Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Multiple endocrine neoplasia (MEN) type 2 syndromes are autosomal dominant clinical associations characterized by a common clinical feature, medullary thyroid carcinoma (MTC). The ability to accurately predict the risk by genetic RET proto-oncogene analysis has resulted in the active follow-up of children at risk for developing early metastatic tumours and which can be prevented by prophylactic thyroidectomy. The C634 and M918T mutations (associated with MEN2A and MEN2B, respectively) are particularly associated with early aggressive behavior and distant metastatic spread requiring early intervention. RET is known to be involved in cellular signalling processes during development and controls the survival, proliferation, differentiation and migration of the enteric nervous system (ENS) progenitor cells, as well as the survival and regeneration of sympathetic neural and kidney cells. The centrality of RET in the etiology of both MEN2 and HSCR is now well established with fairly consistent associations existing between RET genotype and phenotype in MEN2. The relationship between Hirschsprung’s disease (HSCR) MEN2 syndromes appears to be a highly significant one, sharing a common etiological factor in the RET proto-oncogene. It is now well accepted that most HSCR arises from loss of function, RET mutations, RET haploinsufficiency or RET polymorphisms and haplotypes of the RET promotor region. MEN2 syndromes result from gene up regulation due to germline activating mutations in the RET proto-oncogene (1:500,000). MTC is mostly associated with variations in the 5 cysteine RET radicals and codon-risk management protocols are of considerable value but not infallible. Oncogenic RET mutations may, however, vary between specific population groups. RET analysis in MEN has revolutionized the management of children of MEN2 and allowed surgical prediction and prophylaxis to take place. We discuss the role of genetic testing and possible guidelines for the management of patients from MTC families. The future appears full of promise and the current evaluation of RET-targeting tyrosine kinase and other inhibitors are of considerable interest in the management of these conditions     

Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in pediatric patients

Multiple endocrine neoplasia (MEN) 2B is a hereditary syndrome including medullary thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal (GI) disorders, marfanoid facies, and multiple ganglioneuromas. MTC is the major cause of mortality, and often appears during the 1st decade of life. RET proto-oncogene mutations are responsible for MEN 2B. Other RET mutations cause MEN 2A syndrome, familial MTC, or Hirschsprung's disease. We studied three MEN 2B patients with the aim of delineating the best diagnostic and therapeutic protocol. The gold standards for diagnosis are histochemical study of the rectal mucosa and molecular analysis of RET, which in familial cases detects MEN 2B at a preclinical stage so that early total prophylactic thyroidectomy can be performed. In non-familial cases, the diagnosis can be suggested by the presence of GI symptoms, ganglioneuromas, and/or the typical facies. The intestinal innervation pattern, analyzed with the acetylcholinesterase technique, is pathognomonic for MEN 2B. In our protocol a rectal biopsy is, therefore, the first measure. The surgical treatment of MEN 2B is total thyroidectomy with cervical lymphadenectomy of the central compartment of the neck. When possible, this intervention should be performed prophylactically before 1 year of age.     

Multiple endocrine neoplasia type 2 and sporadic medullary thyroid carcinoma: Turkish experience

Multiple endocrine neoplasia type 2 (MEN 2) is a rare autosomal dominantly inherited familial cancer syndrome caused by mutations in the ret proto-oncogene. MEN 2 has three distinct subtypes, which are MEN 2A, MEN 2B and familial medullary thyroid carcinoma. Identification of a disease gene has enabled a DNA-based strategy for detection of direct mutation in patients with MEN 2 syndromes and in patients with sporadic medullary thyroid carcinoma. The identification of mutations responsible for MEN 2 syndromes has resulted in the routine identification of gene carriers early in life before the development of disease, causing timely prophylactic thyroidectomy in these patients. This report includes our clinical and molecular experience on Turkish MEN 2 families and patients with sporadic medullary thyroid carcinoma diagnosed and treated between 1994 and 2005.     

RETMen2B-transgene Produces Sympathoadrenal Tumors But Does Not Prevent Intestinal Aganglionosis in gdnf−/− or gfrα-1−/− Mice

Multiple endocrine neoplasia type 2B (MEN2B) syndrome is caused by a missense mutation in the RET gene, which replaces Met918 by Thr in the intracellular kinase domain of the protein. This single amino acid substitution transforms the receptor into a constitutively active monomeric kinase (RET^Men2B) and produces an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies, and mucosal ganglioneuromas. The ligand, GDNF, stimulates RET activity through a co-receptor, GFRα-1. In vitro studies have shown that the kinase and mitogenic properties of RET^Men2B are enhanced by GDNF/GFRα-1 stimulation. A relevant clinical question is whether ablation of either GDNF or GFRα-1 could alter penetrance or severity of the MEN2B syndrome. We report that ganglioneuromatous tumors caused by a RET^Men2B transgene in mice are not affected grossly or microscopically by the absence of gdnf or gfrα-1. Loss-of-function mutations in ret, gdnf, or gfrα-1 cause pan-intestinal aganglionosis in mice. We find that expression of the RET^Men2B transgene in enteric neural progenitors, after they colonize the gut, does not prevent intestinal aganglionosis associated with gdnf or gfrα-1 deficiency. Received November 9, 2000; accepted January 9, 2001.     

