[Surgical treatment of pheochromocytoma].

This review article contains a summary of modern aspects of preoperative preparation, surgical treatment, and follow-up of patients with adrenal pheochromocytomas. The main component of preoperative preparation is the use of alpha-blockers. The need to prescribe them to all patients is increasingly disputed, especially for patients without severe hypertension. An increasing number of publications demonstrate positive results of treatment without the use of alpha-blockers, advocating an individual approach and the use of the drug according to certain indications. Minimally invasive endoscopic techniques of adrenalectomy have become widespread in surgical treatment. They are represented by laparoscopic and retroperitonescopic technic, including using their single-port modifications. The earliest possible intersection of the central vein in the past was considered the most important aspect of adrenalectomy for pheochromocytoma, currently, due to the development of surgical techniques and anesthesiological manuals, this has ceased to be a mandatory rule of successful surgery. Despite the significant influence of the intersection of this vessel on intraoperative hemodynamics, surgical tactics with its later intersection have their own justifications and do not lead to a deterioration in treatment results. The standard volume of surgical intervention for pheochromocytomas is total adrenalectomy, however, in the presence of hereditary syndromes, such as multiple endocrine neoplasia type 2 syndrome, neurofibomatosis type 1, von Hippel-Lindau syndrome, it is possible to perform cortical-sparing adrenalectomy.

Multiple endocrine neoplasia type IIa associated with Cushing's syndrome.

Multiple Endocrine Neoplasia type IIa (MEN IIa) is an autosomal dominant syndrome characterized by pheochromocytoma, medullary thyroid carcinoma and hyperparathyroidism. Pheochromocytoma occurs in approximately 50% of patients with MEN IIa. This tumor has the capacity to produce ACTH ectopically and manifests as the Cushing syndrome, although it is very rare. We report a 26-year-old woman patient with severe muscle weakness, skin lesions in extremities, hypertension, and new onset diabetes whose laboratory findings included hypokalemia, metabolic alkalosis, high serum level of cortisol, metanephrine, normetanephrine, calcitonin and bilateral adrenal mass in computed tomography as the first clinical manifestations of an ACTH-secreting pheochromocytoma. In the patients with hypertension, new onset diabetes and hypokalemia, the Cushing syndrome and pheochromocytoma should always be ruled out.

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.

The soluble ectodomain of RetC634Y inhibits both the wild-type and the constitutively active Ret.

Substitution of Cys-634 in the extracellular domain of the Ret tyrosine kinase receptor causes its dimerization and activation of its transforming potential. To gain further insight into the molecular basis leading to Ret activation we purified a mutant protein consisting of the entire ectodomain of the Ret carrying a Cys-634-->Tyr substitution (EC-Ret(C634Y)). The protein is glycosylated, like the native one, and is biologically active. By using an in vitro cell system we show that EC-Ret(C634Y) inhibits the membrane-bound receptor Ret(C634Y), interfering with its dimerization. Furthermore, we demonstrate that EC-Ret(C634Y) competes with the wild-type Ret receptor for ligand binding. The results presented support the notion of the possible involvment of glial cell line-derived neurotrophic factor (GDNF) with multiple endocrine neoplasia type 2A (MEN2A) tumours, and describe a useful tool for generating molecular mimetics directed towards specific mutations of the ret oncogene.

Utilidad clínica de los estudios moleculares en el carcinoma medular de tiroides familiar / Clinical use of molecular studies in familiar medullary thyroid carcinoma

El carcinoma medular de tiroides es un tumor maligno secretor de calcitonina, derivado de las células parafoliculares tiroideas. Representa del 5 al 10 por ciento de todos los carcinomas de tiroides, de los cuales el 20 por ciento se originan por mutaciones de la línea germinal. El carcinoma medular de tiroides y el feocromocitoma son los tumores malignos que forman parte de la entidad conocida como neoplasia endocrina múltiple tipo 2A (MEN 2A) y presentan una mutación en el protooncogén RET. Todos los pacientes con MEN 2A desarrollarán en el 100 por ciento un carcinoma medular de tiroides. Sólo es necesaria la mutación de un solo gen para que se desarrolle el tumor; de ahí, la herencia dominante con una penetrancia prácticamente completa en este tipo de tumores. Se han identificado varias mutaciones en el oncogén RET en casos de carcinoma medular de tiroides familiar, la mayoría en los exones 10 y 11. Los resultados comunicados en el International RET Mutation Consortium han demostrado que el 85 por ciento de las familias con síndrome MEN 2A tienen una mutación en el codón 634. El tratamiento de elección en los casos de MEN 2A con la detección de la mutación para desarrollar carcinoma medular de tiroides familiar es la tirodectomía total antes de los 5 años de edad, en prevención a la aparición de un carcinoma. En los casos en que la tirodectomía se realice de forma inadecuada o incompleta todos los pacientes desarrollarán cáncer (AU)

Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations.

