Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031511 (pheochromocytoma)
 14,622 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The members of four generations of a family with Von Hippel-Lindau syndrome (VHL) have been followed by one of us (I.P.) for 30 years. The disease was proved in four members of this family, in three of them associated with pheochromocytoma. The grandmother (I-1) died at the age of 16 years two months after her first birth. The cause of death was not established. Her daughter (II-1) had 9 births with 5 children alive. Paresthesia and difficulties in walking followed by paraparesis and paraplegia were the first signs of the disease at the age of 58 years. The surgical treatment was performed because of an expansive lesion at the level of Th 3-4. Pathohistological examination was not done. It seems that a haemangioblastoma might be the cause of her disease. Diagnosis of pheochromocytoma was documented in a female patient (III-2) in 1972. Two years later she was successfully operated on. Pathohistological examination proved clinical diagnosis. She had also diabetes mellitus, cholelithiasis and cardiomyopathy. She died at the age of 56 years. A right-sided pheochromocytoma was diagnosed in a next female patient (III-4) at the age of 22 years. Her surgical treatment was successful. Retinal haemangioblastomatosis was established 7 years later in this patient. She was blind at the end of her life. Haemangioblastomatosis cerebelli was diagnosed soon, and she died at the age of 51 years. A 12- year old boy (IV-3) presented severe hypertension (36/24 kPa). Left-sided pheochromocytoma was removed in this patient one year later. Right-sided pheochromocytoma was operated on in the same patient at the age of 24 years. An elevated level of urinary dopamine was documented four years after the second operation. A malignant right-sided pheochromocytoma was operated on in the same patient 15 years later. At the same time metastases were found in the lower part of the right lung lobe. A 131-I-MIBG therapy could not be realized. He died at the age of 41. Pathohistological examinations proved the clinical diagnosis in this patient after all of three surgical treatments. MEN 2 syndrome was excluded by proper genetical analyses on the RET-protooncogen. Genetical analyses are in the course to identify the possible mutations of VHL-tumour-suppressor gene through the living members of the family. Multidisciplinary approach is mandatory in diagnosis, follow up and treatment of this specific group of patients. A collaboration among specialists of different fields of medicine (internal medicine, ophthalmology, neurology, radiology, urology, neurosurgery, biochemistry, pathology and genetics) is suggested.
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PMID:[The von Hippel-Lindau syndrome with pheochromocytoma]. 1258 97

Molecular oncogenetics is the study of two distinct gene classes participating in the pathogenesis of malignant diseases: proto-oncogenes and tumour suppressors genes. Stepwise alterations in their structure are the basis of malignancy. Structural abnormalities range widely: gross genetic rearrangements including insertions, deletions, gene amplifications and single nucleotide deleotide deletions and substitutions. These gene alterations are determined by gene testing that increasingly are part of clinical diagnosis. Among many applications of oncogene testing is detection of hereditary forms of malignant disease with outstanding prophylactic and therapeutic importance. Along this line, gene testing provided for effective prevention of specific hereditary tumour types. Analysis of hereditary pheochromocytoma two gene tests are established: detection of multiple endocrine neoplasia type 2 (MEN 2) using mutational analysis of RET gene and detection of von Hippel-Lindau syndrome using mutational analysis of VHL gene. These genes were characterized about a decade ago and their structure determined in detail. Numerous studies focus on expression of these genes in different tissues and the function of respective proteins. In extensive epidemiology the following facts are established: hereditary mutations in the RET gene in > 92% of cases with MEN 2 syndrome while in patients with von Hippel-Lindau syndrome hereditary mutations were detected in VHL gene in > 95% of cases. Such a high genotype--phenotype correlation forms the basis for clinical applications. Gene testing in oncology offers numerous advantages. If a patient with pheochromocytoma presents with hereditary mutation in the RET or VHL gene, family gene testing is recommended. Family member with hereditary gene mutation is indicative of the risk level of nearly 100% for MEN 2 or von Hippel-Lindau syndrome. In such cases surgery is warranted (e.g. in MEN 2 total thyroidectomy by the age of (6). Negative findings in this type of gene testing relive family members from enormous psychological tension and provide them with normal family planning. There are many reasons to believe that this type of gene testing is the foundation of diagnosis for the 3rd millennium. Namely, results of gene testing may provide basis for effective prevention: mutations causative for a disease may be detected, presymptomatically and prenatally; the analysis requires only couple of mL of blood, and mutational status is determined only once in a lifetime.
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PMID:[Genetic tests in oncology practice with emphasis on the RET oncogene and VHL tumor suppressor gene]. 1258 99

