Publications by authors named "Scott Akker"

51 Publications

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

Clin Endocrinol (Oxf) 2021 Sep 24. Epub 2021 Sep 24.

Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.

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.
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http://dx.doi.org/10.1111/cen.14594DOI Listing
September 2021

Performance evaluation of scoring systems for predicting post-operative hypertension cure in primary aldosteronism.

Clin Endocrinol (Oxf) 2021 Oct 19;95(4):576-586. Epub 2021 Jun 19.

Department of Endocrinology, St Bartholomew's Hospital, London, UK.

Objective: Hypertension cure following adrenalectomy in unilateral primary aldosteronism is not guaranteed. Its likelihood is associated with pre-operative parameters, which have been variably combined in six different predictive scoring systems. The relative performance of these systems is currently unknown. The objective of this work was to identify the best performing scoring system for predicting hypertension cure following adrenalectomy for primary aldosteronism.

Design: Retrospective analysis in a single tertiary referral centre.

Patients: Eighty-seven adult patients with unilateral primary aldosteronism who had undergone adrenalectomy between 2004 and 2018 for whom complete data sets were available to calculate all scoring systems.

Measurements: Prediction of hypertension cure by each of the six scoring systems.

Results: Hypertension cure was achieved in 36/87 (41.4%) patients within the first post-operative year, which fell to 18/71 (25.4%) patients at final follow-up (median 53 months, P = .002). Analysis of receiver operating characteristic area under the curves for the different scoring systems identified a difference in performance at early, but not late, follow-up. For all systems, the area under the curve was lower at early compared with late follow-up and compared to performance in the cohorts in which they were originally defined.

Conclusions: No single scoring system performed significantly better than all others when applied in our cohort, although two did display particular advantages. It remains to be determined how best such scoring systems can be incorporated into the routine clinical care of patients with PA.
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http://dx.doi.org/10.1111/cen.14534DOI Listing
October 2021

The Importance of Recognizing a Locally Advanced Pheochromocytoma.

J Clin Endocrinol Metab 2021 Aug;106(9):e3771-e3772

Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, EC1M 6BQ, United Kingdom.

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http://dx.doi.org/10.1210/clinem/dgab366DOI Listing
August 2021

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Nat Rev Endocrinol 2021 07 21;17(7):435-444. Epub 2021 May 21.

INSERM, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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http://dx.doi.org/10.1038/s41574-021-00492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205850PMC
July 2021

Glucocorticoid replacement therapies: past, present and future.

Curr Opin Endocr Metab Res 2019 Oct 4;8:152-159. Epub 2019 Sep 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Since the original description of adrenal insufficiency by Thomas Addison in 1855, there has been an exponential growth in the understanding of adrenal gland biology and its role in the hypothalamic-pituitary-adrenal axis. Despite this, the mainstay of therapeutic glucocorticoid replacement for most clinicians has remained unchanged for nearly 50 years. More recently, there has been better recognition of the morbidity and mortality associated with current approaches and the challenges to tackle in reducing this and improving clinical outcomes. In this review, we have summarised the history of glucocorticoid replacement therapy from its nascence in the 1930s, through common practice and culminating in more recent glucocorticoid replacement strategies plus the potential of stem cell therapy in the future.
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http://dx.doi.org/10.1016/j.coemr.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116186PMC
October 2019

Haemodynamic instability of the phaeochromocytoma.

Gland Surg 2020 Aug;9(4):869-871

Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.21037/gs-20-524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475346PMC
August 2020

Low-grade Cortisol Cosecretion Has Limited Impact on ACTH-stimulated AVS Parameters in Primary Aldosteronism.

J Clin Endocrinol Metab 2020 10;105(10)

Department of Endocrinology, St Bartholomew's Hospital, London, UK.

Context: In primary aldosteronism, cosecretion of cortisol may alter cortisol-derived adrenal venous sampling indices.

Objective: To identify whether cortisol cosecretion in primary aldosteronism alters adrenal venous sampling parameters and interpretation.

Design: Retrospective case-control study.

Setting: A tertiary referral center.

Patients: 144 adult patients with primary aldosteronism who had undergone both adrenocorticotropic hormone-stimulated adrenal venous sampling and dexamethasone suppression testing between 2004 and 2018.

Main Outcome Measures: Adrenal venous sampling indices including adrenal vein aldosterone/cortisol ratios and the selectivity, lateralization, and contralateral suppression indices.

