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.     

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     

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.     

Phaeochromocytoma in children

Phaeochromocytoma is a rare clinical entity in children. Contrary to traditional teaching, which suggested that 10% of phaeochromocytomas are "familial", a germline mutation has been identified in up to 59% (27/48) of apparently sporadic phaeochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline mutation in the Von Hippel-Lindau gene, the genes encoding the subunits B and D of succinate dehydrogenase, the RET proto-oncogene predisposing to multiple endocrine neoplasia type 2, or the neurofibromatosis type 1 gene. Of these, the Von Hippel-Lindau gene is the most commonly mutated gene in children presenting with a phaeochromocytoma. Genetic counselling is recommended before gene testing and investigation of the wider family. This review provides guidance on the aetiology, investigation, management, histopathology, genetics and follow-up of children with a phaeochromocytoma.     

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.     

Importance of early diagnosis and follow-up in multiple endocrine neoplasia (MEN II B)

Three patients with a sporadic form of multiple endocrine neoplasia (MEN) IIb are presented. MEN IIb is the association of medullary carcinoma of the thyroid (MTC), pheochromocytoma and multiple mucosal neuromata.The age at diagnosis and primary therapy of MTC was relatively late (8, 16, 18 years) although thyroid enlargement (two cases), typical marfanoid habitus (two cases) or multiple mucosal neuromata (one case) had been evident since early childhood. The diagnosis was confirmed by measurements of tumour markers like calcitonin (CT) and carcinoembryonic antigen (CEA) for MTC, measurements of vanillylmandelic acid for pheochromocytoma, evaluation of the thyroid gland by sonography, scintigraphy and fine needle biopsy, and investigation of the adrenals by computer tomography and meta-(I-131) iodobenzylguanidine (I-131-MIBG) scintigraphy.After surgical treatment determinations of tumour markers confirmed relapses of MTC in all cases.Early diagnosis of MEN IIb, which could be made by recognition of the typical clinical appearance, is of special importance because of the poor prognosis of MTC.Abbreviations MEN Multiple endocrine neoplasia - MTC medullary carcinoma of the thyroid - CT calcitonin - CEA carcinoembryonic antigen - VMA vanillylmandelic acid - I-131 MIBG meta (I-131) iodobenzylguanidine - MMN multiple mucosal neuroma syndrome     

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.     

Medullary Thyroid Carcinoma in Children

The vast majority of medullary thyroid carcinomas (MTC) in children are inherited as part of the multiple endocrine neoplasia (MEN) syndromes MEN2A and MEN2B, and the related variant, familial MTC. Prophylactic surgery in infants and children identified through genetic screening leads to the highest survival in these patients. This article summarizes the current recommendations for screening, treatment, and surveillance of children with MTC to provide a concise clinically relevant review for pediatric practitioners.     

Multiple endocrine neoplasia type 2b (MEN 2b). Report of 2 pediatric cases

Two new sporadic cases of multiple endocrine neoplasia type 2b (MEN 2b) are described. Both patients were diagnosed in pediatric age and presented the characteristic features of the syndrome (facies "sui generis", Marfanoid habitus, mucosal neuromas, history of chronic gastrointestinal disturbances) and developed medullary thyroid carcinoma (MTC). In the former case, metastatic neck adenopathies were the first sign by which the disease was recognized. Antitumor treatment consisted of total thyroidectomy, cervical node dissection, administration of I131 and neck irradiation. This patient is alive and well 20 months from diagnosis, still having high serum levels of thyrocalcitonin (TC). In the latter case, the syndrome was diagnosed on clinical grounds before the development of a MTC. The patient was then strictly followed-up and thyroidectomy performed only when serum TC levels rose to abnormally high values: no tumor spread was documented at that time. She is alive and well 4 years from diagnosis.--Early recognition of MEN 2b syndrome is necessary in order to detect and properly treat MTC.     

Multiple endocrine neoplasia (MEN) syndromes

Multiple endocrine neoplasia (MEN) syndromes are characterised by the combined occurrence of two or more endocrine tumours in a patient. These autosomal dominant conditions occur in four types: MEN1 due to inactivating MEN1 mutations; MEN2A and MEN2B (MEN3) due to activating mutations of RET and MEN4 due to inactivating cyclin-dependent kinase inhibitor 1B (CDKN1B) mutations. Each MEN syndrome exhibits different combinations of pancreatic islet, anterior pituitary, parathyroid, medullary thyroid and adrenal tumours. This article provides an overview of the clinical features, treatments and molecular genetics of each endocrine tumour syndrome.     

Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, accounts for 3% of childhood malignancies. Multiple Endocrine Neoplasia (MEN) type 2A is an autosomal dominant syndrome associated with near universal development of medullary thyroid carcinoma. We describe a previously unreported association of MEN‐2A with metastatic alveolar RMS and review the literature on associated hereditary cancer predisposition syndromes and current therapeutic options. The high penetrance of malignancy in patients with MEN warrants a heightened suspicion for the development of nonendocrine malignancies. The diagnosis of RMS should prompt consideration of screening for familial genetic syndromes in certain patients. Pediatr Blood Cancer. 2010;55:1213–1216. © 2010 Wiley‐Liss, Inc.     

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 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 endocrine neoplasia type 2B diagnosed on suction rectal biopsy in infancy: a report of 2 cases.

Suction rectal biopsies in a newborn and a 10-month-old infant presenting with intestinal obstruction showed marked increase in neurons and nerve bundles in the submucosa. Although there were no syndromic features or a positive family history, mutation analysis of the RET proto-oncogene showed a de novo germline Met918Thr mutation in both patients, confirming the diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). Thyroidectomy was performed at 9 and 14 months, showing medullary carcinoma and focal prominent C-cell hyperplasia, respectively. These 2 cases are presented to emphasize that when the submucosal plexus is obviously and prominently increased in suction rectal biopsies, diffuse intestinal ganglioneuromatosis should be considered. As this can be associated with genetic conditions, especially MEN 2B, it is crucial that further investigations be performed to ensure proper patient management, such as early thyroidectomy.     

Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma

Hepatoblastoma is the most common primary liver tumor in childhood and occurs more commonly in families with familial adenomatous polyposis. Germline mutations of the gene responsible for familial adenomatous polyposis--adenomatous polyposis coli (APC)--are described in patients with hepatoblastoma even without a family history. We investigated children presenting with apparently sporadic hepatoblastoma between 1991 and 2004. Blood samples were available from 29 children (18 boys) whose conditions were diagnosed at a median age of 22 months (range 6-119 months). No germline APC mutations were found, which does not support the need for routine screening in sporadic hepatoblastoma in the absence of a suggestive family history of colorectal cancer or suspicion of familial adenomatous polyposis.     

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.     

Dominantly inherited isolated hyperparathyroidism: a syndromic association?

Dominantly inherited isolated hyperparathyroidism (DIIH) is rare in childhood. It may be the first biochemical abnormality in the multiple endocrine neoplasia type I (MEN I) and type II (MEN II) syndromes. Its clinical course is usually asymptomatic or of low morbidity. Radiographic examination is most often normal. We describe six members of a family with distinctive phenotype and DIIH. Limited systemic symptoms and severe radiographic osteitis fibrosa cystica were further unusual features in this family. The diagnosis of DIIH was made only after a 9-year-old girl developed hypercalcaemic crisis after a pathological femoral fracture. Distinctive phenotype, unusual clinical course and unparalleled radiographic changes suggest a not yet described syndromic association. Received: 10 March 1998 Accepted: 25 May 1998     

Paediatric presentation of type 2 neurofibromatosis.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a highly penetrant autosomal dominant condition predisposing affected individuals to schwannomas and meningiomas. The proportion of children presenting with meningioma or schwannoma who have NF2 is not well described, and neither is the mode of presentation in most children with the inherited disease. AIMS: To determine the frequency of childhood meningioma and schwannoma cases caused by NF2 and the mode of presentation. METHODS: The records of the Manchester Children's Tumour Registry from 1954 were searched for cases of meningioma and schwannoma. Paediatric presentation in a large UK series of NF2 was also studied. RESULTS: 18% (61/334) of patients with NF2 on the UK database presented in the paediatric age group (0-15 years), frequently with the symptoms of an isolated tumour. More than half had no family history to alert the clinician to their susceptibility. Three of 22 children presenting with a meningioma on the Manchester Children's Tumour Registry have gone on to develop classic features of NF2. CONCLUSIONS: Clinicians should suspect NF2 in children presenting with meningioma, schwannoma, and skin features, such as neurofibromas/schwannomas, but fewer than 6 café au lait patches, who thus fall short of a diagnosis of neurofibromatosis type 1.     

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.