SDHD Mutations Research Articles

PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROMES IN POLISH PHEOCHROMOCYTOMA REGISTRY - CLINICAL CHARACTERISTICS: PP.18.195

Objective: To present clinical characteristics of pheochromocytoma-paraganglioma syndromes based on Polish Pheochromocytoma Registry. Design and methods: The study included 59 participants with 33 index cases from the Polish Pheochromocytoma Registry. There were 29 patients (pts) with SDHB (15 M, 14F, mean age 35 ± 18 yr), 23 pts SDHD (13 M, 10F, mean age 34 ± 12 yr) and 7 pts with SDHC mutations (4 M, 3F, mean age 44 ± 16 yr). Results: For SDHB index cases median age of diagnosis was 36 (95%CI 33–51) yr compared with 28 (95%CI 25–39) yr for the SDHD and 41 (95%CI 21–99) for SDHC (NS). There was difference in the age-related penetrance for the disease between SDHB and SDHD (SDHD 78% vs SDHB 49% by 40 yr of age, p = 0,037) and between SDHD and SDHC (33% by 40yr), p = 0,018, and a highly significant difference in the penetrance for head and neck paraganglioma (HNP) between SDHB and SDHD (SDHD 65% by 40 yr of age vs SDHB 18% by 40 yr of age, p < 0,0001). Penetrance for pheo was 40% by 40 yr of age in SDHB and 44% by 40 yr of age in SDHD (NS). There was only 1 pts with pheo in SDHC group. SDHB mutations were associated with a higher rate of malignancy than SDHD (3 of 17 (18%) vs 0 of 23 (p < 0,05) and of extraadenal tumor (SDHB 11 of 17, 65% vs SDHD 7 of 23, 30%, p < 0,05). SDHD group was characterized by higher incidence of multifocal tumors (SDHD 16 of 23 (70%) vs SDHB 5 of 17 (29%), p < 0,01), HNP (SDHD 19 of 23(83%) vs SDHB 5 of 17 (29%), p < 0,001 and recurrence (SDHD 14 of 23 (61%) vs SDHB 3 of 17 (18%), p < 0,01. Conclusions: For clinical follow-up, features of SDHB mutation-associated disease include a higher rate of malignancy, and extraadrenal tumors. SDHD mutation carriers, in addition to HNP, should be observed for multifocal tumors, and the possibility of extraadrenal pheo.

SDHA is a tumor suppressor gene causing paraganglioma

Mitochondrial succinate-coenzyme Q reductase (complex II) consists of four subunits, SDHA, SDHB, SDHC and SDHD. Heterozygous germline mutations in SDHB, SDHC, SDHD and SDHAF2 [encoding for succinate dehydrogenase (SDH) complex assembly factor 2] cause hereditary paragangliomas and pheochromocytomas. Surprisingly, no genetic link between SDHA and paraganglioma/pheochromocytoma syndrome has ever been established. We identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. The functionality of the SDHA mutant was assessed by studying SDHA, SDHB, HIF-1alpha and CD34 protein expression using immunohistochemistry and by examining the effect of the mutation in a yeast model. Microarray analyses were performed to study gene expression involved in energy metabolism and hypoxic pathways. We also investigated 202 paragangliomas or pheochromocytomas for loss of heterozygosity (LOH) at the SDHA, SDHB, SDHC and SDHD loci by BAC array comparative genomic hybridization. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumor tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. LOH was detected at the SDHA locus in the patient's tumor but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas. The SDHA gene should be added to the list of genes encoding tricarboxylic acid cycle proteins that act as tumor suppressor genes and can now be considered as a new paraganglioma/pheochromocytoma susceptibility gene.

Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes

Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (SDHB mutations) or significant multiorgan disease (RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.

Identification of a 4.9-kilo base-pair Alu-mediated founder SDHD deletion in two extended paraganglioma families from Austria

Hereditary paraganglioma (PGL) is characterized by the development of highly vascularized paraganglionic tumors as a result of germline mutations in the SDHB, SDHC or SDHD subunit genes of succinate dehydrogenase (SDH; mitochondrial complex II), or in the Von Hippel-Lindau tumor-suppressor gene. Although many PGL mutations have been described, gross SDHD deletions have not yet been implicated as founder mutations and are rarely characterized at the DNA sequence level. We investigated the genetic basis of head and neck PGLs observed in 20 subjects from two unrelated multiplex pedigrees from Austria and identified a 4944-base pair partial SDHD deletion, which escaped PCR-based detection methods. The deletion occurred between Alu elements and was present within the same haplotype context in both pedigrees, indicating a founder effect. The deletion caused tumors only after a paternal transmission similar to other conventional SDHD mutations, suggesting preservation of genomic imprinting mechanisms operating at this locus. These data describe a large SDHD deletion at the genomic sequence level and indicate that gross SDHD deletions could be a founder PGL mutation in certain populations.

SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma

Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype. We undertook a multicentre study in Spain and The Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype. We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred. SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes. Dutch Cancer Society, European Union 6th Framework Program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer.

Relevance of Germline Mutation Screening in Both Familial and Sporadic Head and Neck Paraganglioma for Early Diagnosis and Clinical Management

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation.Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution.Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular.Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management.

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation. Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution. Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular. Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Sdhd and Sdhd/H19 Knockout Mice Do Not Develop Paraganglioma or Pheochromocytoma

BackgroundMitochondrial succinate dehydrogenase (SDH) is a component of both the tricarboxylic acid cycle and the electron transport chain. Mutations of SDHD, the first protein of intermediary metabolism shown to be involved in tumorigenesis, lead to the human tumors paraganglioma (PGL) and pheochromocytoma (PC). SDHD is remarkable in showing an ‘imprinted’ tumor suppressor phenotype. Mutations of SDHD show a very high penetrance in man and we postulated that knockout of Sdhd would lead to the development of PGL/PC, probably in aged mice.Methodology/Principal FindingsWe generated a conventional knockout of Sdhd in the mouse, removing the entire third exon. We also crossed this mouse with a knockout of H19, a postulated imprinted modifier gene of Sdhd tumorigenesis, to evaluate if loss of these genes together would lead to the initiation or enhancement of tumor development. Homozygous knockout of Sdhd results in embryonic lethality. No paraganglioma or other tumor development was seen in Sdhd KO mice followed for their entire lifespan, in sharp contrast to the highly penetrant phenotype in humans. Heterozygous Sdhd KO mice did not show hyperplasia of paraganglioma-related tissues such as the carotid body or of the adrenal medulla, or any genotype-related pathology, with similar body and organ weights to wildtype mice. A cohort of Sdhd/H19 KO mice developed several cases of profound cardiac hypertrophy, but showed no evidence of PGL/PC.ConclusionsKnockout of Sdhd in the mouse does not result in a disease phenotype. H19 may not be an initiator of PGL/PC tumorigenesis.

Paraganglioma: Carotid Body Tumor

Extra-adrenal paragangliomas are neoplasms of the paraganglia located within the paravertebral sympathetic and parasympathetic chains. Thus paragangliomas may arise anywhere along these tracts and common sites of occurrence include abdomen, retroperitoneum, chest and mediastinum and various head and neck locations such as jugulotympanic membrane, orbit, nasopharynx, larynx, vagal body and carotid body. Recent literature suggests a molecular basis for the development of some paragangliomas, i.e. germline mutations. Six genes have been identified and are thought to contribute to the development of pheochromocytoma/paraganglioma. These include RET, VHL, NF1 and SDH subunits SDHB, SDHC, and SDHD. SDHD and SDHB mutations account for a significant percentage of head and neck paragangliomas. It is well know that paragangliomas may be hereditary and may be part of genetic syndromes such as Von Hippel-Lindau syndrome, neurofibromatosis type I (von Recklinghausen disease), MEN 2A and MEN 2B. When features of these more commonly known syndromes are not present, many familial cases, often associated with the above mentioned germline mutations, go unrecognized. In the head and neck region the normal paraganglia are associated with the parasympathetic nervous system and paragangliomas arising from these parasympathetic sites account for up to 70% of extra-adrenal paragangliomas. The most common site is the carotid body. Carotid body paragangliomas arise at the bifurcation of the internal and external carotid arteries and have classic radiographic

