OBJECTIVE: To explore the pathological characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A) with cutaneous lichen amyloidosis (CLA). METHODS: Clinical data of 51 members from 7 unrelated pedigrees of MEN2A-CLA were collected. Systemic clinical investigations including biochemical testing, imaging examination, germline RET variant screening and histopathological examination were carried out. RESULTS: RET gene variants were detected in 28 patients with MEN2A (C634G/F/R/S/W and C611Y) including 12 males and 16 females, with the mean age of diagnosis being (41.1 ± 18.3) years old, which were consistent with their clinical manifestations. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), hyperparathyroidism (HPTH) and CLA among 28 MEN2A patients were 89.3%, 28.6%, 7.1% and 28.6%, respectively. Comparison of the incidence of MTC/PHEO/HPTH and CLA between C611Y and C634G/F/R/S/W, only PHEO and CLA in C611Y were lower than those in C634G/F/R/S/W (P < 0.05; P < 0.05). Among 8 patients with CLA, the male to female ratio was 2 : 6. The clinical features included pruritus in the interscapular region and presence of dry, thickened, scaly, brown pigment, clustered or desquamate-like plaques. The mean onset age of CLA [(18.4 ± 4.6) years] versus the mean age at diagnosis of CLA or MEN2A were significantly different (P < 0.001; P < 0.001). CONCLUSION MEN2A-CLA may be the early clinical manifestation of MEN2A and most frequently occurred along with RET-C634 variant. To facilitate the recognition of MEN2A-CLA, to combine family investigation and screening of RET variant are helpful for early diagnosis and standardized treatment, which can improve the long-term outcome of MEN2A-specific tumors.
Adolescent ; Adrenal Gland Neoplasms ; Adult ; Amyloidosis, Familial ; Carcinoma, Neuroendocrine ; China ; Female ; Humans ; Lichens ; Male ; Middle Aged ; Multiple Endocrine Neoplasia Type 2a/genetics* ; Pheochromocytoma ; Proto-Oncogene Proteins c-ret/genetics* ; Skin Diseases, Genetic ; Thyroid Neoplasms/genetics* ; Young Adult

OBJECTIVE: To analyze the germline variations of genes RET, VHL, SDHD and SDHB in patients with pheochromocytoma and/or paraganglioma and to evaluate variations of these genes in Chinese patients. METHODS: Patients who were treated in Peking University First Hospital from September 2012 to March 2014 and diagnosed with pheochromocytoma and/or paraganglioma by pathologists were included in this study. Twelve patients were included in total, of whom 11 had pheochromocytoma, and 1 had paraganglioma. Deoxyribonucleic acid (DNA) was extracted from the leukocytes of peripheral blood of the patients. The exons 10, 11, 13-16 of the RET gene, and all exons of VHL, SDHB and SDHD genes and their nearby introns (±20 bp) were amplified with polymerase chain reactions, and the products were sent to a biotechnology company for sequencing. The sequencing results were compared with wildtype sequences of these genes to identify variations. One of the patients was diagnosed with multiple endocrine neoplasia type 2A. A family analysis was performed in his kindred, and his family members received genetic tests for the related variations. RESULTS: Three patients were found to have germline gene variations. A c.136C>T (p.R46X) variation of the SDHB gene was found in a patient with malignant pheochromocytoma. A c.1901G>A (C634Y) variation, as well as c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were found in a patient with multiple endocrine neoplasia type 2A. After a family analysis, five family members of this patient were found to have the same variations. c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were also found in a clinical sporadic patient without evidence of malignancy. A patient with congenital single ventricle malformation and pheochromocytoma was included in this study, and no variation with clinical significance was found in the four genes of this patient. CONCLUSION 25% (3/12) patients with pheochromocytoma or paraganglioma were found to have missense or nonsense germline gene variations in this study, including the c.136C>T (p.R46X) variation of the SDHB gene, the c.1901G>A (C634Y) variation of the RET gene, and c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene. The former two variations have already been confirmed to be pathogenic. The existence of these variations in Chinese patients with pheochromocytoma and/or paraganglioma was validated in this study, which supports the conclusion that genetic testing is necessary to be generally performed in patients with pheochromocytoma and/or paraganglioma.
Adrenal Gland Neoplasms/genetics* ; Genetic Testing ; Germ-Line Mutation ; Humans ; Paraganglioma/genetics* ; Pheochromocytoma/genetics* ; Proto-Oncogene Proteins c-ret/genetics* ; Succinate Dehydrogenase/genetics* ; Von Hippel-Lindau Tumor Suppressor Protein/genetics*

