Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.

Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

[Clinical and genetic profile of patients with medullary thyroid cancer treated in the Cancer Centre--Institute of Oncology in Warsaw]. / Analiza kliniczna i genetyczna chorych na raka rdzeniastego tarczycy w Centrum Onkologii--Instytucie w Warszawie.

INTRODUCTION: The aim of this study was to analyse the distribution and frequency of mutations and their correlations with clinical phenotypes of patients with MTC, to reveal the differences between sporadic and familial type of MTC, and to describe the phenotypes of patients. MATERIALS AND METHODS: 212 patients with medullary thyroid cancer (MTC) were treated in Cancer Centre in Warsaw between 1997 and 2005. In most patients, DNA isolated from peripheral blood leukocytes was tested for RET gene mutations by sequencing and accordingly MTC form was assessed. Genetic testing was performed in the relatives of patients with familial MTC in order to distinguish asymptomatic mutation carriers from noncarriers. RESULTS: RET gene mutations were identified in 46 patients (22%). The others were found noncarriers and sporadic MTC was diagnosed. MEN 2A/FMTC syndrome (multiple endocrine neoplasia type 2A/ familial type of MTC) was diagnosed in 44 patients, MEN 2B syndrome (multiple endocrine neoplasia type 2B) in 2 patients. In patients with sporadic and familial MTC, age at diagnosis and multifocal occurrence was analysed, and the results were found to be in accordance with those of other research centres. However, the distribution and frequency of mutations, as well as some clinical data, such as the frequency of pheochromocytoma occurrence as the first manifestation of MEN syndrome, differed from the published data, and further studies are necessary to reveal the reasons of these differences. CONCLUSIONS: DNA testing for RET gene mutations is reliable as a diagnostic tool and therefore it should be performed for screening of all patients with MTC or other diseases of MEN syndrome.

Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease.

More than 50% of patients with typical MEN-2B have a de novo M918T germline mutation of the RET protooncogene. However, even in typical MEN-2B, extrathyroidal manifestations of MEN-2B can be found to be differently expressed. We analyzed the clinical manifestation and course in 21 patients harboring a de novo RET M918T mutation. Mean age at MEN-2B diagnosis was 14.2 years (range: 1-31 years). All patients had medullary thyroid carcinoma (MTC). At the time of syndrome diagnosis, oral manifestations (bumpy lips, ganglioneuroma), ocular manifestations (corneal fibers, conjunctivitis sicca), intestinal dysfunctions, musculoskeletal manifestations, and pheochromocytoma were found in 86%, 90%, 74%, 79%, and 19% of the patients, respectively. At the time of follow-up examination, the symptoms were found at higher frequency. Severe intestinal manifestation was predominantly found in patients with prepubertal onset (< or = 12 years) of MTC (n = 4/10) compared with patients with late onset (> 12 years) of MTC (n = 0/11) (40% versus 0%; p = 0.019). Although biochemical cure was found only in four patients with early onset of MTC, the long-term prognosis for patients with early onset of MTC was poorer than for patients presenting with late onset of MTC (p = 0.005). During mean follow-up of 55.8 months (range: 3-161 months), seven patients (33%) died from MTC. In conclusion, whereas most typical MEN-2B symptoms were found to be age-related, severe intestinal manifestation was found to be predominantly expressed in patients with early onset of MTC. Furthermore, in patients with early onset of MTC who could not be biochemically cured, the long-term prognosis was found to be worse than that of non-cured patients with late onset of MTC, suggesting an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation.

Clinical manifestations of familial medullary thyroid carcinoma.

We conducted a large-scale nation-wide questionnaire survey to ascertain the status of familial medullary thyroid carcinoma (MTC) in Japan in 2002. Out of a total of 271 MTC cases (male to female ratio 1:1.4), multiple endocrine neoplasia (MEN) 2A accounted for 83 cases (30.6%), familial MTC (FMTC) for 14 cases (5.1%), MEN for 11 cases (4.1%), and sporadic MTC for 163 cases (60.1%). Mean age at the time of diagnosis was 35.6 in MEN2A, 34.6 in FMTC, 30.5 in MEN2B, and 47.6 in sporadic MTC. Forty-five percent of MEN2A patients had pheochromocytoma and 11% of MEN2A patients had parathyroid disorders when MTC was diagnosed. Finally, the RET oncogene test yielded the largest number of initial findings that led to diagnosis of familial MTC.

[From gene to disease; from the RET gene to multiple endocrine neoplasia types 2A and 2B, sporadic and familial medullary thyroid carcinoma, Hirschsprung disease and papillary thyroid carcinoma]. / Van gen naar ziekte; van het RET-gen naar multipele endocriene neoplasie type 2A en 2B, sporadisch en familiair medullair schildkliercarcinoom, ziekte van Hirschsprung en papillair schildkliercarcinoom.