A reason to panic in pregnancy

An 18-year-old woman presented to us in June, 2004, at 27 weeks’ gestation with aproteinuric hypertension (178/111 mm Hg) and intermittent panic attacks (palpitations, left abdominal pain, and perspiration). 24-h urinary catecholamine excretion was >20 000 nmol. Ultrasonography showed a 6·9 cm × 3·6 cm × 4·6 cm structure obscuring the left adrenal gland. Haemodynamic stability was achieved with phenoxybenzamine and labetolol, for the presumptive diagnosis of phaeochromocytoma. A staging CT was undertaken before elective caesarean at 37 weeks’; a healthy infant was delivered. The tumour was resected a month later. Histologically the tumour arose from the sympathetic paraganglion cells; the left adrenal gland itself was normal. Some vascular invasion was noted. DNA analysis showed VHL and RET genes to be normal, but there was a succinate dehydrogenase complex subunit B (SDH-B) gene mutation, predisposing her to paraganglioma syndrome type I. Postoperative ultrasound showed a 3·2 cm mass anterior to the inferior vena cava at the aortic bifurcation, but the patient declined further investigation. She remained asymptomatic until the 32nd week of her next pregnancy, when fl ushing and palpitations were associated with rising urinary catecholamine secretions (to 4423 nmol/day). MRI showed that the mass had grown slightly to 3·5 cm. Despite an asystolic episode during caesarean section at term, the patient survived to undergo laparoscopic resection of the tumour 6 weeks’ postpartum. Again, paraganglioma was identifi ed histologically. The patient remained asymptomatic at follow-up in April, 2009. Paragangliomas account for only 10–15% of catecholamine-secreting tumours. A large series put the prevalence of paraganglioma and phaeo chromocytoma during pregnancy at fi ve per million. Maternal and fetal mortality are 4% and 11%, respectively, which is related to delay in presentation and diagnosis. In pregnancy phaeochromocytomas may initially be missed, because the symptoms can mimic pre-eclampsia (table). Urinary catecholamine secretion and plasma metanephrines are not raised in normal pregnancy or pre-eclampsia and confi rm the diagnosis of phaeochromo cytoma. Adequate medical management is required before delivery and surgery. Inpatient observation and management are recommended because of the unpredictable nature of phaeochromocytoma in pregnancy, although successful outpatient management was achieved when our patient declined admission. Resection should promptly follow medical stabilisation in cases diagnosed prior to 24 weeks’; after this time maintenance medical therapy should continue to optimise fetal maturity. Elective caesarean allows close monitoring and is the preferred mode of delivery since labour can be lethal. Planned caesarean also off ers the opportunity for simultaneous tumour resection, but delaying this into the puerperium decreases vascularity and improves access. Germline mutations account for a quarter of phaeochromocytomas; commonly disease is of young onset and is multifocal or extra-adrenal. Associated familial syndromes including Von Recklinghausen’s disease, Von Hippel-Lindau disease, and multiple endocrine neoplasia types IIa and IIb. Mutations in SDH-B, SDH-C, and SDH-D genes account for 33% of patients with phaeochromocytoma due to genetic abnormalities. SDH genes code for discrete subunits of the mitochondrial enzyme complex II (involved in Kreb’s cycle) and act as classic tumour suppression genes. SDHB mutations are associated with a 33% risk of recurrence and malignancy, and SDH-D mutations with an increased risk of multifocal paragangliomas, and renal and thyroid carcinomas. In women of reproductive age, genetic testing for one of the familial syndromes associated with phaeochromocytoma should be considered when there is family history of an associated syndrome, if the patient has any clinical features associated with a syndrome, or if the woman has extra-adrenal or multifocal disease. Although, the penetrance of RET and VHL is understood, the proportion of women with SDH mutations who develop clinical disease is unknown, complicating genetic counselling. Women known to have syndromes associated with phaeochromocytomas should receive preconceptual counselling about risks of disease developing during pregnancy.

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan-Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a 'wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients.

Commentary on Germline SDHB mutations and familial renal cell carcinoma

Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2), and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings (1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, (2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and (3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.

The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes

A genetic predisposition for paragangliomas and adrenal or extra-adrenal phaeochromocytomas was recognized years ago. Beside the well-known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel 'paraganglioma-phaeochromocytoma syndrome' caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest-derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent-of-origin effect for SDHD mutations. Life-time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation.

The Succinate Dehydrogenase Genetic Testing in a Large Prospective Series of Patients with Paragangliomas

Germline mutations in SDHx genes cause hereditary paraganglioma. The aim of the study was to assess the indications for succinate dehydrogenase (SDH) genetic testing in a prospective study. A total of 445 patients with head and neck and/or thoracic-abdominal or pelvic paragangliomas were recruited over 5 yr in 20 referral centers. In addition to classical direct sequencing of the SDHB, SDHC, and SDHD genes, two methods for detecting large genomic deletions or duplications were used, quantitative multiplex PCR of short fluorescent fragments (QMPSF) and multiplex ligation-dependent probe amplification (MLPA). A large variety of SDH germline mutations were found by direct sequencing in 220 patients and by QMPSF and MLPA in 22 patients (9.1%): 130 in SDHD, 96 in SDHB, and 16 in SDHC. Mutation carriers were younger and more frequently had multiple or malignant paraganglioma than patients without mutations. A head and neck paraganglioma was present in 97.7% of the SDHD and 87.5% of the SDHC mutation carriers, but in only 42.7% of the SDHB carriers. A thoracic-abdominal or pelvic location was present in 63.5% of the SDHB, 16.1% of the SDHD, and in 12.5% of the SDHC mutation carriers. Multiple paragangliomas were diagnosed in 66.9% of the SDHD mutation carriers. A malignant paraganglioma was documented in 37.5% of the SDHB, 3.1% of the SDHD, and none of the SDHC mutation carriers. SDH genetic testing, including tests for large genomic deletions, is indicated in all patients with head and neck and/or thoracic-abdominal or pelvic paraganglioma and can be targeted according to clinical criteria.