The association between Hirschsprung’s disease and multiple endocrine neoplasia type 2a: a systematic review

Purpose

The co-occurrence of Hirschsprung’s disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a “Janus” mutation in the RET proto-oncogene––a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above.

Methods

A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a “Janus” RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS.

Results

The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a “Janus” mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a “Janus” mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease.

Conclusion

While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings re-inforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon.     

Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations

BACKGROUND: Paraganglioma (PGL) and phaeochromocytoma (PCC) are chemotherapy and radiation-resistant neuroendocrine tumors that arise from sympathetic tissue, and rarely occur in children. PCC may be associated with predisposing (germline) conditions like the multiple endocrine neoplasia type 2 (MEN2; OMIM 164761), von Hippel-Lindau syndrome (VHL; OMIM 193300), and rarely neurofibromatosis type 1 syndrome (NF1; OMIM 162200) and multiple endocrine neoplasia type 1 (MEN1; OMIM 131100). PGL, on the other hand, may be related to predisposing germline conditions like the familial PGL syndrome and the NF1 syndrome. In adult studies, one of the highest predisposing factors for germline mutation among patients presenting apparently sporadic PCC/PGL was their age at presentation. The aim of this study was to determine the rate of germline mutations among the rare patients presenting with sporadic PGL during childhood. PROCEDURE: In this study, we report the genetic analysis for predisposing conditions for the only three PGL cases retrospectively identified at our pediatric institution in the last 20 years. RESULTS: None had NF1 clinical associated lesions. Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene. We report a novel mutation, c.778 del C. Importantly, several non-symptomatic relatives were found to be carriers, thus ensuring them a clinical follow-up. CONCLUSION: According to our findings, PGL presenting during childhood represents an early manifestation of an adult disease caused by predisposing germline mutations. These results underline the importance of genetic studies in pediatric PGLs.     

Multiple endocrine neoplasia: paediatric perspective

Neuroendocrine tumours constitute a heterogeneous association of neoplasms, originated from a common precursor cell population. They include endocrine glands, such as the pituitary, the parathyroids, the cells of the neuroendocrine adrenals, endocrine islets within glandular tissue (thyroid, pancreas) and dispersed cells (diffuse endocrine system). Neuroendocrine tumours can occur sporadically or in a familial context, such as multiple endocrine neoplasia (MEN) syndromes. These are inherited autosomal dominant cancer syndromes, transmitted with 100% penetrance. They are categorized into MEN type 1 and type 2. The dream of each physician who treats cancer is to develop a strategy that will have a significantly favourable impact on morbidity and mortality associated with malignant tumours. This has been achieved as a result of improved screening and early treatment strategies in MEN. MEN 2 and medullary thyroid carcinoma (MTC) are of special relevance in childhood, because they require urgent and early diagnosis and treatment. The explication of the genetic basis of MTC has revolutionised management of the familial forms of this tumour.     

Multiple endocrine neoplasia type 2A in a kindred with C634Y mutation

Multiple endocrine neoplasia type 2A (MEN 2A) is most frequently caused by codon 634 activating mutations. Medullary thyroid carcinoma has occurred before the age of 2, with pheochromocytomas and primary hyperparathyroidism occurring later in childhood. We report cases of 4 siblings with C634Y-positive MEN 2A (all <11 years old): 3 with medullary thyroid carcinoma (1 had nodal metastasis, and another had a parathyroid adenoma) and 1 with C-cell hyperplasia.     

Multiple endokrine Neoplasie Typ 2 und medulläres Schilddrüsenkarzinom

Multiple endocrine neoplasia type 2 is a rare hereditary tumour syndrome characterised by the presence of medullary thyroid carcinoma, primary hyperparathyroidism, and bilateral pheochromocytoma in a single patient. The expression and penetrance of the different tumours is variable depending on the different mutations of the RET proto-oncogene—on one end of the spectrum, an aggressive medullary thyroid carcinoma can exist in a young child, and on the other end, an older individual might have a mild asymptomatic tumour. The specific RET mutation guides the timing of prophylactic thyroidectomy and the extent of surgery. Cure of hereditary medullary thyroid carcinoma is possible. Good cooperation among paediatrician, endocrinologist, geneticist, and surgeon is necessary when caring for families with a child with multiple endocrine neoplasia type 2.     

