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Paul Benjamin Loughrey Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Federico Roncaroli Geoffrey Jefferson Brain Research Centre, Division of Neuroscience and Experimental Psychology, School of Medicine, Manchester University, Manchester, UK

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Estelle Healy Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Philip Weir Department of Neurosurgery, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Madhu Basetti Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK

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Ruth T Casey Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Steven J Hunter Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Márta Korbonits Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.

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Paul Benjamin Loughrey Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Brian Herron Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Stephen Cooke Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Philip Weir Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Jayna Elizabeth Smyth Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Karen R Mullan Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Estelle G Healy Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Jane Evanson Department of Radiology, Barts Health NHS Trust, London, UK

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Stephanie G Craig Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK

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Jacqueline A James Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
Northern Ireland Biobank, Belfast Health and Social Care Trust, Belfast, UK

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Márta Korbonits Department of Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Steven J Hunter Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Cushing’s disease is a rare condition that occurs due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing’s disease in Northern Ireland (NI) from 2000 to 2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing’s disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing’s disease of 1.39–1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤ 50 nmol/L (1.8 µg/dL) and ≤ 138 nmol/L (5 µg/dL), respectively, in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer-term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing’s disease had a significantly higher mortality rate compared to the NI general population (standardised mortality ratio 8.10, 95% CI 3.3–16.7, P < 0.001). Annual incidence of Cushing’s disease in NI is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.

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