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

Havekes, Bas; Klaauw, Agatha A. van der; Weiss, Marjan M.; Jansen, Jeroen C.; Mey, Andel G. L. van der; Vriends, Annette H. J. T.; Bonsing, Bert A.; Romijn, Johannes A.; Corssmit, Eleonora P M

doi:10.1677/erc-09-0024

Cited by 23 publications

(27 citation statements)

References 32 publications

(31 reference statements)

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“…Although in our study, only three patients are described with deletions of SDHD and only one patient with a deletion of SDHC, the phenotype of these patients does not seem to be essentially different from the phenotype described for point mutations of SDHD (Amar et al 2005, Benn et al 2006, Havekes et al 2009) and SDHC (Schiavi et al 2005, Mannelli et al 2007. SDHD mutations are typically associated with multifocal head and neck paragangliomas and usually benign adrenal and extra-adrenal paragangliomas.…”

Section: Discussioncontrasting

confidence: 54%

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Bayley

Weiss

Grimbergen

et al. 2009

Endocrine-Related Cancer

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A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg-AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb-Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.

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Section: Discussioncontrasting

confidence: 54%

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Bayley

Weiss

Grimbergen

et al. 2009

Endocrine-Related Cancer

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“…As patients with HNPGL have the ability to (co)secrete noradrenaline (11,17,18), this catecholamine and its metabolite NMN should be measured as well. Combining the results of free MNs and 3MT in plasma resulted in a slightly, but significantly, higher number of patients with biochemically active HNPGL compared with the combined results of urinary excretion rates.…”

Section: Discussionmentioning

confidence: 99%

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites

Duinen

Corssmit

Jong

et al. 2013

European Journal of Endocrinology

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Context: A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. Objective: To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. Patients and methods: We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. Results: Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (PZ0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (PZ1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (PZ0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P!0.05). Conclusions: The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

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“…Patients with a SDHx mutation, MEN2 disease, or VHL disease are advised to be screened for pheochromocytoma annually. In case of increased plasma/urinary catecholamines or their metabolites, additional radiological investigation should be performed to identify the culprit lesion (2,6,13,27). The prevalence of pheochromocytoma is quite low in patients with NF, and therefore, screening is not recommended in all patients, but it may be justified in those patients with NF with hypertension, or in those patients who will undergo provocative interventions, such as surgery or pregnancy (7).…”

Section: Discussionmentioning

confidence: 99%

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms

Duinen¹,

Steenvoorden²,

Bonsing³

et al. 2010

European Journal of Endocrinology

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Context: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess. Objective: To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes. Design: Retrospective follow-up study. Patients and methods: We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: nZ28 and pheochromocytomas detected by screening: nZ32) in our center. Results: Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P!0.01), palpitations (PZ0.01), paleness (PZ0.01), nausea (P!0.01), and vomiting (PZ0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41G2 vs 47G3 years, PZ0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7G0.5 vs 7.3G0.7 cm, P!0.01). Conclusions: Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.

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

Cited by 23 publications

References 32 publications

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms

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