TheRET proto-oncogene: A challenge to our understanding of disease pathogenesis

RET gene alterations as disease-causative mutations have been demonstrated in five different disease entities: Hirschsprung's disease (HD); papillary thyroid carcinoma; and three types of inherited cancer syndromes: multiple endocrine neoplasia (MEN) 2A, MEN 213, and familial medullary thyroid carcinoma. RET is expressed during embryogenesis in a temporally and spatially regulated manner, and plays an important role in the normal development of a variety of cell lineages, particularly in the establishment of the enteric nervous system.RET mutations observed in patients with HD are scattered along the gene without any hot spots, and possess a loss-of-function effect.RET mutations are detected with a higher incidence among familial cases (50%) than sporadic cases (15%–20%), and are more closely associated with long-segment HD than short-segment disease. In contrast to HD mutations, missense mutations observed in MEN 2 syndromes occur at specific codons, and gene rearrangements are characteristic in papillary thyroid carcinoma. Both missense mutations and gene rearrangements act in a dominant fashion, and cause constitutive phosphorylation on the tyrosine of RET and highly enhance RET kinase activity, leading to transforming or oncogenic activity.     

A concise genetic and clinical guide to multiple endocrine neoplasias and related syndromes

Several familial neoplastic syndromes are associated with endocrine gland oncogenesis. The main ones are: multiple endocrine neoplasia type 1 (MEN 1), which affects primarily the pituitary, pancreas, and parathyroid glands; MEN 2A and MEN 2B, which involve mainly the thyroid and parathyroid glands and the adrenal medulla; familial medullary thyroid carcinoma (FMTC), which affects only the thyroid gland; and, finally, Carney complex, which affects the adrenal cortex, pituitary, thyroid gland, and the gonads. Carney complex is also associated with pigmentation abnormalities and myxoid and other neoplasms of mesenchymal origin. Thus, this syndrome also belongs to another group of genetic disorders, those associated with pigmentation defects and multiple tumors, including tumors of the endocrine glands. Peutz-Jeghers syndrome and Cowden disease are just two of these disorders that have recently been elucidated at the molecular level. von Hippel-Lindau disease is another condition that affects the pancreas and adrenal medulla and its gene is also known. The inheritance of the MENs, Carney complex, and related syndromes is autosomal dominant. Clinical recognition of these syndromes at a young age improves clinical outcome and prognosis of the various tumors and decreases associated morbidity and mortality. This review considers a wider, more inclusive view of the MEN syndromes, summarizes their clinical features and presents the newest information on their molecular elucidation.     

Different expression of the Asn264LysfsX35 mutation of the GNAS gene in a family with pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine diseases characterised by hypocalcaemia, hyperphosphataemia and resistance to PTH. There are different forms of PHP. PHP-Ia is the most frequent form and shows multi-hormonal resistance, GNAS (Gs_α) mutations and signs of Albright?s hereditary osteodystrophy (AHO). PseudoPHP (PPHP) have isolated AHO without hormonal resistance and it is also caused by GNAS mutations. We present a family that share the same inactivating GNAS mutation (Asn264LysfsX35); the mother being affected with PPHP and the two daughters with PHP-Ia. We discuss the different clinical phenotypes and the dominant mode of inheritance with genetic imprinting where the phenotype of the offspring depends on the sex of the parent affected.     

The contribution of associated congenital anomalies in understanding Hirschsprung’s disease

Hirschsprung’s disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5–32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene–gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down’s syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20–25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential “modifying” associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.     

Orolabial signs are important clues for diagnosis of the rare endocrine syndrome MEN 2B. Presentation of two unrelated cases

Multiple endocrine neoplasia syndromes (MEN) are genetic disorders with glandular hyperplasia and consecutive malignant neoplasia. MEN type 2B is the least common form of these tumor syndromes. It presents with typical dysmorphic features, mucosal neuromas, ganglioneuromatosis, medullary thyroid carcinoma (MTC) and phaeochromocytoma. The prognosis depends on the presence of MTC. We have surprisingly found two unrelated patients with this syndrome at our department within two weeks. In the medical history of a 17-year-old boy, Crohn’s disease had been considered because of abdominal pain and distention. He had marfanoid appearance and previously undergone minor surgeries for a large tongue with neuromas and hypertrophic gums. Two weeks later, a 10-year-old girl presented with a hard palpable mass on her neck. She had thickened lips, neuromas on the tongue and a solitary thyroid nodule. Genetic analysis was carried out in both patients and a heterozygous M918T mutation of the RET proto-oncogene was found. Laboratory tests and imaging studies were consistent with MTC. Phaeochromocytoma was not present. Both patients underwent total thyroidectomy and lymph node dissection. Histological examination confirmed the diagnosis of MTC. In conclusion, the initial diagnosis of MEN 2B should be suspected on the presence of typical facial/oral signs and gastrointestinal symptoms. Hormonal tests and imaging techniques of the thyroid and the adrenals can confirm the clinical diagnosis of MEN 2B and genetic analysis can prove its germline origin.     

Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema,hypsarrhythmia and optic atrophy may be allelic syndromes

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations.Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome.In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers.The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.     

Sporadic phaeochromocytoma in childhood: clinical and molecular variability

Sporadic phaeochromocytoma is an infrequent tumour during paediatric age and may or may not be associated with specific autosomal dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL) type 2 or neurofibromatosis (NF) type 1. We report two cases of benign, adrenal, and unilateral phaeochromocytoma that clearly demonstrate the clinical and molecular heterogeneity of this disease during the paediatric period. The first patient presented a characteristic symptomatic form of sporadic phaeochromocytoma. The second patient, an incidental finding, was practically asymptomatic and had a de novo germline point mutation in the VHL gene (Arg167Trp). The frequency of de novo mutations in susceptible genes (especially the VHL gene) in paediatric patients with sporadic phaeochromocytoma and the elevated mortality of these cancer syndromes suggest that screening for mutations should be performed even in cases of non-familial sporadic phaeochromocytoma.     

Cholesterol Side-Chain Cleavage Enzyme (SCC) Deficiency

Cholesterol side-chain cleavage enzyme (SCC) catalyzes the conversion of cholesterol to pregnenolone, the first step in the biosynthesis of all steroid hormones. It was once postulated that SCC deficiency would be lethal, but recent studies have established that SCC deficiency is an autosomal recessive disorder caused by inactivating mutations in the CYP11A1 gene. Clinical manifestations include adrenal insufficiency and 46,XY sex reversal due to disrupted steroidogenesis, which are similar to StAR deficiency. Further accumulation of patients with SCC deficiency should clarify the similarities and differences between SCC deficiency and StAR deficiency.     

Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood

A 12-year-old boy with tuberous sclerosis complex (TSC) presented with a large retroperitoneal tumour. Exploratory surgery revealed an infiltrative tumour originating from the pancreas, with local metastases to the lymph nodes. The histologal diagnosis was a malignant islet cell tumour. Retrospectively measured pancreatic hormone levels, however, were normal. A connection between the malignancy and TSC was demonstrated by loss of heterozygosity of the TSC2 gene in the tumour. The primary mutation Q478X in this patient was identified in exon 13 of the TSC2 gene on chromosome 16. Conclusion Pancreatic islet cell tumours have been mainly associated with multiple endocrine neoplasia syndrome type 1. In our case we demonstrate a direct relationship of this tumour to tuberous sclerosis complex, in the absence of further signs of multiple endocrine neoplasia syndrome type 1. Received: 17 February 1998 / Accepted in revised form: 8 July 1998     

Monogene Ursachen des nephrotischen Syndroms

Steroid-resistant nephrotic syndrome (SRNS) represents a frequent cause of end-stage renal disease in children. Renal histology shows focal segmental glomerulosclerosis in about 80% of cases. Recently, it became apparent that up to 28% of all cases of childhood nephrotic syndrome are caused by recessive mutations of podocin (NPHS2). Additional monogenic causes are mutations of nephrin (NPHS1), WT1, PLCE1, or LAMB2. The related gene products are expressed in the glomerular podocyte and are essential for development and maintenance of the glomerular filtration barrier. These genetic insights have led to a better understanding of the pathogenesis of SRNS and will allow for unequivocal molecular genetic diagnostics and for stratification in therapeutic studies.     

Phaeochromocytoma associated with a de novo VHL mutation as form fruste of von Hippel-Lindau disease

 Phaeochromocytomas usually occur sporadically but may be associated with dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL) and type 1 neurofibromatosis. We report on a boy presenting at age 8 years with an isolated benign phaeochromocytoma of the left adrenal. Three years later a second adrenal phaeochromocytoma was diagnosed on the right side and removed. His family history was negative. Genetic analysis did not show a mutation in the MEN 2 susceptible proto-oncogene rearranged during transfection; however, we found a germline missense mutation in the VHL gene (nucleotide 695 G to A transversion) which has been described only twice before in the literature. Both parents had normal (wild type) VHL copies indicating that our patient had a de novo germline VHL mutation. Careful clinical evaluation of the patient at 18 years did not reveal any other manifestations of VHL disease. Conclusion Carriers of von Hippel-Lindau germline mutations can present with a form fruste of von Hippel-Lindau disease presenting initially with unilateral phaeo-chromocytoma and therefore mutation analysis should be carried out. Received: 21 June 2000 and in revised form: 18 February 2001 / Accepted: 20 February 2001