OBJECTIVE: The RET proto-oncogene is known to be the susceptibility gene for various disease phenotypes, including multiple endocrine neoplasia type 2 (MEN 2). Recent studies have also suggested an involvement of RET in the development of the mammalian kidney. Although kidney agenesis or dysgenesis has been observed in mice lacking functional ret, no clinically relevant kidney abnormalities have been reported in individuals with known RET mutations and familial medullary thyroid carcinoma (FMTC). We have studied a family with five members affected with isolated FMTC. DNA analysis was performed and the involved RET mutation was identified. Amongst these patients were a woman and her son. DESIGN: Case report. SETTING: University department. PATIENTS: A 32-year-old woman and her son with FMTC and unilateral renal agenesis. RESULTS: The woman's abdominal ultrasound findings demonstrated unilateral renal absence of the left kidney. Her son, when only a few months old, had undergone surgical treatment for Hirschsprung's disease. Abdominal ultrasonography was performed recently, and left-side renal absence was diagnosed. Intravenous pyelography confirmed the agenesis of his left kidney, whilst the contralateral kidney displayed compensatory hypertrophy. CONCLUSIONS: The involvement of the RET proto-oncogene in the early growth and differentiation of the human kidney is now generally accepted. We believe that at least a proportion of patients with MEN 2 may have undiagnosed renal malformations. We suggest therefore that noninvasive imaging techniques, such as ultrasonography, should be used to explore the presence of renal abnormalities in subjects with demonstrated RET mutations.

Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation.

The catalytic activities of Ret tyrosine kinases as the products of oncogene RET with multiple endocrine neoplasia type 2A (Ret-MEN2A) or 2B (Ret-MEN2B) mutations and the hybrid gene from c-RET and RFP (Rfp-Ret) were higher than those of c-Ret. We demonstrated that ultraviolet light (UV) irradiation induced activation of c-Ret and superactivation of genetically mutated, and thereby constitutively activated, Ret-MEN2A, Ret-MEN2B, and Rfp-Ret. We found that small proportions of c-Ret and Ret-MEN2B and a large proportion of MEN2A were dimerized due to disulfide bonds and that high kinase activity resided in these fractions. The UV-induced activation of c-Ret and superactivation of Ret-MEN2A and Ret-MEN2B were then shown to be closely associated with promotion of the disulfide bond-mediated dimerization of the Ret proteins. Furthermore, we showed that a large proportion of Rfp-Ret was dimerized or polymerized and that almost all kinase activities resided in the highly polymerized but not dimerized fraction. The UV-induced superactivation of Rfp-Ret was also found to be closely associated with promotion of polymerization but not with dimerization of Rfp-Ret. Further experiments revealed that UV induced intracellular dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Most importantly, the levels of basal kinase activity and dimerization of Ret-TPC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-TPC-1 was replaced with alanine, were low and were not increased by UV irradiation. These results suggest that the cysteine at this position works as the primary target of dimerization of Ret proteins inside the cell for both the maintenance of the basal kinase activity and its promotion by UV, possibly in co-operation with the cysteine(s) in the extracellular domain of Ret-MEN2A and Rfp-Ret, which is the target of dimerization and polymerization outside the cell. The potential biological significance of the UV-mediated superactivation of mutant Ret through the newly proposed mechanism in oncogenesis is discussed.

Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations.

The ret proto-oncogene encodes a receptor tyrosine kinase whose ligands belong to the glial cell line-derived neurotrophic factor (GDNF) protein family. Its germline mutations are responsible for the development of multiple endocrine neoplasia (MEN) types 2A and 2B and Hirschsprung's disease (HSCR). MEN2A and MEN2B mutations result in the constitutive activation of Ret by different molecular mechanisms. MEN2A mutations involve cysteine residues present in the Ret extracellular domain and induce disulfide-linked Ret dimerization on the cell surface. MEN2B mutations were identified in methionine 918 in the tyrosine kinase domain and activate Ret without dimerization, probably due to a conformational change of its catalytic core region. In contrast to MEN2 mutations, HSCR mutations represent loss of function mutations. We found that most of HSCR mutations detected in the extracellular domain impair the Ret cell surface expression. More interestingly, ret mutations in cysteines 618 and 620 were reported in several families who developed both MEN2A and HSCR. It was suggested that these mutations might have two biological effects on Ret function, leading to the development of different clinical phenotypes in the same patients.

[Endocrine surgery from the viewpoint of the pediatric surgeon]. / Endokrine Chirurgie aus der Sicht des Kinderchirurgen.

The extent of surgery for thyroid tumors is discussed. Prophylactic thyroidectomy in MEN II a and b is advocated. Pancreatic surgery is necessary in cases of nesidioblastosis, islet cell carcinoma, papillary-cystic neoplasia and pancreaticoblastoma. Gastrointestinal tumors with hormonal activity are very rare. "Incidental carcinoid" is occasionally found. Early detection of Zollinger-Ellison syndrome in childhood usually allows for complete removal of a gastrinoma. Benign and malignant neoplasms of the adrenals warrant radical surgery. We report one case of minimally invasive bilateral removal of the adrenals for nodular hyperplasia. Pheochromocytoma in childhood presents several peculiarities influencing perioperative management. It may occur as part of MEN II a.

RET oncogene.

RET mutations have been identified as the underlying cause of two congenital diseases that predominately affect tissues of neural crest origin: the MEN 2 cancer syndromes and a proportion of cases of dominantly inherited Hirschsprung disease, a disorder of gut development. This review summarizes the disease-causing mutations and our present understanding of their possible effects on RET protein function.

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.

[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.