On 2017 May 11, Jean-Pierre Bayley commented:

Should we screen carriers of maternally inherited SDHD mutations?

Jean-Pierre Bayley (1), Jeroen C Jansen (2), Eleonora P M Corssmit (3) and Frederik J Hes (4) 1. Department of Human Genetics, 2. Department of Otorhinolaryngology, 3. Department of Endocrinology and Metabolic Diseases, 4. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands

We wish to comment on the above paper by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133. 3

In this paper a prospective study is presented that identified and described 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 amongst 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 amongst 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.

NB. A version of this comment has been posted on the Journal of Medical Genetics website and has been commented on in turn by Burnichon and colleagues.

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.

On 2017 May 11, Jean-Pierre Bayley commented:

Should we screen carriers of maternally inherited SDHD mutations?

Jean-Pierre Bayley (1), Jeroen C Jansen (2), Eleonora P M Corssmit (3) and Frederik J Hes (4) 1. Department of Human Genetics, 2. Department of Otorhinolaryngology, 3. Department of Endocrinology and Metabolic Diseases, 4. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands

We wish to comment on the above paper by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133. 3

In this paper a prospective study is presented that identified and described 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 amongst 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 amongst 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.

NB. A version of this comment has been posted on the Journal of Medical Genetics website and has been commented on in turn by Burnichon and colleagues.

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.