OBJECTIVETo investigate the clinical features and mutations of RET proto-oncogene in a pedigree affected with multiple endocrine neoplasia type 2A (MEN2A).

METHODSClinical data of the family members was collected. Genomic DNA from peripheral blood leukocytes were extracted and subjected to PCR amplification. Exons 8, 10, 11, 13, 14, 15, 16 of the RET gene was sequenced.

RESULTSA missense mutation p.C634W was detected in 8 members from the family. Among them, 3 were diagnosed with pheochromocytoma, 1 with medullary thyroid carcinoma, 1 with medullary thyroid carcinoma and pheochromocytoma, 1 with medullary thyroid carcinoma and hyperparathyroidism. One member was found with thyroid enlargement but refused further examination, and another one was identified as carrier of the RET gene mutation.

CONCLUSIONA p.C634W mutation has been detected in a family affected with MEN2A, in which most carriers have developed clinical symptoms. RET mutation detection should be routinely performed for families affected with MEN2A.

Adult ; Aged ; Base Sequence ; Carcinoma, Medullary ; genetics ; Carcinoma, Neuroendocrine ; genetics ; Child ; Child, Preschool ; Exons ; genetics ; Family Health ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; Male ; Middle Aged ; Multiple Endocrine Neoplasia Type 2a ; genetics ; Mutation, Missense ; Pedigree ; Pheochromocytoma ; genetics ; Proto-Oncogene Proteins c-ret ; genetics ; Sequence Analysis, DNA ; methods ; Thyroid Neoplasms ; genetics

Pheochromocytoma is a tumor derived from chromaffin tissue in the adrenergic system with excessive secretion of catecholamine.Pheochromocytoma occurs at any age of patients,commonly in 40-60 years,and the incidence is slightly higher in women than in men.In recent years,studies have shown that the mutations of von Hippel-Lindau gene (VHL),rearranged during transfection gene (RET),neurofibromatosis type 1 gene (NF-1),succinate dehydrogenase gene (SDH),transmembrane protein 127 gene (TMEM127),myelocytomatosis oncogene-associated factor X gene (MAX) are associated with pheochromocytoma.Immunohistochemical studies have revealed that a number of molecular markers,such as telomerase,vascular endothelial growth factor,cyclooxygenase-2,adrenomedullin,plasma chromaffin protein A,signal transducer and activator of transcription-3 are of value in identification of tumor origin,its biological behaviors and differentiation of pheochromocytoma. This article reviews the newest research progresses in molecular biology of pheochromocytoma.
Adrenal Gland Neoplasms ; genetics ; Biomarkers, Tumor ; genetics ; Humans ; Mutation ; Pheochromocytoma ; genetics