The RET gene encodes a receptor tyrosine kinase involved in normal and neoplastic development of neural crest cell lineages. Activating RET mutations are present in patients with multiple endocrine neoplasia types 2A and 2B (MEN2A, 2B) and in familial medullary thyroid carcinoma (FMTC) patients, whereas inactivating RET mutations are found in patients with Hirschsprung (HSCR) disease. In particular for MEN2A and FMTC, the clinical management largely depends on the specific mutation found.

Multiple endocrine neoplasia type 2B--genetic basis and clinical expression.

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

[Genetic analysis of RET mutations in families with multiple endocrine neoplasia type II in the community of Murcia]. / Análisis genético de las mutaciones de RET en las familias con neoplasia endocrina múltiple tipo 2 de la Comunidad de Murcia.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) syndromes are inherited following an autosomal dominant pattern. RET protooncogen mutations have been associated with MEN 2. The identification of these mutations enables us to diagnose MEN 2. The objectives were to recognize RET mutations and gene carriers in the area of Murcia and to sep up the relationship between genotype and phenotype. PATIENTS AND METHODS: 284 subjects from 14 MEN 2A kindreds and one MEN 2B family from the Community of Murcia, Spain, were studied. 48 out of them had MEN 2 tumours and 236 subjects were at risk. The initial screening test was single-strand conformation polymorphism (SSCP) in 8 MEN 2A families and denaturing gradient gel electrophoresis (DGGE) in 6 MEN 2A families; the results in all the subjects were confirmed with restriction analysis. The MEN 2A family in which the Cfo-I enzyme detected but did not specify the type of mutation received DNA sequence assay. The MEN 2B kindred was studied with restriction analysis. RESULTS: TGC-->TAC and TGC-->CGC mutations of codon 634 were found in 13 and one MEN 2A kindreds, respectively. ATG-->ACG mutation of codon 918 was present in the MEN 2B family. Clinical diagnosis was confirmed in the 48 patients, 44 new gene carriers were detected and 192 carriers of normal alleles were ruled out. The incidence of hyperparathyroidism was highest if RET mutation was TGC-->CGC. CONCLUSIONS: Community of Murcia is one of the areas with the highest prevalence of MEN 2. The risk of hyperparathyroidism is increased if TGC-->CGC is present.

Genetic testing in multiple endocrine neoplasia and related syndromes.

Multiple Endocrine Neoplasia (MEN) syndromes are inherited diseases characterised by endocrine tumours occuring as autosomal dominant genetic diseases with high penetrance. In MEN1, most tumours affect the parathyroids, endocrine pancreas, anterior pituitary, and adrenal glands. The MEN1 gene has been cloned recently and encodes a nuclear protein without known function so far. More than 200 germline mutations have been identified in MEN1 patients throughout the entire coding sequence and no genotype-phenotype correlation has been found. Now, MEN1 gene screening is a powerful tool in pre-symptomatic diagnosis for MEN1 patients and those with inherited MEN1 related syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma (MTC) which is associated with phaechromocytoma and parathyroid tumours in MEN2A, phaechromocytoma and mucosal neuromas in MEN2B. Familial isolated MTC is characterised by MTC only, and the three variants of MEN2 are related to germline missense mutations of the RET proto-oncogene, which encodes a tyrosine-kinase receptor. Germline RET mutations in MEN2 patients are related to the two main functionnal domains in the RET protein, the extracellular ligand binding domain (MEN2A and FMTC) and the intracellular catalytic domain (MEN2A, MEN2B and FMTC). Genotype-phenotype correlations have been established but must be used carefully in clinical practice. RET mutation analysis is now available for patients and prophylactic thyroidectomy in gene-carriers could be the most reliable way to cure the patients. Mechanisms of tumourigenesis induced by MEN2-related RET germline mutations have been analysed by in vitro studies and the generation of transgenic mice which develop true bilateral MTC. Recent insights on MEN syndrome pathogenesis and related inherited endocrine disorders have a major clinical impact and fundamental studies are now in progress in order to identify all genetic events leading from a normal endocrine tissue towards a fully malignant phenotype.

Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes.

Since the discovery that germ-line mutations in the RET protooncogene are responsible for the multiple endocrine neoplasia (MEN) syndromes types 2A and 2B, prophylactic thyroidectomy has been recommended for MEN patients to prevent medullary thyroid carcinoma (MTC). In this report, we present the medium-term follow up results on the earliest group of 18 patients having prophylactic thyroidectomy for MEN 2A. There were no operative complications. Microscopic or grossly evident MTC was present in 14 (78%) of the resected patients. None of the patients had metastasis of their MTC to regional lymph nodes. At three years' follow up, there is no evidence of residual or recurrent MTC, based on biochemical testing. We conclude that prophylactic thyroidectomy, based on direct DNA testing for RET gene mutations, is an effective and safe way to manage MTC in patients with MEN 2A.

