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• Response
  Nelly Burnichon
  Published on: 13 April 2017
• Should we screen carriers of maternally inherited SDHD mutations?
  Jean-Pierre Bayley
  Published on: 21 February 2017

• Published on: 13 April 2017

  Response

  • Nelly Burnichon, Doctor PARCC Team 13 56 rue Leblanc Paris 75015 France

  We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
  In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
  Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...

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  We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
  In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
  Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confirm or not our data.
  Based on the results of our prospective study, we suggest to inform adult patients of the potential risk and to propose them a first screening that would include imaging. Our clinical experience of 18 years of genetic counselling and management of subjects with genetically determined forms of PPGL within a specialized multidisciplinary team is different from those of our colleagues. In the PGL.EVA study [2,3], we observed a significant decrease of depression and anxiety after initial screening. In the subgroup with tumor diagnosis, we observed a tendency for decrease of depression and no increase of anxiety. In the present study, evaluation of the feeling of patients at the reception of our letter revealed their satisfaction to the interest given by an expert center and to the possibility to take advantage of science progress.
  Moreover, they clearly expressed being comforted by the possibility to communicate with an expert center of the disease in case of symptoms.

  We think that in 2017 a large PPGL revealed by a complication, such as deafness or cardiac complications, in SDHD mutation carrier relatives would be unacceptable. Beyond the mortality rate, which cannot be definitely assessed with a mean duration of follow-up of 7.6 years only as in the paper published by van Hulsteijn [4], the quality of life should also be considered. Interestingly, the same Dutch team reported in 2013 that the quality of life is decreased in patients with paraganglioma (significantly impaired scores on physical, psychological and social subscales) after questioning 174 patients versus 100 controls [5].
  So we do believe that after several reports of clinical cases, our study is a new step forward evidencebased guidelines for SDHD families. Our current recommendations might be further re-evaluated with new data from prospective or randomized studies as well as with the assessment of the natural history of the SDHD-related disease following a prospective long term follow-up of the patients enrolled in hereditary paraganglioma registries equivalent to the French PGL.R.
  Anne-Paule Gimenez-Roqueplo
  Khadija Lahlou-Laforêt
  Nelly Burnichon
  References
  [1]. Hensen EF et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet 2012; 81:284-288
  [2]. Lahlou-Laforêt K. Consoli SM, Caumont-Prim A., Rohmer V., Gimenez-Roqueplo AP, on behalf of the PGL.EVA investigators. Psychological impact of tumor screening in SDHx mutation carriers recruited in a 3 year national protocol. IMPAHC 2015, 5-7 May 2015, Manchester
  [3]. Gimenez-Roqueplo et al. Imaging Work-Up for Screening of Paraganglioma and Pheochromocytoma in SDHx Mutation Carriers: A Multicenter Prospective Study from the PGL.EVA Investigators. J Clin Endocrinol Metab 2014; 98: E162-E173
  [4]. Van Hulsteijn LT et al. No evidence for increased mortality in SDHD variant carriers compared with the general population. Eur J Hum Genet 2015; :23:1713-1716
  [5]. van Hulsteijn LT et al. Quality of life is decreased in patients with paragangliomas. Eur J Endocrinol 2013;168:689-97.

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  Conflict of Interest:
  None declared.

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• Published on: 21 February 2017

  Should we screen carriers of maternally inherited SDHD mutations?

  • Jean-Pierre Bayley
  • Other Contributors:
    • Jeroen C Jansen, Eleonora P M Corssmit, Frederik J Hes

  Dear Editor,

  We are writing to comment on a recent paper published in your journal by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133.

  In this paper a case study is presented describing development of pheochromocytoma in a carrier of an SDHD mutation. Although at first sight not an uncommon occu...

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  Dear Editor,

  We are writing to comment on a recent paper published in your journal by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133.

