Miles Levy

AIP Mutation in Pituitary Adenomas in the 18th Century and Today

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patients teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Increased Population Risk of AIP-related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027–0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011–0.0047) and zero in ROI (0–0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non‐Irish patients (0–2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275–5,000) years. tMRCA‐based simulations predicted 432 (90–5,175) current carriers, including 86 affected (18–1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP‐related disease.

Cardiac Paraganglioma associated with SDHB mutation and elevated 3-methoxytyramine levels

Discussion Paragangliomas almost all produce catecholamines. These catecholamines are metabolized by the tumor within the chromaffin cells to form the orthomethylated products, which are metanephrine (MN), normetanephrine (NM), and 3-methoxytyramine (3-MT) [4]. Sometimes the tumour secretes only these metabolites, and not the catecholamines making it a more sensitive way to detect these tumours. The catecholamine’s and their metabolites are excreted in the urine. The persistently high 3-MT in the absence of high MN or NM in this case is an uncommon biochemical presentation of a paraganglioma.

Siadh associated with neuromyelitis optica involving hypothalamus

Case report • Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a cause of hyponatraemia which has been associated with many central nervous system (CNS) disorders . However, its association with neuromyelitis optica (NMO) or NMO spectrum disorders (NMOSD) is rare. • NMO and NMOSD are inflammatory, autoimmune, demyelinating disorders of CNS predominantly affecting optic nerves and spinal cord but also certain brain regions. They are associated with the presence of IgG antibodies to aquaporin-4 (highly expressed in hypothalamus, brainstem, periventricle & spine). • We report here a case of NMOSD relapse which presented with hyponatraemia due to SIADH.

Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI

OBJECTIVE To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

Cushing's disease detected following an adrenal incidentaloma

Conclusion: • Specific nurse led adrenal incidentaloma clinics are useful to ensure patients receive appropriate initial investigations in a timely manner and helps reduce patients’ visits to hospital for appointments. • Functional adrenal tumours picked up from incidentalomas are not uncommon however functional pituitary lesions discovered following the detection of an adrenal incidentaloma is less common. • It is important to ensure adequate investigations are performed to confirm the diagnosis before proceeding to definitive management. • This patient has undergone a trans-spenoidal hypophasectomy and is doing well on replacement hydrocortisone. She has managed to stop all of her anti-hypertensives and her Cushing’s Disease is in remission. Clinical Cases ePoster – EP2