Hereditary Paraganglioma Research Articles

A Novel Mutation (P236S) in the Succinate Dehydrogenase Subunit B Gene in a Japanese Patient with a Posterior Mediastinal Paraganglioma

Succinate dehydrogenase subunit B gene (SDHB) is associated with the development of hereditary paraganglioma (PGL) and pheochromocytoma (PCC). Here we describe a novel germline mutation in SDHB in a 69-year-old Japanese woman with a posterior mediastinal PGL. We summarize the clinical presentation, diagnostic work-up, and pathological features of a patient with a posterior mediastinal PGL and review the pertinent literature. Direct sequencing of SDHB and SDHD was performed. The patient presented with a posterior mediastinal tumor and was normotensive. She underwent abdominal tumor resection at the age of 38 years, but clinical and pathological diagnoses were unknown. She had no family history of hypertension, PGL, or PCC. Imaging studies suggested that the tumor was neurogenic. Endocrinological examinations showed normal plasma catecholamine levels. The tumor was completely removed without metastasis. Pathological findings confirmed PGL. Immunohistochemical staining showed that the tumor cells were positive for chromogranin A, synaptophysin, and CD56, and the Ki67 index was low (<1 %). The patient has not experienced recurrence or metastasis for the last 5 years. DNA sequencing revealed a novel P236S (c.843 C > T) mutation in SDHB. The P236S germline mutation in SDHB was associated with posterior mediastinal PGL. Strict follow-up of the patient is necessary because the SDHB mutation may be related to malignancy.

No difference in phenotype of the main Dutch SDHD founder mutations

SDHD mutations predispose carriers to hereditary paraganglioma syndrome. The objective of this study was to assess the genotype-phenotype correlation of a large Dutch cohort of SDHD mutation carriers and evaluate potential differences in clinical phenotypes due to specific SDHD gene mutations. Retrospective, descriptive single-centre study. All consecutive SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center were included. Subjects were investigated according to structured protocols used for standard care, including repetitive biochemical and radiological screening for paragangliomas. Two hundred and one SDHD mutation carriers with a mean age at presentation of 42·6 ± 14·4 years and a mean follow-up of 5·8 ± 5·4 years were evaluated. Eighty-one percent carried the SDHD c.274G>T (p.Asp92Tyr) mutation and 13% the SDHD c.416T>C (p.Leu139Pro) mutation. No differences in clinical phenotype between these two specific SDHD mutations were found. Ninety-one percent developed one or multiple paragangliomas in the head and neck region (HNPGLs), of which the carotid body tumour was the most prevalent (85%). Eighteen carriers developed pheochromocytomas, fifteen sympathetic paragangliomas and nine carriers (4%) suffered from malignant paraganglioma. By end of follow-up, sixteen SDHD mutation carriers (8%) displayed no biochemical or radiological evidence of manifest disease. The two main Dutch SDHD founder mutations do not differ in clinical expression. SDHD mutations are associated with the development of multiple HNPGLs and predominantly benign disease.

Update on pediatric cancer predisposition syndromes

Hereditary cancer syndromes in children and adolescents are becoming more recognized in the field of pediatric hematology/oncology. A recent workshop held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included several interactive sessions related to specific familial cancer syndromes, genetic testing and screening, and ethical issues in caring for families with inherited cancer risk. This review highlights the workshop presentations, including a brief background about pediatric cancer predisposition syndromes and the importance of learning about them for the practicing pediatric hematologists/oncologists. This is followed by a brief summary of the newly described cancer predisposition syndromes including Rhabdoid Tumor Predisposition Syndrome, Hereditary Paragangliomas and Pheochromocytoma Syndrome, and Familial Pleuropulmonaryblastoma Tumor Predisposition (DICER1) Syndrome. The next section covers genetic testing and screening for pediatric cancer predisposition syndromes. Ethical issues are also discussed including preimplantation genetic diagnosis or testing (PGD/PGT), suspicious lesions found on tumor screening, and incidental mutations discovered by whole genome sequencing. Finally, the perspective of a family with Li-Fraumeni Syndrome is shared.