  In this paper a case study is presented describing development of pheochromocytoma in a carrier of an SDHD mutation. Although at first sight not an uncommon occurrence in carriers of these mutations, this case is unusual because the mutation was inherited via the maternal line. This is now only the third reported case of confirmed phaeochromocytoma development following maternal transmission of an SDHD mutation. [1-3] The patient in question was identified among a cohort of 20 maternal mutation carriers who underwent imaging surveillance. Based on the identification of one patient in this cohort (5%), the authors make recommendations for the clinical care of carriers of a maternally inherited SDHD mutation. They advise targeted familial genetic testing from the age of 18 in families with SDHD mutations, and that identified carriers undergo imaging and biochemical workup to detect asymptomatic tumours. If the first workup is negative, the authors suggest that patients be informed about paraganglioma-phaeochromocytoma (PPGL) symptoms and recommend an annual clinical examination and blood pressure measurement, with a new workup indicated in case of symptoms suggestive of PPGL. Although this paper is a meaningful contribution to the literature, we are concerned that the authors base their subsequent clinical recommendations on a relatively small cohort. In a recent study, we described one confirmed case of maternal transmission and concluded that "we consider the increase in risk represented by these reports to be negligible." [2]

  Two reasons underlie this statement. Firstly, the somatic rearrangements underlying the maternal cases identified to date are far more complex (loss of the paternal wild-type SDHD allele by mitotic recombination, followed by loss of the recombined paternal chromosome containing the paternal 11q23 region and the maternal 11p15 region) than the molecular events seen in paternal cases (loss of whole chromosome 11). Secondly, our conclusions were based, implicitly, on many previous studies at our centre over the past three decades in which we described various aspects of the large SDHD cohort collected by us over that period. Genetic aspects of this cohort, and 601 patients with paternally transmitted SDHD mutations, were described by Hensen and co-workers in 2012. [4] As all previous studies suggest that mutations are equally transmissible via the paternal or maternal line, our identification of a single maternal case among this cohort suggests that the penetrance of maternally transmitted mutations is very low. Using the calculation employed by Burnichon and colleagues and assuming that at least 600 maternal mutation carriers are alive in the Netherlands, we arrive at an estimate of 0.17% (1/601 = 0.17%), rather than their figure of 5%. In addition to our own cohort, 1000's of SDHD mutation carriers have been identified world-wide. Assuming that 1 in 20 maternally transmitted mutations result in tumours, many more maternally inherited cases would have come to our attention, even without surveillance.

  In our opinion the question of management of maternally inherited SDHD mutations comes down to a risk-benefit analysis. The most obvious implication of the recommendations made by Burnichon and colleagues in our patient population would be the institution of surveillance, with all the attendant practical, financial and psychological burdens for 600 carriers of maternally inherited SDHD mutations in order to identify a single case. Furthermore, SDHD-associated PPGL mortality rates and survival in a Dutch cohort of SDHD variant carriers was not substantially increased compared with the general population. [5] In practice, carriers of maternally inherited SDHD mutations at our centre are not advised to undergo surveillance. Instead, we reassure them that their risk of developing PPGL is exceptionally low (described three times worldwide), but that they should be aware, more so than the general population, of symptoms that are suggestive of paraganglioma or phaeochromocytoma. Many families have been in our care for over 25 years and in that time we have found no evidence to suggest that this policy should be revised.

  References

  1 Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM, Cooke A, Murday VA, Davidson HR, Perry CG, Lindsay RS. Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect. J Clin Endocrinol Metab 2011;96:E2009-E2013.

  2 Bayley JP, Oldenburg RA, Nuk J, Hoekstra AS, van der Meer CA, Korpershoek E, McGillivray B, Corssmit EP, Dinjens WN, de Krijger RR, Devilee P, Jansen JC, Hes FJ. Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. BMC Med Genet 2014;15:111.

  3 Burnichon N, Mazzella JM, Drui D, Amar L, Bertherat J, Coupier I, Delemer B, Guilhem I, Herman P, Kerlan V, Tabarin A, Wion N, Lahlou- Laforet K, Favier J, Gimenez-Roqueplo AP. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet 2017;54:125-33.

  4 Hensen EF, van DN, Jansen JC, Corssmit EP, Tops CM, Romijn JA, Vriends AH, Van Der Mey AG, Cornelisse CJ, Devilee P, Bayley JP. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet 2012;81:284-8.

  5 van Hulsteijn LT, Heesterman B, Jansen JC, Bayley JP, Hes FJ, Corssmit EP, Dekkers OM. No evidence for increased mortality in SDHD variant carriers compared with the general population. Eur J Hum Genet 2015;23:1713-6.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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