SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma.

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient's SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient's father's paraganglioma. LEARNING POINTS: Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease. SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.Immunohistochemistry may not always predict the presence of SDHx mutations.

Preimplantation genetic diagnosis: understanding what parents plan to tell their children about their conception.

Over 10,000 babies have been born by PGD and PGS worldwide (Simpson, Prenatal Diagnosis 30(7): 682-695 2010). The experience of parents who have undergone this procedure and their children's well-being are documented, but no research to date has explored whether parents intend to tell their children how they were conceived and whether this raises special issues for them. PGD practitioners recommend research in this area as parents of children born by PGD increasingly ask questions pertaining to disclosure. We conducted 30 in-depth interviews with couples who have had a baby conceived by PGD. We explored what couples plan to tell their children about how they were conceived, when they plan to do this, and issues they anticipate may arise. The couples had a family history of a monogenic disorder or chromosome rearrangement. Six themes emerged which highlight key issues: (1) To tell or not to tell? (2) Primary reason for undergoing PGD, (3) The ideal time to tell, (4) Situations which may warrant earlier disclosure, (5) Words which parents might choose, and (6) Issues which parents anticipate may arise. We conclude that parents are likely to inform their children about PGD because there is an affected sibling or relative about whom they ask questions, and/or their children are carriers of a condition their parents feel obliged to tell them about. Parents felt they would benefit from access to a genetic counsellor at the time of disclosure and are optimistic about the future of reproductive technology for their children.