First Report of Bilateral Pheochromocytoma in the Clinical Spectrum ofHIF2A-Related Polycythemia-Paraganglioma Syndrome

Molecular genetic research has so far resulted in the identification of 10 well-characterized susceptibility genes for hereditary pheochromocytoma (PHEO) or paraganglioma (PGL). Recently, a new syndrome characterized by multiple PGLs and somatostatinomas associated with congenital polycythemia due to somatic mutations in HIF2A has been reported. The aim of the study was to define the genetic defect in a new case of bilateral PHEO and multiple PGLs associated with congenital polycythemia. A female patient presented with neonatal polycythemia (treated by phlebotomies, 1 session approximately every 4 mo), mildly enlarged cerebral ventricles, and bilateral PHEO and multiple PGLs. There was no family history of any neuroendocrine tumor or polycythemia. Surgical removal of the tumors only temporarily normalized plasma erythropoietin (Epo) levels and discontinued phlebotomies. No germline mutations were initially detected in the SDHB, SDHC, SDHD, VHL, and PHD2 genes, known to be associated with polycythemia. The PHEOs presented with a typical noradrenergic biochemical phenotype. A heterozygous missense mutation (c.1589C>T) was identified in exon 12 of HIF2A, resulting in an alanine 530 substitution in the HIF-2α protein with valine (A530V). This somatic mutation was detected in the tissue from 1 PHEO and 1 PGL, with no HIF2A germline mutation found. This mutation led to stabilization of HIF-2α and hence a gain-of-function phenotype, as in previously published studies. This case represents the first association of a somatic HIF2A gain-of-function mutation with PHEO and congenital polycythemia, and it alerts physicians to perform proper genetic screening in patients presenting with multiple norepinephrine-producing PHEOs and polycythemia. This report also extends the previous findings of a new syndrome of only multiple PGLs, somatostatinomas, and polycythemia to multiple PHEOs.

Definition of a new algorithm for molecular-genetic testing of patients with hereditary pheochromocytoma and paraganglioma syndromes

Definition of a new algorithm for molecular-genetic testing of patients with hereditary pheochromocytoma and paraganglioma syndromes

SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed ‘wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.

High incidence of extraadrenal paraganglioma in families with SDHx syndromes detected by functional imaging with [18F]fluorodihydroxyphenylalanine PET

Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed. Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years. Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected. FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.

The Role of SDH Assembly Factor 2 and YgfY in Flavinylation of Succinate Dehydrogenase Flavoprotein

A mutation of the mitochondrial protein SDH assembly factor 2 (AF2) has been linked to hereditary paraganglioma in humans (Hao et al.(2009), Science 325,1139-42). These authors showed that AF2 is required for flavinylation of the succinate dehydrogenase flavoprotein (SDHA) in human cells or yeast, and that yeast SDHA heterogenously expressed in E. coli is flavinated only if yeast AF2 is coexpressed. We have extended these observations to the human protein: hSDHA is flavinated in E. coli only if coexpressed with human AF2. Flavinylation does not occur when purified recombinant hSDHA and AF2 are mixed with FAD in the presence or absence of succinate, fumarate, and MgATP, so some other factor provided by E. coli is required. We will report results fractionating E. coli cell lysate to determine the factors required and elucidate the role of AF2 in flavinylation. The E. coli protein YgfY is a distant homolog of mitochondrial AF2, and E. coli has SDH, the flavoprotein of which is very similar to that of mitochondrial SDH. We show here that a strain of E. coli with YgfY deleted is unable to grow with succinate as carbon source or to accumulate flavinylated SDH flavoprotein in its membranes. These observations are consistent with but do not prove a role for YgfY in maturation of SDH flavoprotein.