Epigenomic and genomic changes affect gene expression and contribute to tumor development. The histone modifications trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) are epigenetic regulators associated to active and silenced genes, respectively and alterations of these modifications have been observed in cancer. Furthermore, genomic aberrations such as DNA copy number changes are common events in tumors. Pheochromocytoma is a rare endocrine tumor of the adrenal gland that mostly occurs sporadic with unknown epigenetic/genetic cause. The majority of cases are benign. Here we aimed to combine the genome-wide profiling of H3K4me3 and H3K27me3, obtained by the ChIP-chip methodology, and DNA copy number data with global gene expression examination in a malignant pheochromocytoma sample. The integrated analysis of the tumor expression levels, in relation to normal adrenal medulla, indicated that either histone modifications or chromosomal alterations, or both, have great impact on the expression of a substantial fraction of the genes in the investigated sample. Candidate tumor suppressor genes identified with decreased expression, a H3K27me3 mark and/or in regions of deletion were for instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, PTPRE and CDH11. More genes were found with increased expression, a H3K4me3 mark, and/or in regions of gain. Potential oncogenes detected among those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, IGF2, and the H3K27 trimethylase gene EZH2. Our approach to associate histone methylations and DNA copy number changes to gene expression revealed apparent impact on global gene transcription, and enabled the identification of candidate tumor genes for further exploration.
Adrenal Gland Neoplasms/*genetics/*pathology ; *Epigenesis, Genetic ; Female ; Gene Dosage/genetics ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks/genetics ; Genome, Human/*genetics ; *Genomics ; Histones/metabolism ; Humans ; Lysine/metabolism ; Methylation ; Pheochromocytoma/*genetics/*pathology ; Protein Processing, Post-Translational ; Tumor Suppressor Proteins/genetics/metabolism

OBJECTIVETo investigate the clinical and genetic features of a Chinese family with von Hippel-Lindau (VHL) disease revealed by bilateral pheochromocytoma.

METHODSThe proband and other members in a Chinese family with familial pheochromocytoma were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of 8 family members (including 3 patients) was amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced.

RESULTSThe first presentation in the proband, his mother, and his sister was bilateral pheochromocytoma, and the missense mutation of 695G-A (Arg161Gln) in exon 3 of VHL gene was detected in the three patients. In the follow-up study, the proband and his mother were found to have other VHL tumors, induding retinal and cerebellar hemangioblastomas and pancreatic tumor. Neither clinical presentation of VHL disease nor gene mutation was found in other family members.

CONCLUSIONVHL disease should be suspected in some patients with familial pheochromocytoma, and VHL gene screening helps to achieve early diagnosis of the disease.

Adrenal Gland Neoplasms ; diagnostic imaging ; genetics ; Adult ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pheochromocytoma ; diagnostic imaging ; genetics ; Tomography, X-Ray Computed ; Von Hippel-Lindau Tumor Suppressor Protein ; genetics ; von Hippel-Lindau Disease ; diagnostic imaging ; genetics

OBJECTIVETo carry out a genetic detection and analysis of Von Hippel-Lindau (VHL) gene in Chinese patients with sporadic pheochromocytoma.

METHODSDNA samples were extracted from peripheral blood cells and fresh pheochromocytoma specimens from 41 patients with sporadic pheochromocytoma were assayed by polymerase chain reaction and direct sequencing. The DNA samples of 50 healthy volunteers were extracted from peripheral blood as a control. The PCR products of exon 1, exon 2 and exon 3 were used for molecular analysis of the VHL gene. The genetic detection of family members of VHL gene mutations was also performed.

RESULTSOne of mutations was located at nucleotide 572 (G-->C) in exon 2, presenting a codon 120 from arginine (R) to threonine (T). Tow small insertions were locatated at nucleotide 623T (TTTGTtG) in exon 2, leading to a frameshift mutation. There were also three carriers of G572C and three carriers of 623T (TTTGTtG) in family members of the three cases.

CONCLUSIONThere are some Chinese patients with sporadic pheochromocytoma with tumorigenic VHL gene mutations. It is recommended to use the genetic detection and analysis of VHL gene as a routine examination for patients with sporadic pheoehromoeytoma under the age of 50 years with questionable family history. The genetic detection and analysis of VHL gene may be useful as a marker for the diagnosis of hereditary pheochromocytoma.

Adrenal Gland Neoplasms ; genetics ; Adult ; DNA Mutational Analysis ; DNA, Neoplasm ; genetics ; Exons ; Family ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Pheochromocytoma ; genetics ; Von Hippel-Lindau Tumor Suppressor Protein ; genetics

OBJECTIVETo detect the VHL gene mutations in a Chinese family with nonsyndromic pheochromocytoma.

