy in gene carriers. We present a large kindred with the Y791F mutation in the RET proto-oncogene that did not have medullary thyroid carcinomas. Eight members of a Danish family with the Y791F mutation participated. All gene carriers underwent pentagastrin testing, and measurements of serum calcitonin. In the index person, exons 10, 11, and 13-16 of the RET proto-oncogene were screened. In the rest of the individuals only exon 13 was analysed. Mutation analysis was done by direct bidirectional sequencing of PCR products on an ABI 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). The index person was screened genetically due to goitre at a young age. A total of 27 members of the family underwent genetic testing. Twelve (44.4%, 95% CI: 25.5%-64.7%) had the mutation (age range 13-84 years). None of these had abnormal pentagastrin tests (0%, 95% CI: 0%-26.5%). We found no significant differences in basal serum calcitonin concentrations between gene carriers (mean +/- SD: 0.16 +/- 0.54 pmol/l, n = 11) and non-gene carriers (0.55 +/- 0.86 pmol/l, n = 6, 2 P = 0.29). None showed signs of primary hyperparathyroidism or phaeochromocytoma. The Y791F RET proto-oncogene mutation may have a low penetrance. In selected cases, prophylactic thyroidectomy may be replaced by watchful waiting with repeated pentagastrin testing, provided careful evaluation of risks and benefits is performed.

Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a.

Germline mutated RET proto-oncogene, causing multiple endocrine neoplasia (MEN)-2a syndrome is the indication for prophylactic total thyroidectomy. Literature regarding the risk and the extent of early surgical intervention is scarce and the optimum age for surgery is still controversial. To optimize management in these young children we evaluate our experience and results. From 1990 to 2001 preventive total thyroidectomy was performed in 13 MEN-2a gene carriers (4 boys and 9 girls; median age 7 (4-14) years). Preoperative assessment, surgical procedure, pathological examination, postoperative complications and treatment results were studied. Surgery existed of a total thyroidectomy alone (n=3) in children with normal basal calcitonin and in combination with tracheo-esophageal exploration (n=6) or central compartment dissection (n=4) in case of abnormal calcitonin levels. Eight children presented with medullary thyroid cancer (MTC), three (median: 5 (4-12) years) with microscopic MTC and five (median 6 (4-14) years) with frank invasive MTC. Four of these five patients were younger than 6 years. Except for long-lasting hypoparathyroidism in one patient there were no complications. At a median follow-up of 6.5 years all patients are disease free. MTC in RET mutated MEN-2a gene carriers in childhood are found at the age of 4 years. Therefore, DNA testing should be done preferably before that age. Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal.

Surgery_Schwartz

MTC for RET point mutations has largely replaced using provocative testing with pentagastrin or calcium-stimulated calcitonin levels to make the diagnosis. Calcitonin and CEA are used to identify patients with persistent or recurrent MTC. Calcitonin is a more sensitive tumor marker, but CEA is a better predictor of prognosis.Treatment. The ATA published revised guidelines for the man-agement of medullary cancers in 2015.59 A neck ultrasound is recommended to evaluate the central and lateral neck compart-ments and the superior mediastinum. Serum calcitonin, CEA, calcium levels should also be measured, and RET proto-onco-gene mutation testing should be performed. Pheochromocy-tomas need to be excluded. If patients are found to have a pheochromocytoma, this must be operated on first. Primary hyperparathyroidism, if present, is treated at the time of thyroidectomy. These tumors are generally (>50%) bilateral. Total thyroidectomy is the treatment of choice for patients with MTC because of

Surgery_Schwartz

and amyloid. Marked heterogeneity is present; cells may be polygonal or spindle shaped. The presence of amyloid is a diagnostic finding, but immunohistochemistry for calcitonin is more commonly used as a diagnostic tumor marker. These tumors also stain positively for CEA and calcito-nin gene–related peptide.Diagnosis. The diagnosis of MTC is established by history, physical examination, raised serum calcitonin, or CEA levels, and FNAB cytology of the thyroid mass. Attention to family history is important because about 25% of patients with MTC have familial disease. Because it is not possible to distinguish sporadic from familial disease at initial presentation, all new patients with MTC should be screened for RET point mutations, pheochromocytoma, and HPT. Screening of patients with famil-ial MTC for RET point mutations has largely replaced using provocative testing with pentagastrin or calcium-stimulated calcitonin levels to make the diagnosis. Calcitonin and CEA are used to identify

[Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family].