The role of complex II in disease

Genetically defined mitochondrial deficiencies that result in the loss of complex II function lead to a range of clinical conditions. An array of tumor syndromes caused by complex II-associated gene mutations, in both succinate dehydrogenase and associated accessory factor genes (SDHA, SDHB, SDHC, SDHD, SDHAF1, SDHAF2), have been identified over the last 12 years and include hereditary paraganglioma–pheochromocytomas, a diverse group of renal cell carcinomas, and a specific subtype of gastrointestinal stromal tumors (GIST). In addition, congenital complex II deficiencies due to inherited homozygous mutations of the catalytic components of complex II (SDHA and SDHB) and the SDHAF1 assembly factor lead to childhood disease including Leigh syndrome, cardiomyopathy and infantile leukodystrophies. The role of complex II subunit gene mutations in tumorigenesis has been the subject of intensive research and these data have led to a variety of compelling hypotheses. Among the most widely researched are the stabilization of hypoxia inducible factor 1 under normoxia, and the generation of reactive oxygen species due to defective succinate:ubiquinone oxidoreductase function. Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.

The genetics of paragangliomas

Over the last decade, it has been clearly established that one-third of all paragangliomas are genetically determined. Genetic testing, guided by the family history and clinical findings, must now be proposed to all subjects undergoing surgery for head and neck paraganglioma. When a mutation is identified on one of the susceptibility genes (SDHD, SDHB, SDHC, SDHAF2, VHL), at-risk subjects should be investigated for the presence of other supra- and infradiaphragmatic paragangliomas and functional catecholamine-secreting paragangliomas and/or phaeochromocytomas. Identification of a germline mutation on the SDHB gene is a high-risk factor for malignancy and poor prognosis and requires close surveillance of subjects carrying this mutation. The diagnosis of hereditary paraganglioma also allows predictive genetic screening in first-degree relatives of the index subject. Genetic testing for paraganglioma is therefore now an important component of the diagnostic and therapeutic management of these patients.

Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas

Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.

High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations

Hereditary paraganglioma is a benign tumor syndrome with an age-dependent penetrance. Carriers of germline mutations in the SDHB or SDHD genes may develop parasympathetic paragangliomas in the head and neck region or sympathetic catecholamine-secreting abdominal and thoracic paragangliomas (pheochromocytomas). In this study, we aimed to establish paraganglioma risk in 101 asymptomatic germline mutation carriers and evaluate the results of our surveillance regimen. Asymptomatic carriers of an SDHD or SDHB mutation were included once disease status was established by MRI diagnosis. Clinical surveillance revealed a head and neck paraganglioma in 28 of the 47 (59.6%) asymptomatic SDHD mutation carriers. Risk of tumor development was significantly lower in SDHB mutation carriers: 2/17 (11.8%, P=0.001). Sympathetic paragangliomas were encountered in two SDHD mutation carriers and in one SDHB mutation carrier. In conclusion, asymptomatic carriers of an SDHD mutation are at a high risk for occult parasympathetic paraganglioma. SDHB carrier risk is considerably lower, consistent with lower penetrance of SDHB mutations. For both syndromes, the risk of symptomless sympathetic paragangliomas is small.

Hereditary Head and Neck Paragangliomas

Objective: Paragangliomas are rare neuroendocrine tumors derived from the extra-adrenal paraganglia of the autonomic nervous system. Little information has been accumulated describing the differences in clinical expression between hereditary versus nonhereditary paraganglia. We examined the differences in clinical characteristics, presenting symptoms, and tumor types of hereditary head and neck paragangliomas. Method: A retrospective review of the medical records was performed in order to formulate a database of patients with head and neck paragangliomas. Clinical characteristics, tumor type and location, presentation, and genetic results of each patient were included. Hereditary paragangliomas were compared to the general database of head and neck paragangliomas. Results: Eighty patients with the diagnosis of a head and neck paraganglioma were evaluated at the University of Utah during the years of 2000 to 2010. Thirteen of the 80 were confirmed to be hereditary paragangliomas through genetic testing or through family history. Patients with a known hereditary component presented earlier in life than those of the general paraganglioma population. Over half of the patients who presented under the age of 30 years were confirmed to be hereditary. The most common presenting symptom was a neck mass (54%). A genetic mutation was found in all those tested under the age of 30 years. Conclusion: Our study evaluates a large population of hereditary paragangliomas. We found that patients who present at a younger age may be at an increased risk of possessing a genetic mutation. Further research will determine if genetic testing is necessary in all patients who present under the age of 30 years.