METHODSMutations of VHL gene were detected in a Chinese family with nonsyndromic pheochromocytoma. Five patients and fifteen relatives were involved in this study. Peripheral blood was collected and total genomic DNA was prepared for polymerase chain reaction (PCR). PCR products of all the three exons of VHL gene were purified and a direct gene sequence analysis was performed.

RESULTSAll the five patients presented a codon 125 from Histidine (H) to Proline (P) change at nucleotide 587 (A --> C) in exon 2. Seven members of fifteen relatives were carriers with the same VHL gene mutation. Two carriers were detected with bilateral adrenal tumors and right renal cyst respectively by ultrasonic inspection.

CONCLUSIONThe novel VHL gene mutation detected in this kindred may be the causative gene. Genetic test can detect the carriers in an early period. It is recommended as a routine method of genetic test in nonsyndromic pheochromocytoma patients.

Adolescent ; Adrenal Gland Neoplasms ; diagnosis ; ethnology ; genetics ; Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; China ; DNA Mutational Analysis ; Family Health ; Female ; Genetic Testing ; Humans ; Male ; Mutation ; Pedigree ; Pheochromocytoma ; diagnosis ; ethnology ; genetics ; Polymerase Chain Reaction ; Von Hippel-Lindau Tumor Suppressor Protein ; genetics ; Young Adult

OBJECTIVETo screen the mutations of RET proto-oncogene in sporadic patients with pheochromocytoma.

METHODSForty-two cases of sporadic pheochromocytoma were tested for mutations of RET gene. Of these 42 DNA samples, 12 were extracted from peripheral blood cells and 30 from paraffin-embedded pheochromocytoma specimens. The PCR product of exon 10 and exon 11 was used to molecular analysis of the RET proto-oncogene.

RESULTSAmong 42 patients, 2 were found to have RET gene mutations. One of mutations located at codon 634 (TGC>TAC) in exon 11 of RET proto-oncogene. Another one located at codon 632 (GAG>AAG).

CONCLUSIONSome patients with apparently sporadic pheochromacytoma were carrier of mutations, a routine genetic analysis for mutations of RET gene is indicated for these patients.

Adrenal Gland Neoplasms ; diagnosis ; genetics ; Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; China ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease ; genetics ; Genetic Testing ; Humans ; Male ; Middle Aged ; Mutation ; Pheochromocytoma ; diagnosis ; genetics ; Polymerase Chain Reaction ; Proto-Oncogene Proteins c-ret ; genetics

OBJECTIVETo investigate the expression of chromogranin A (CgA) and synaptophysin (Syn) for differential diagnosis of different kinds of adrenal gland tumors.

METHODSThe samples of 69 adrenal gland tumors and 4 normal adrenal glands were immunohistochemically analyzed for the expression of chromogranin A and synaptophysin. The statistical analysis of the data was performed using chi-square test.

RESULTSIn the normal adrenal gland, CgA and Syn was exclusively detected in the medulla. CgA was detected in all pheochromocytomas 25/25 (100%), and gave less or no expression in adrenocortical tumors. Syn was detected in adrenocortical adenomas 27/28 (96.4%), adrenocortical carcinoma 7/8 (87.5%), pheochromocytoma 24/25 (96.0%) and adrenal metastatic carcinoma 6/8 (75.0%), respectively.

CONCLUSIONThere is statistically significant difference of CgA expression between adrenalcortical and adrenal medullary tumors, and also between benign and malignant pheochromocytomas. CgA and Syn are immunohistochemically reliable markers in the differential diagnosis of various kinds of adrenal gland tumors.

Adrenal Gland Neoplasms ; diagnosis ; metabolism ; Adrenocortical Adenoma ; diagnosis ; metabolism ; Adrenocortical Carcinoma ; diagnosis ; metabolism ; Chromogranin A ; biosynthesis ; genetics ; Diagnosis, Differential ; Female ; Humans ; Male ; Pheochromocytoma ; diagnosis ; metabolism ; Synaptophysin ; biosynthesis ; genetics