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are characterized by development of medullary thyroid carcinoma (MTC) and caused by germline RET mutations. Patients with MEN 2A also develop pheochromocytoma and/or hyperparathyroidism (HPT). However, MEN 2A-affected individuals could display the FMTC phenotype at first clinical manifestation. To establish the correct phenotype and improve clinical management of patients affected by hereditary MTC, clinical screening, RET mutational analysis, penetrance of MTC, and genotype-phenotype correlation were performed in a large, suspected FMTC kindred of 86 individuals. Germline C634Y RET mutation was confirmed in 22 individuals, 15 of whom were thyroidectomized when high serum calcitonin levels were detected. MTC was confirmed in 12 individuals and C-cell hyperplasia in 3. HPT was detected in two patients. High penetrance of MTC at young age (79% at 30 yr of age) was found. This family was considered to be affected by FMTC for several years because MTC was the sole clinical manifestation. However, our results allowed reclassifying the family as MEN 2A, thereby improving clinical management of family members. Our findings regarding penetrance and genotype-phenotype correlation suggest that patients considered to have FMTC may in fact have MEN 2A in some kindreds.
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PMID:Penetrance of inherited medullary thyroid carcinoma and genotype-phenotype correlation in a large multiple endocrine neoplasia type 2A family with C634Y RET mutation. 1274 65

The spectrum of mutations of the RET protooncogene was analyzed in Russian patients with inherited or sporadic medullary thyroid carcinoma (MTC). Four RET exons (11, 13, 15, and 16) were subjected to molecular analysis, and mutations were revealed and identified in 47.4% (9/19) patients with sporadic MTC. In total, six mutations (including three new ones) were observed. The most common mutation affected codon 918 to cause substitution of methionine with threonine and accounted for 31.6% alleles. Analysis of exons 11 and 16 revealed four mutations in patients with inherited multiple endocrine neoplasia type 2 (MEN 2). Mutations were found in each patient. Thyroidectomy was performed in four asymptomatic carriers of RET mutations from three MET 2A families (in two families, affected relatives had bilateral pheochromocytoma). In two patients, analysis of the surgery material revealed MTC microfoci in both lobes of the thyroid gland. The results provide the ground for constructing a bank of genetic information on Russian MTC patients with the clinically verified diagnosis.
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PMID:[Analysis of mutations in the RET proto-oncogene in patients with medullary thyroid tumor]. 1288 27

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
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PMID:Pheochromocytoma: the expanding genetic differential diagnosis. 1292 44

Standard cytogenetic data are reported for benign and malignant thyroid and pituitary tumors. These identified chromosomal rearrangements activating RET and PPAR gamma 1 in a subset of papillary (PTCs) and follicular thyroid carcinomas (FTCs) and amplification of PKC epsilon in FTCs. Increases in complex karyotypes accompany progression in thyroid lesions. For pituitary tumors, karyotypic abnormalities more often affect functioning than nonfunctioning tumors. Such differences extend into comparative genomic hybridization (CGH), with a similar distribution for chromosomal imbalances. CGH data are reported on all varieties of endocrine tumors, supporting some cytogenetic findings and adding new hotspots for genomic imbalances. Increases in genomic imbalance accompany clinical progression in malignant thyroid tumors, adult adrenocortical tumors, parathyroid tumors, and some pancreatic endocrine tumors (PETs), e.g., insulinomas. Pheochromocytoma and FTC show more losses than gains. Specific patterns of imbalances are emerging for gastrointestinal PETs regarding location and hormone status; for pheochromocytomas, medullary thyroid carcinomas, and parathyroid tumors regarding genetic syndrome association; and for pituitary tumors regarding hormone status.
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PMID:Standard and molecular cytogenetics of endocrine tumors. 1295 42

Medullary thyroid carcinoma (MTC) rarely causes ectopic ACTH syndrome. We describe a 38-yr-old man with renal stones who had a 5-cm MTC removed in 1992. He was RET-protooncogene positive (codon 618). Serum calcitonin was 1597 pg/ml postoperatively. In 1996 he had rib fractures, bruising, weakness, and three to four stools per day. Laboratory studies revealed an elevated 24-h urine-free cortisol (780 micro g/d), epinephrine (66 micro g/d), and calcium (558 mg/d). Baseline serum cortisol was 23.9 micro g/dl and decreased to 12.9 and 4.5 micro g/dl after 2 mg and 8 mg dexamethasone suppression, respectively. Plasma ACTH was 170 pg/ml and decreased to 75 and 24 pg/ml after dexamethasone. Bone density t-score was -4.3 (trochanter). Computed tomography scans showed multiple cervical nodes and 2-cm right adrenal nodule. Magnetic resonance imaging (MRI) scan showed a prominent, homogeneous pituitary; the adrenal MRI scan was not typical for a pheochromocytoma. Serum CRH was less than 6.6 pg/ml. Bilateral adrenalectomy revealed two adjacent right adrenal pheochromocytomas and corrected the elevated urine cortisol (30 micro g/d), epinephrine (0 micro g/d), and calcium (281 mg/d) but not plasma ACTH (125 pg/ml). Neck dissection reduced calcitonin by 96% (5300 to 120 pg/ml) and ACTH by 91% (125 to 11 pg/ml). Carcinoembryonic antigen was reduced from 32.0 to 2.3 ng/ml. Immunohistochemical stain was negative for ACTH in the MTC-positive lymph nodes and the pheochromocytoma. Proopiomelanocortin mRNA by in situ hybridization was positive in the MTC but not in the pheochromocytoma. A repeat pituitary MRI scan was normal. The differential diagnosis of ACTH-dependent Cushing's syndrome in this case included pituitary disease or ectopic ACTH, either from medullary thyroid carcinoma or pheochromocytoma. ACTH stains were unrevealing, but proopiomelanocortin mRNA in situ hybridization in MTC tissue and plasma ACTH response to neck dissection confirmed MTC as the source of ectopic ACTH.
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PMID:Cushing's syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. 1455 23

