Multiple endocrine neoplasia type 2B: Frequency of physical stigmata-Results of the GPOH-MET registry.

BACKGROUND: Multiple endocrine neoplasia (MEN) 2B is characterized by early development of aggressive medullary thyroid carcinoma (MTC), visible physical stigmata, and associated symptoms. In most cases, de novo mutations are revealed. There are premonitory symptoms and stigmata that enable early diagnosis, before an inoperable MTC develops. The German Society for Paediatric Oncology and Haematology (GPOH)-Malignant Endocrine Tumours (MET) registry maintains records of children with MTC in Germany since 1997. METHODS: Children with a diagnosis of MTC in MEN 2B recorded in the GPOH-MET study were analyzed retrospectively. Stigmata and symptoms associated with MEN 2B were examined. RESULTS: From inception through 2017, 24 patients aged 0.2-17.3 years were included. Symptoms affecting the oral/dental (88.0%), musculoskeletal (79.2%), and gastrointestinal (70.8%) systems were recognized most frequently. Gastrointestinal and musculoskeletal symptoms preceded symptoms of MTC. Twelve patients had short stature. Regarding the prevalence of single symptoms, neuromas of the lips and the oral cavity were mentioned most frequently. Five patients died from MTC. Patients diagnosed by tumor symptoms showed more advanced disease than those with disease detected by other means. Children diagnosed via associated stigmata and symptoms or positive family history had significantly improved overall survival (OS) compared to children diagnosed via symptoms of MTC (OS 100% vs 53.3%). CONCLUSIONS: In children with MEN 2B, oral/dental, musculoskeletal, and gastrointestinal symptoms are most common. If children are diagnosed via associated symptoms and stigmata, OS is improved. Most of the children were diagnosed with growth disturbances; this finding requires verification and ranging in other patient cohorts.

Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2.

Distinct dominant activating mutations in the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2 (MEN 2). Concise examination of the mutated codons led to the detection of a striking genotype-phenotype correlation between the mutated codon and the MEN 2 phenotype in terms of onset and aggressiveness of the disease, suggesting that manifestation and clinical progression is conditioned by the type of mutation. To gain insight into the molecular basis for this genotype-phenotype correlation, we analysed the impact of common and rare mutations identified in MEN 2A (C609Y, C634R), MEN 2B (A883F, M918T) and familial medullary thyroid carcinoma (Y791F) patients on several aspects of cell transformation, including proliferation, apoptosis, anchorage-independent growth and signaling. We found that tumor cells arising from distinct extracellular or intracellular MEN 2 mutations clearly differ in their proliferation properties owing to the activation of different molecular pathways, but importantly, also in resistance to apoptosis. Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients.

Putting the bits and pieces of the RET proto-oncogene puzzle together.

The RET proto-oncogene has been implicated in the causation of papillary thyroid carcinoma, multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B), and Hirschsprung's disease. The mutations in these syndromes can be categorized into activating or inactivating mutations. Activating mutations of a cysteine-rich extracellular region cause enhanced dimerization of the RET tyrosine kinase receptor and autophosphorylation, and are causative for MEN 2A and familial medullary thyroid carcinoma (FMTC). An activating mutation of the tyrosine kinase domain causes increased autophosphorylation but does not affect the state of dimerization. A variety of inactivating mutations of the RET proto-oncogene, which result in defective protein formation, are causative for Hirschsprung's disease.

Multiple endocrine neoplasia (MEN IIB) with Cushing's syndrome due to medullary thyroid carcinoma producing corticotropin-releasing hormone.

We describe a case of Cushing's syndrome caused by a medullary thyroid carcinoma (MCT) secreting corticotropin-releasing-hormone (CRH) in a young woman presenting mucosal neuromas located on the top of the tongue and eyelid areas. Laboratory studies showed, basally and after dexamethasone suppression test, serum cortisol and plasma pituitary corticotrophin (ACTH) levels agreed with an ectopic Cushing's syndrome. Immunohistochemical studies of the MCT tissue revealed a production of CRH and scattered cells containing vasopressin but not ACTH peptides. This is the first demonstrated case of a CRH-secreting tumor in multiple endocrine neoplasia (MEN IIB) syndrome.

[Hereditary multiple endocrine neoplasia. New genetic data and clinical applications in type 1 multiple endocrine neoplasia]. / Les multi-endocrinopathies héréditaires. Nouvelles données génétiques et applications cliniques dans le cadre des néoplasies endocriniennes multiples de type 1.

Multiple endocrine neoplasia (MEN) is a group of characteristic affections involving benign or malignant secreting tumours of several endocrine glands. Recent progress in genetic mapping has led to the precise localization of the genes causing these familial diseases. This technique provides new means of diagnosis greatly improving conventional diagnostic methods. In type 1 MEN, laboratory tests are directed to identifying the target gland and its effect on hormone status. Imaging techniques including echography, CT scan, magnetic resonance imaging, echoendoscopy and scintigraphy add further information. The molecular genetics approach is an indirect one based on a family study. Blood samples must be obtained from at least two certain probands and at least two healthy members of the family. By mapping the genes with precise genetic probes, the morbid haplotype could be identified and used to predict the risk of morbidity in the descendance. The GENEM 1 (Groupe d'Etudes sur les Néoplasies endocriniennes multiples de type 1) is a multidisciplinary collaboration between endocrine surgeons, endocrinologists, gastroenterologists, geneticians, pathologists and biologists working towards identifying the causal gene and better understand the pathophysiology of these tumours. We are undoubtedly on the threshold of this discovery which could help improve the diagnosis of this generally poorly recognized disease with an underestimated prevalence.

Parent-of-origin effects in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.