Paragangliomas and the Pheochromocytoma—Paraganglioma Syndrome, the SDHX-Factor

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors that occur sporadically and in the context of hereditary tumor syndromes. One of these tumor syndromes is the PCC-PGL syndrome, where patients have multiple PGLs and/or PCCs. Although it has been known that most PGLs show loss of 11q, the associated tumor suppressor gene SDHD was only recently discovered. Mutations in this tumor suppressor gene were found in up to 60% of PGL patients. Recent investigations have shown that SDHD mutations not only cause this syndrome, but also that SDHB and SDHC are involved in the pathogenesis of the PCC-PGL syndrome. These studies have also shown that clinical indications (family history of PCC or PGL, multifocal disease, younger age) have high specificity but low sensitivity for the detection of PCC-PGL syndrome. In an international collaboration, we have shown, with SDHB immunohistochemistry (IHC), that SDH-related PCCs and PGLs can be easily distinguished from PCCs and PGLs with other genetic backgrounds. This detection of the inherited PCC-PGL syndrome is of major importance for PCC and PGL patients, as well as for their family members, because they are at increased risk for development of multiple, various, and malignant neoplasms. In addition, after identification of an SDHB, C, or D germline mutation, surveillance can be offered to family members carrying the mutation.

The Risk of Head and Neck Paragangliomas and Pheochromocytomas in SDHD Mutation Carriers

Background: In The Netherlands, most hereditary head and neck paraganglioma syndromes are caused by 2 founder mutations in the SDHD gene. In SDHD-linked paragangliomas, the risk of developing a tumor depends on the sex of the parent that transmits the mutation: as a rule, paragangliomas do not develop when the mutation is inherited via the mother. In this study, we assess the risk of developing paragangliomas and associated pheochromocytomas, as well as paraganglioma-related symptoms, upon paternal transmission of an SDHD mutation.

Pheochromocytomas and extra-adrenal paragangliomas detected by screening in patients with SDHD-associated head-and-neck paragangliomas

Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas for which screening has been advised. To assess clinical, biochemical, and radiological outcomes of screening in a large single-center cohort of SDHD-positive patients with HNP and to address the necessity for repetitive follow-up, we evaluated 93 patients with SDHD-associated HNP (p.Asp92Tyr, p.Leu139Pro). Screening consisted of measurement of 24 h urinary excretion of catecholamines and/or their metabolites in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients, in whom urinary excretion was above the reference limit, imaging studies with (123)I-MIBG (metaiodobenzylguanidine) scintigraphy and magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate blockade. Median follow-up was 4.5 years (range 0.5-19.5 years). Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients. Paragangliomas that do not secrete catecholamines might be more prevalent than previously reported. Future studies will have to establish whether routine imaging studies should be included in the screening of SDHD mutation carriers, irrespective of biochemical screening.

Clinical aspects of SDHx-related pheochromocytoma and paraganglioma

Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [(18)F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.

Familial endocrine tumours: phaeochromocytomas and extra-adrenal paragangliomas

About 30% of phaeochromocytomas (PCCs), sympathetic paragangliomas (sPGLs) and parasympathetic paragangliomas (pPGLs) are due to a familial syndrome. In half of these patients the presentation is syndromic or accompanied by a positive family history. However, over 10% of patients with clinically sporadic disease are still affected by an inheritable disease. Patients with multiple and/or bilateral tumours or disease onset at a young age are at an increased likelihood of such a syndrome and require genetic counselling and DNA testing. A genotype–phenotype correlation is emerging: multiple endocrine neoplasia type 2 (MEN-2) and von Hippel – Lindau disease-associated adrenal PCCs are often bilateral. Extra-adrenal (malignant) sPGLs are more typical in SDHB families. Multiple pPGLs (sometimes together with PCCs) occur in the setting of SDHD mutations, and SDHC families suffer from familial singular pPGLs. Some familial tumours also show typical histological features which should be looked for and reported by the pathologist. We review endocrine tumour syndromes with PCCs and/or PGLs, and summarize their genetic background and clinical and morphological features, and give recommendations for genetic testing.