Approximately 75% of pheochromocytomas are sporadic. Germline mutations in RET, VHL, SDHB, and SDHD have been shown to cause the 25% that are hereditary. Germline high penetrance gain-of-function RET mutations cause multiple endocrine neoplasia type 2, of which medullary thyroid carcinoma (MTC) and pheochromocytoma are components, whereas loss-of-function mutations cause Hirschprung disease (HSCR). A low-penetrance founder locus, in linkage disequilibrium with a RET ancestral haplotype comprising specific alleles at three intron (IVS) 1 single nucleotide polymorphisms (SNPs) (haplotype 0) and SNP A45A, predisposes to the majority of isolated HSCR. A different low-penetrance locus, in linkage disequilibrium with IVS 1 haplotype 2 and SNP S836S, was associated with a subset of sporadic MTC. We, therefore, sought to determine whether RET might also be a low-penetrance gene for apparently sporadic pheochromocytoma. We analyzed 104 pheochromocytoma cases without germline mutations in RET, VHL, SDHD, and SDHB for their status at A45, S836, three IVS 1 SNPs, and a novel upstream insertion/deletion variant. Pheochromocytoma cases were not associated with either A45A or S836S, but we found that cases were associated with haplotype 0 (P = 0.032). However, unlike HSCR, this pheochromocytoma-associated haplotype 0 was not associated with A45A. Taken together with the strengthening of association with the addition of the 5' insertion/deletion variant data (P = 0.016), our observations suggest the presence of a low-penetrance pheochromocytoma susceptibility locus in a region upstream of the putative loci for HSCR and apparently sporadic MTC.
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PMID:Intronic single nucleotide polymorphisms in the RET protooncogene are associated with a subset of apparently sporadic pheochromocytoma and may modulate age of onset. 1455 73

Multiple endocrine neoplasia Type 2 is a rare familial cancer syndrome transmitted in an autosomal dominant manner. It is characterized by the association of medullary thyroid carcinoma with pheochromocytoma and hyperparathyroidism. Medullary thyroid carcinoma, present in virtually all patients, is the principal cause of death. In 1993, germline mutations in the RET proto-oncogene were identified as the underlying cause of the syndrome. Genetic screening of at-risk family members can now be performed with high specificity and sensitivity. The ability to determine gene carrier status at a preclinical stage is of great value as it allows early prophylactic thyroidectomy. The specific RET codon mutation correlates with clinical variants of the syndrome, age at onset and aggressiveness of medullary thyroid carcinoma. This review will focus on mutational spectrum, genotype-phenotype correlations and clinical decisions based on genetic information.
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PMID:Molecular diagnosis of multiple endocrine neoplasia Type 2. 1462 4

Until very recently, the majority of hereditary pheochromocytomas were related to the MEN 2 and the VHL. In rare instances, hereditary pheochromocytoma was reported in patients with NF1. In addition, nonsyndromic hereditary pheochromocytomas have been reported. Recently, three more genes (SDHD, SDHB, and SDHC) which are all related subunits of the mitochondrial complex II have been identified to cause susceptibility to pheochromocytoma and/or paraganglioma. Hence, mutation analysis of VHL, RET, SDHB, and SDHD is generally recommended in patients with pheochromocytoma regardless of their family history or other features suggestive for a hereditary form. Mutation analysis should start with VHL and RET. However, in the presence of extra-adrenal pheochromocytoma, it may be more useful to screen for VHL, SDHD and SDHB mutations. It is of interest that various different genes can lead to one type of tumor formation. A common pathway (i.e. oxygen sensing) has been shown for VHL and SDHX. However, although several genes that are involved in the pathogenesis of hereditary pheochromocytoma are known, the precise molecular steps in tumorigenesis are widely unknown. In addition, recent data in MEN 2 pheochromocytomas point to a 'second hit' mechanism as a trigger for tumor formation. The molecular pathogenesis of sporadic pheochromocytomas remains obscure [114].
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PMID:The genetic basis of pheochromocytoma. 1467 4


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