Hereditary pheochromocytoma and paraganglioma

Hereditary pheochromocytomas (pheo) and paragangliomas (pgl) are caused by identifiable germline mutations. The previously well-known associated syndromes include neurofibromatosis type 1, multiple endocrine neoplasia 2 A and B, and von Hippel-Lindau syndrome. Newly discovered mutations in the succinate dehydrogenase gene complex have been identified as a cause of inherited pgls and pheos. It is now clear that up to 30% of patients presenting with sporadic pheos/pgls harbor a recognizable germline mutation, and therefore directed genetic testing is recommended for many of these patients.

Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE in Individuals with Neck or Mediastinal Paraganglioma (PGL)

Paragangliomas (PGLs) are neuroendocrine tum-ors that arise embryologically from the neural crest. Sympathetic PGLs can be located in the thoracic-abdominal region while parasympathetic PGLs are mainly situated in the head and neck region. Most PGLs are sporadic, but in 30% of cases they are hereditary (associated with mutations of SDHB, SDHC, SDHD, SDHAF2, SDHA, TMEM, MAX, and VHL); they can be classified into 4 different paraganglioma syndromes: PGL1, PGL2, PGL3, and PGL4. Surgery is the treatment of choice for both sympathetic and parasympathetic PGLs. Other types of treatment include medical agents (such as gemcitabine, cisplatin, or sunitinib) and radiotherapy (external-beam radiotherapy or stereotactic surgery). Surgery and radiotherapy, however, can cause important side effects such as vascular complications and peripheral nerve damage (hypoglossal, recurrent laryngeal, glossopharyngeal, and vagus). Another possible treatment option is the use of peptide receptor radionuclide therapy (PRRT), including PRRT with 177Lu-DOTATATE. We studied 4 patients with hereditary nonmetastatic paraganglioma syndrome type 1 (PGL1), with progressive disease, in whom surgical excision was not possible. They were treated with 177Lu-DOTATATE (3-5 cycles) and all had a partial response (PR) or a stable disease (SD) to the treatment. In conclusion, a good alternative treatment when surgical or radiation therapy are contraindicated could be radiometabolic therapy with 177Lu-DOTATATE.

Screening of Mutations in Genes that Predispose to Hereditary Paragangliomas and Pheochromocytomas

Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes.

Improved anatomic visualization of a glomus caroticum tumour within the carotic bifurcation with combined 68Ga-DOTATATE PET/MRI

A 12-year-old girl from a family with hereditary paraganglioma was referred for somatostatin receptor PET. A glomus caroticum tumour of the left side had been resected 1 year before, and now a paraganglioma of the right side was suspected. In the current investigation with 136 MBq Ga-DOTATATE and PET/CT, a focal uptake in the right neck was seen, highly suspicious of one further glomus tumour (a red arrow) contralateral to the previously resected tumour. No further foci were detected in the trunk. The girl was transferred to a combined PET/MRI scanner (Ingenuity PET-MR, TOF-PET, 3 TMRI; Philips). Positioned in a head coil (NV-16 head coil), first an attenuation MR scan was performed. From 2 h after injection, a PET scan of the head and neck area was acquired, and afterwards a diagnosticMRI scan was performed including nonenhanced time-of-flight MR angiography. The glomus tumour can be seen in close proximity to the bifurcation of the carotid artery (b–e). Glomus tumours can be imaged by somatostatin receptor ligands (preferably PET ligands such as Ga-DOTATOC/Ga-DOTATATE or SPECT ligands such as Inoctreotide) [2], F-DOPA PET [1] or I-MIBG. The combination of PET (or SPECT) and a morphological imaging method such as CT brings the advantage of exact anatomic localization which is necessary if a resection of the tumour is considered. With the advent of the newly introduced PET/MRI scanner, the combination of superb soft-tissue contrast of MRI and a specific PET tracer forms a highly sophisticated imaging tool for this indication. To

P2-13-02: Parent of Origin of BRCA Mutation May Determine Age at Breast Cancer Diagnosis.