Genetic testing of RET proto-oncogen allows an early diagnosis of Multiple Endocrine Neoplasia syndrome type 2 and establish a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of an early diagnosis with genetic testing followed by prompt surgery on the cure of MTC versus a later diagnosis with serum calcitonin. Retrospective descriptive study of 8 members of a MEN 2A family by C634Y mutation. We performed serum calcitonin screening until 1999 and subsequently RET genetic testing was obtained. Carriers underwent total thyroidectomy and periodic determination of calcitonin, urinary metanephrines, calcium, phosphorus and neck and abdominal imaging techniques. Five patients were diagnosed by calcitonin familial screening and all of them have high calcitonin by now. Three patients were diagnosed by genetic testing (an adult and two children) and they are free of disease. Calcitonin was closely monitored in children and they underwent surgery when it started to raise, at 6 and 10 years old respectively, finding nodular C-cell hyperplasia in both. Of 8 carriers 3 developed pheochromocytomas, bilateral and asynchronous, one-half had normal urinary metanephrines and two of them were simultaneous with MTC. No patient had biochemical data suggesting hyperparathyroidism although in one patient multiple parathyroid adenomas were found at thyroidectomy. RET genetic analysis has achieved an early diagnosis and treatment with no development of MTC in our patients, adjusting the time and type of surgery and allowing a genotype-phenotype correlation. It demonstrates how a genetic alteration is associated with a pathology that we can prevent and manage improving the prognosis of our patients.

Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience.

When mutations of the RETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i. e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age </= 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0-1/pNX/pN0-1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.

Surgery_Schwartz

children who are RET-positive and calcitonin-negative with a normal ultrasound examination. When the cal-citonin is increased or the ultrasound suggests a thyroid cancer, a prophylactic central neck dissection is indicated.Postoperative Follow-Up and Prognosis. Patients are fol-lowed by annual measurements of calcitonin and CEA levels, in addition to history and physical examination. Other modalities used to localize recurrent disease include ultrasound, CT, MRI, and more recently, FDG-PET/CT scans. Prognosis is related to disease stage. The 10-year survival rate is approximately 80% but decreases to 45% in patients with lymph node involvement. Survival also is significantly influenced by disease type. It is best in patients with non-MEN familial MTC, followed by those with MEN2A, and then those with sporadic disease. Progno-sis is the worst (survival of 35% at 10 years) in patients with MEN2B. Performing prophylactic surgery in RET oncogene mutation carriers not only improves

Medullary thyroid carcinoma: surgical treatment advances.

Since medullary thyroid cancer (MTC) was first recognized as a distinct tumor in 1959, it became clear that MTC is more difficult to cure than papillary thyroid cancer and has higher rates of recurrence and mortality. MTC represents 5-8% of thyroid cancers. It derives from parafollicular cells of the ultimobranchial body derived from the neural crest. MTC secretes calcitonin and other hormonal peptides and is considered part of the amine precursor uptake and decarboxilation system. MTC may occur either as a hereditary or nonhereditary entity. Hereditary MTC can occur either alone as the familial MTC or as the thyroid manifestation of multiple endocrine neoplasia (MEN) type 2 syndromes (MEN 2A MEN 2B). Activating point mutations of the RET proto-oncogene have demonstrated to be causative of the familial form of medullary thyroid cancer, both isolated familial MTC and associated with MEN 2A and 2B. In the last 10 years, major improvements and new technologies have been proposed and applied in thyroid surgery; among these are molecular diagnosis with genetic screening and mini-invasive video-assisted thyroidectomy. The history of thyroid surgery starts with Billroth, Kocher and Halsted, who developed the technique for thyroidectomy between 1873 and 1910. Prophylactic surgery for patients carrying a positive RET proto-oncogene has proven to be highly effective in curing those likely to experience the development of MTC. Video-assisted procedures with central compartment dissection have proved feasible for patients carrying a positive RET proto-oncogene. This paper reviews relevant medical literature published in the English language on surgery of MTC in well-controlled trials. We discuss the particular ethical and legal issues that thyroid prophylactic surgery raises. Searches were last updated in February 2007.

Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children.

Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.

Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing.

To evaluate the impact of genetic testing in the management of familial multiple endocrine neoplasia 2A patients. Retrospective study. University teaching hospital, Hong Kong. Twenty-two patients from eight multiple endocrine neoplasia 2A families underwent prophylactic total thyroidectomy based on a positive RET mutation genetic testing. All mutations were located at codon 634 of exon 11. Nineteen patients had preoperative basal serum calcitonin measured, and the 12 with normal levels had pentagastrin stimulation tests. Preoperative thyroid ultrasound examination was performed for 17 patients. There were 13 females and 9 males with a median age of 25.1 (range, 6.1-71.9) years. Histopathology revealed medullary thyroid carcinoma in 17 (77%), C-cell hyperplasia in four (18%), and normal pathology in one (5%) of the patients. Five patients with either C-cell hyperplasia or normal pathology were among the youngest (age range, 6-9 years). The youngest patient with medullary thyroid carcinoma was nearly 9 years old. The median size of medullary thyroid carcinomas was 8.3 (range, 0.1-18) mm, but there were no lymph node metastases. Of 15 patients with normal basal calcitonin levels, 10 had medullary thyroid carcinoma, though two tested negative with the pentagastrin-stimulated calcitonin assay. Five of six patients with normal preoperative ultrasonographic examinations had medullary thyroid carcinoma. Three (14%) of the patients were prescribed long-term calcium and vitamin D supplementation. After a median follow-up of 49 (range, 13-128) months, no patient had recurrence of medullary thyroid carcinoma. Genetic testing has replaced conventional biochemical and radiological modalities to identifying multiple endocrine neoplasia 2A carriers, in order to offer them prophylactic thyroidectomy. Chinese multiple endocrine neoplasia 2A patients with codon 634 mutation seem to have less aggressive forms of medullary thyroid carcinoma, for whom prophylactic thyroidectomy can be considered at the age of 8 years.

Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center.

Genetic study of the RET proto-oncogene has modified the management, treatment, and prognosis of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia 2A (MEN 2A), for patients with less advanced tumor stages. Classically, the diagnosis was based on an increase in basal and poststimulus peak calcitonin (bCT and pCT). Prophylactic thyroidectomy, based on results of genetic testing, may reduce recurrences in MTC. Of 82 MTC (MEN 2A) patients genetically diagnosed and surgically treated at our center, 22 received a prophylactic thyroidectomy (RET +, bCT and pCT with normal values and asymptomatic). We analyzed age, gender, phenotype, RET mutation, cervical ultrasound, laboratory tests (bCT, pCT, and CEA), surgery, histologic data, TNM, and followup. The 22 patients belonged to 8 families with MTC (MEN 2A). Mean age was 15.2 years (range 5 to 36 years). The RET mutation in 21 patients was Cys-->Tyr and in the remaining patient both in codon 634 in exon 11. The median values of bCT and pCT were 38 pg/mL (range < 15 to 75 pg/mL) and 148.5 pg/mL (range < 15 to 250 pg/mL), respectively. Total thyroidectomy was performed in 8 patients (age < or = 10 years) and associated central neck dissection in 14 patients (age> 10 years). Histologic study showed 7 C-cell hyperplasias and 15 MTCs (8 bilateral); the median size was 0.2 cm (range < 0.1 to 0.7cm); 1 patient had metastatic adenopathies. According to TNM, 7 were stage 0, 14 were stage I, and 1 was stage III. Postsurgery bCT and pCT values were normal in all patients, with a curative rate of 100%. MTC patients compared with C-cell hyperplasia patients were older on average, had higher mean bCT, mean pCT, and mean CEA. Prophylactic thyroidectomy based on genetic testing allows identification and treatment of patients at an early stage of the disease and decreases recurrence rates. pCT values above the upper limit of normal may be markers for the presence of MTC and should be considered in selecting operative procedures for these patients.

Pediatrics_Nelson

Treatment includes total thyroidectomy, selective regional node dissection, and radioablation with 131I for residual or recurrent disease. The prognosis is usually good if the disease is diagnosed early. Medullary carcinoma of the thyroid may be asymptomatic except for a mass. Diagnosis is based on the presenceof elevated calcitonin levels, either in the basal state or after pentagastrin stimulation (difficult to obtain) and histologicexamination. This tumor most often occurs with multipleendocrine neoplasia 2a or 2b (MEN), possibly in a familial pattern. In some families, the presence of mutations ofthe RET proto-oncogene is predictive of the development of medullary carcinoma of the thyroid. The location of the mutation can help determine when removal of the thyroid iswarranted. Genetic screening of other members of the family is indicated after a proband is recognized. Prophylacticthyroidectomy is indicated for the family members with thesame allele.

Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family.

Analysis of the RET proto-oncogen is very important for diagnosis and prognosis of medullary thyroid cancer (MTC). Genotype-phenotype correlation is also well known. Here we report features of the largest known family in Turkey with the V804M-mutated RET proto-oncogene. Thirty members from three generations were evaluated. A RET proto-oncogen mutation, calcitonin (Ct) measurement and thyroid ultrasound were performed on all individuals. Seventeen members had V804M mutation. Fourteen of these patients underwent total thyroidectomy and additional central lymph node dissection for five subjects. The mean age of patients with MTC was 46.5 (30-61) years. The mean calcitonin level of RET positive members was 13.27 pg/mL (1-49.8 pg/mL). Three had a basal Ct level above normal limits. Seven of the 14 patients were diagnosed with MTC, and two were diagnosed with papillary thyroid cancer without MTC. One patient had central neck metastasis. Hyperparathyroidism or pheochromocytoma was not detected in any case. Patients who were RET negative, had normal Ct levels and no suspected nodule on ultrasound examination. Our study revealed a relatively good prognosis in patients with V804M mutation. Despite the surgery was performed in older age no advance disease was observed.