Genotype–phenotype correlations in <em>SDHx</em>-associated pituitary disease- a case series. — ASN Events
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Genotype–phenotype correlations in SDHx-associated pituitary disease- a case series. (#303)

Annabelle G Hayes 1 2 , Morton Burt 3 , Lyndal Tycon 4 , Sunita De Sousa 5 , James McNeil 5 , Richard Carroll 6 , Venessa Tsang 1 , Roderick Clifton-Bligh 1 2
  1. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
  2. Cancer Genetics Laboratory , Kolling Institute, Sydney, NSW, Australia
  3. Diabetes and Endocrine Service, Flinders Medical Centre, Adelaide, SA, Australia
  4. Department of Endocrinology, Royal North Shore Hospital , Sydney, NSW, Australia
  5. Royal Adelaide Hospital, Adelaide, SA, Australia
  6. Endocrine, Diabetes and Research Centre, Wellington Regional Hospital, Wellington, New Zealand

Germline mutations in succinate dehydrogenase (SDHx) genes are a recognised driver of paraganglioma and cluster 1 pheochromocytoma through disruption of mitochondrial metabolism and activation of pseudohypoxia signaling. The contribution of SDHx variants to the “3PA” phenotype—pituitary adenoma, paraganglioma, and pheochromocytoma—is increasingly recognised, although pituitary surveillance is not routinely incorporated into genetic screening protocols [1,2]. This study aims to characterise genotype–phenotype correlations in SDHx-associated pituitary disease, with particular focus on mutation type and the tissue-specific effects of succinate accumulation across the spectrum of variant pathogenicity.

Methods: We collated a trans-Tasman case series of individuals with SDHx variants who developed pituitary tumours, identified either through symptomatic presentation or following diagnosis of SDH-related paraganglioma. Clinical, radiological, and genetic data were analysed to explore associations between variant class and tumour phenotype.

Results: Nine cases were identified, with a median age at diagnosis of 29 years (range 6–58). SDHB variants were present in 6/9 cases. Among tumours with defined subtype, 6/8 were prolactinomas, and 4/9 were cystic macroadenomas. Genetic characterisation, available in 7 cases, demonstrated a predominance of missense variants (5/7), suggesting partial loss-of-function mechanisms. In 5/7 cases, SDHx-associated paraganglioma or related tumours preceded the diagnosis of pituitary pathology, supporting a temporal sequence consistent with systemic metabolic predisposition.

Conclusion: This series highlights emerging genotype–phenotype relationships in SDHx-associated tumorigenesis. Specific variant classes may influence tissue susceptibility to oncometabolite accumulation and downstream signaling effects. Improved molecular characterisation may help distinguish sporadic pituitary adenomas from those driven by SDH deficiency and succinate-mediated pseudohypoxia. Establishing a causal genetic link has important clinical implications but often requires tumour tissue analysis for confirmation, difficult in conservatively managed pituitary pathology [2].

  1. [1] Taïeb D, Nölting S, Perrier ND, et al. Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement. Nature Reviews Endocrinology. 2024;20(3):168-184.
  2. [2] Branzoli F, Salgues B, Marjańska M, et al. SDHx mutation and pituitary adenoma: can in vivo 1H-MR spectroscopy unravel the link? Endocrine-Related Cancer. 2023 2023-02-01;30(2).