No evidence for increased mortality in SDHD variant carriers compared with the general population
Leonie T van Hulsteijn*,1,6, Berdine Heesterman2,6, Jeroen C Jansen2, Jean-Pierre Bayley3, Frederik J Hes4,
Eleonora PM Corssmit1 and Olaf M Dekkers1,5
Germline variants in subunit D of the succinate dehydrogenase gene (SDHD variants) are associated with an increased risk of developing paragangliomas. The aim of this study was to compare mortality rates and survival in a Dutch cohort of SDHD variant carriers with those in the general population. The study was conducted at the Leiden University Medical Center, a tertiary referral center for patients with paragangliomas. Included subjects all tested positive for SDHD variants before 1 July 2012 and visited the departments of Otorhinolaryngology or Endocrinology at least once or had a diagnosed paraganglioma and a
SDHD variant-positive family history. Clinical data were retrieved from medical records, information on mortality was obtained from the Municipal Personal Records Database, and mortality rates for the Dutch population were obtained from the Dutch
Central Bureau of Statistics, stratified by sex, age and date. SDHD variant carriers were followed from the date of first SDHD variant-related contact until death, emigration or 12 December 2012 and the standardized mortality ratio (SMR) was calculated.
Two-hundred and seventy-five SDHD variant carriers were included in the study, of which 80% carried the c.274G4T, p. (Asp92Tyr) variant, had a mean duration of follow-up of 7.6 years, yielding 2242 person-years of observation for analysis. There were 18 deaths in the SDHD variant carrier group; two were paraganglioma related. The SMR for the whole cohort was 1.07 (95% confidence interval 0.67–1.73). In conclusion, mortality in SDHD variant carriers is not substantially increased. Additional studies are required to confirm these findings.
European Journal of Human Genetics advance online publication, 11 March 2015; doi:10.1038/ejhg.2015.36
Germline variants in subunit D of the succinate dehydrogenase (SDH) gene predispose carriers to the development of paragangliomas (PGLs).1 SDHD variants are mainly associated with multifocal PGLs in the head and neck region (HNPGLs), although sympathetic PGLs (sPGLs; extra-adrenal PGLs) and adrenal PGLs (ie, pheochromocytomas,
PCC) also occur.2–4 Although the majority of HNPGLs are benign and indolent tumors,5 their location in close proximity to important neurovascular structures may lead to serious morbidity.6 Neurovascular complications occur in up to 60% of cases following surgical treatment, for example, cranial nerve injury and lesions to the carotid artery.7,8 It is therefore of great importance to carefully consider whether HNPGL should be treated, and a ‘wait and scan’ policy is often the best option.5
Because of their ability to hypersecrete catecholamines, PCC and sPGLs can give rise to severe cardiovascular complications, such as shock, myocardial infarction, dissecting aortic aneurysms or heart failure due to toxic cardiomyopathy.9–12 In order to avoid these potentially lethal complications, adrenalectomy is indicated for PCC,13 and with implementation of appropriate preoperative care to modulate the effects of catecholamine release, perioperative mortality is nil.14–16
The pooled incidence of malignant PGL, defined as the presence of metastases,17–19 in populations comprising both unaffected SDHD variant carriers and SDHD variant carriers with manifest nonmalignant PGL is about 8%.20 Prognosis in malignant PGL is poor, with reported 5-year survival rates of 20–55% for malignant sPGL and
PCC21,22 and 60% for malignant HNPGL,23 although a few cases of survival for 420 years after diagnosis have been described.24,25
An increasing number of SDHD variant carriers are now being identified through (presymptomatic) testing of family members of
SDHD variant carriers with manifest disease, that is, index cases. It is important that these newly identified variant carriers receive reliable prognostic information, including the impact of SDHD variants on mortality and survival. As SDHD variants are associated with a high risk for HNPGLs, and fatal cases of (untreated) PCC have been described, it is important to know whether this translates into increased mortality risk. As this question has not yet been addressed for SDHD variant carriers, the objective of this study was to compare mortality rates and survival in a Dutch cohort of SDHD variant carriers with that of the general Dutch population.
SUBJECTS AND METHODS
The database of the Laboratory for Diagnostic Genome Analysis of the Leiden
University Medical Center (LUMC), a tertiary referral center for patients with
PGLs, was used to identify carriers of SDHD variants. Screening for SDH variants was performed in all persons diagnosed with PGL who agreed to 1Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands ; 2Department of Otorhinolaryngology, Leiden University
Medical Center, Leiden, The Netherlands; 3Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 4Department of Clinical Genetics, Leiden
University Medical Center, Leiden, The Netherlands; 5Departments of Epidemiology, Leiden University Medical Center, Leiden, The Netherlands *Correspondence: Dr LT van Hulsteijn, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, Leiden RC 2300,
The Netherlands. Tel: +31 (0) 71 5268170; Fax: +31 (0) 71 5266868; E-mail: L.T.van_Hulsteijn@lumc.nl 6These authors contributed equally to this work.
Received 7 August 2014; revised 29 December 2014; accepted 3 February 2015
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