Abstract Background: Genetic diseases may display parent-of-origin effects. In such cases, the risk depends on the specific parent or origin allele. Imprinting effect is evident in autosomal dominant hereditary paraganglioma leads to tumors only if inherited from paternal germline. Cancer penetrance in mutations carriers may be determined by the parent origin of BRCA mutation. Methods: From 2007–2010 we analyzed 1889 consecutive (136 ovarian + 1753 breast) breast (BrCa) or ovarian cancer (OvCa) patients presenting for treatment at our outpatient facility. In 130 patients with BRCA 1 or 2 mutations the parent of origin for the mutation was known. Of the 130 patients 2 had both BRCA1 and BRCA2 mutated paternally inherited and were excluded from this analysis. Of the breast cancer patients: 28 patients had paternal and 29 had maternal BRCA1 mutations, 24 had paternal and 21 had maternal BRCA 2 mutations. Of the ovarian cancer patients 6 had paternal and 10 had maternal BRCA1 mutations, 7 had paternal and 3 had maternal BRCA2 mutations. In carriers of BRCA mutations the mean age at diagnosis for ovarian cancer was 51 (range 21–70) and for breast cancer was 43 (range 24–78). Two-sample t-test was used to compare the mean age at diagnosis in patients with BRCA 1 or 2 mutations of paternal or maternal inheritance. For breast cancer maternal allele versus paternal allele 2-sample t-test and p-value were compared for the age at first diagnosis. For breast cancer patients BRCA1 maternal inheritance (mean+SD yrs) 45.73+11.22 versus paternal inheritance 38.04+7.14 2-sample t-test p-value p&amp;lt;0.0020. For breast cancer BRCA2 maternal inheritance (mean+SD yrs) 50.65+10.44 versus paternal inheritance 41.68+6.16, 2-sample t-test p-value p&amp;lt;0.0008. Results: Significantly younger age at breast cancer diagnosis was observed in paternal vs. maternal inheritance of BRCA1 mutation (38 vs 46, respectively, p&amp;lt;0.0020) and BRCA2 mutation (42 vs 51 respectively, p&amp;lt;0.0008). There was no significant difference between paternal and maternal age of ovarian cancer diagnosis of BRCA1 (p&amp;lt;0.1415) or BRCA2 mutation (p&amp;lt;0.3470). Conclusion: The restrospective nature of the study may introduce ascertainment bias. However, the breast and ovarian cancers cases in BRCA1 &amp; 2 carriers with maternal or paternal inheritance mirror the Mendelian autosomal dominant pattern in our unselected consecutive cohort of patients. Maternal and paternal inherited BRCA alleles may not be exchangeable. Women with paternally inherited mutations in BRCA gene mutations develop breast cancer at younger age compared with women who inherit the gene mutations from their mothers. In this small sample, clear differences at age of cancer diagnosis are apparent in paternal inheritance of BRCA gene mutation. If this observation duplicates in larger cohorts results will have important implications for recommendation of surgical risk reduction in BRCA mutation carriers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-13-02.

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

Novel germline SDHD deletion associated with an unusual sympathetic head and neck paraganglioma

Paragangliomas (PGLs) are rare tumors arising either from sympathetic or parasympathetic-associated chromaffin tissue. PGLs can occur either sporadically or as part of a hereditary syndrome. Sympathetic head and neck PGLs are extremely rare tumors and only a few cases have been reported to date. We report the pedigree of a patient with a head and neck PGL arising from the right sympathetic trunk. SDHD mutation analysis was performed using standard sequencing, multiplex ligation-dependent probe amplification, chromosome 11-specific comparative genome hybridization, and long-range/short-range polymerase chain reaction (PCR) approaches. A previously unreported chromosome 11q deletion encompassing 5 annotated genes (SDHD, DLAT, PIH1D2, C11Orf57, and TIMM8B) was detected in the proband. PGL families considered "mutation-negative" may be attributable to large gene deletions not detectable by standard sequencing methods. Therefore, deletion analysis should be offered to families or individuals at risk for hereditary PGLs.