A nationwide clinical survey of patients with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma in Japan.

MEN (multiple endocrine neoplasia) type 2 syndrome is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and/or developmental anomalies. Germ-line mutations of the RET proto-oncogene have recently been identified as the underlying cause of the syndrome. Accordingly, several investigators have advocated prophylactic total thyroidectomy for medullary thyroid carcinoma at an early age in MEN 2 gene carriers identified by DNA analysis. Before applying this strategy in Japan, the biological behavior of each category of tumor in MEN 2 syndrome, and medullary thyroid carcinoma in particular, should be well understood. We conducted a nationwide questionnaire survey to clarify the clinicopathological features of MEN 2 in Japan, obtaining data for 230 patients diagnosed as having MEN 2. They included 84 males and 146 females, with a median age of 37.5 years (range 5-83). Patients were categorized as 179 with MEN 2A, 17 with MEN 2B, 12 with familial medullary thyroid carcinoma and 22 'other'. Medullary thyroid carcinoma, pheochromocytoma and parathyroid lesions occurred in 224 (97%), 132 (57%) and 25 (11%) patients respectively. Twelve patients (5.2%) died of medullary thyroid carcinoma and 11 patients died of other or unknown causes. Of 163 patients for whom follow-up data were obtained, 82 (50%) experienced recurrences of medullary thyroid carcinoma, including symptomatic recurrent tumors in 24 patients and elevated calcitonin levels alone in 54. In the era of RET mutational analysis for screening relatives of patients with MEN 2, these data provide useful information about surgical management for patients with MEN 2 in Japan.

Malignant endocrine tumours in childhood and adolescence--results of a retrospective analysis.

BACKGROUND: Malignant endocrine tumours (MET) are rare neoplasms in childhood and data on such tumours are scarcely available. The aim of this retrospective study was to collect data over a period of 11 years (1984-1995) and to give the basis for a prospective study. PATIENTS AND METHOD: 180 departments of paediatrics, nuclear medicine and children's surgery were asked for reporting of patients with MET by a questionnaire. 35% of the departments answered (however, 75% of the paediatric departments). RESULTS: 96 children with MET were reported: 73 with thyroid cancer (50 papillary, 15 follicular, 7 medullar, 1 anaplastic; 1:1,9 boys to girls, both mean and median age 11 3/4 years), 12 with adrenocortical cancer and 11 with other malignant endocrine tumours. Metastases were found at diagnosis in 41 of 65 children with papillary or follicular carcinoma. 37 patients (pts.) are in first continuous complete remission (CCR), 4 in partial remission (PR) and in 24 (!) children the remission state or the outcome is not known. 6 of 7 children with medullary cancer have had metastases at diagnosis. 1 patient is in CCR, 1 patient is living in PR, 1 in relapse. 4 children are lost of follow up (lfu.). In sex-ratio no difference was found in 12 pts. suffering from adrenocortical cancer (mean age 5 1/4 years, median age 2 1/2 years). 11 tumours showed hormonal activity. 5 children disclosed metastases at diagnosis. All patients were treated by surgery, 6 received chemotherapy additionally. 4 children are living in CCR, 3 pts. in remission of unknown state, 4 died (all of them with metastases at diagnosis), 1 patient is lfu. The other MET reported: 8 carcinoids (7 x appendix, 1 x lung), 2 phaeochromocytomas, 1 islet cell cancer. 8 pts. are in CCR, 2 are lfu. The child with the islet cell carcinoma died. CONCLUSIONS: Since only 35% of the clinics answered this retrospective analysis cannot give any statement about the incidence of MET in children. As to the prognosis thyroid cancer seems to have a favourable prognosis in childhood and adolescence. In contrast, metastatic adrenocortical cancer is incurable in this age group. Carcinoids of the appendix can be treated curatively by appendectomy. To better understand the biology of MET in children and adolescence and to achieve a better prognosis for some types of these tumours, much more data are needed. For these reason a multicenter prospective therapy study for childhood MET seems to be necessary.

Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families.

Multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) are three dominantly inherited disorders linked to the same disease locus on chromosome 10. Two types of germline mutation of the RET proto-onco-gene, which codes for a transmembrane tyrosine kinase, are associated with MEN 2. Missense mutations at cysteine residues in the extra-cytoplasmic domain are exclusively associated with MEN 2A and FMTC. In MEN 2B patients, a single point mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosine kinase domain. We now report the identification of a mutation at codon 918 in the germline of 16 patients out of 18 unrelated MEN 2B families analyzed. In these families we have been able to demonstrate that, in five cases, the mutation arose de novo, and that, in one kindred, it was coinherited with the disease. These results indicate that a unique mutation at codon 918 of the RET gene is the most prevalent genetic defect causing MEN 2B, but also that rare MEN 2B cases are associated with different mutations yet to be defined.