Results: 21 (14.6%) patients had evidence of cortisol cosecretion (defined as a failure to suppress cortisol to ≤50 nmol/L post dexamethasone). Patients with evidence of cortisol cosecretion had a higher inferior vena cava cortisol concentration (P = .01) than those without. No difference was observed between the groups in terms of selectivity index, lateralization index, lateralization of aldosterone excess, or adrenal vein cannulation rate.

Conclusions: Cortisol cosecretion alters some parameters in adrenocorticotrophic hormone-stimulated adrenal venous sampling but does not result in alterations in patient management.
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http://dx.doi.org/10.1210/clinem/dgaa519DOI Listing
October 2020

First-positive surveillance screening in an asymptomatic SDHA germline mutation carrier

Endocrinol Diabetes Metab Case Rep 2019 May 30;2019(1). Epub 2019 May 30.

Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

Summary: At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified. Among these, mutations in the subunits of succinate dehydrogenase complex (SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants were identified retrospectively. We report the case of an asymptomatic suspected carotid body tumour found during surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge, this is the first screen that detected PPGL found in a previously identified SDHA pathogenic variant carrier, during surveillance imaging. This finding supports the use of cascade genetic testing and surveillance screening in all carriers of a pathogenic SDHA variant.

Learning Points: SDH mutations are important causes of PPGL disease. SDHA is much rarer compared to SDHB and SDHD mutations. Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL. Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease. Surveillance screening for SDH-related disease should be performed in identified carriers of a pathogenic SDHA variant.
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http://dx.doi.org/10.1530/EDM-19-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548220PMC
May 2019

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy.

Endocrinol Diabetes Metab Case Rep 2019 May 3;2019. Epub 2019 May 3.

Department of Endocrinology, St. Bartholomew's Hospital, West Smithfield, London, UK.

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing's syndrome, Liddle's syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.
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http://dx.doi.org/10.1530/EDM-18-0164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499913PMC
May 2019

Impact of thyroiditis on 131I uptake during ablative therapy for differentiated thyroid cancer.

Endocr Connect 2019 May;8(5):571-578

Barts Health NHS Trust, Barts and the London School of Medicine and Dentistry, London, UK.

Context: Differentiated thyroid cancer (DTC) is usually treated by thyroidectomy followed by radioiodine ablation and generally has a good prognosis. It may now be possible to limit the amount of treatment without impacting on efficacy. It is not known whether coexistent thyroiditis impacts on radioiodine uptake or on its potential efficacy, but this could provide a rationale for modification to current therapeutic protocols.

Design: This was a retrospective cohort study of radioiodine uptake on imaging after radioiodine ablation for DTC in patients with and without concurrent thyroiditis. All patients with histologically confirmed DTC treated with radioiodine ablation after thyroidectomy in a single centre from 2012 to 2015 were included. The primary outcome assessed was the presence of low or no iodine uptake on post-ablation scan, as reported by a nuclear medicine physician blinded to the presence or absence of thyroiditis.

Results: One hundred thirty patients with available histopathology results were included. Thyroiditis was identified in 42 post-operative specimens and 15 of these patients had low or no iodine uptake on post-ablation scan, compared to only 2 of 88 patients without thyroiditis (P < 0.0001) with further data analysis dividing the groups by ablation activity received (1100 MBq or 3000 MBq).

Conclusions: Concurrent thyroiditis may impair the uptake of radioactive iodine in management of DTC. Given that patients with DTC and thyroiditis already have a good prognosis, adopting a more selective approach to this step in therapy may be indicated. Large, longitudinal studies would be required to determine if omitting radioactive iodine therapy from those patients with concurrent thyroiditis has a measurable impact on mortality from thyroid cancer.
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http://dx.doi.org/10.1530/EC-19-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499916PMC
May 2019

Diffusion-weighted imaging (DWI) highlights SDHB-related tumours: A pilot study.

Clin Endocrinol (Oxf) 2019 07 11;91(1):104-109. Epub 2019 Apr 11.

Department of Endocrinology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.

Objective: There is consensus that asymptomatic carriers of SDHB mutations should undergo periodic surveillance imaging. MRI has the advantage of avoiding radiation exposure but its sensitivity and specificity for detecting phaeochromocytoma and paraganglioma (PPGL) are dependent on sequences performed and expertise of reporting radiologists. We aim to highlight the additional value of diffusion-weighted imaging (DWI) for MR based surveillance, demonstrating DWI's ability to identify small PPGLs at all body sites.

Design: We presented DWI sequences taken as part of SDHB surveillance to a radiologist, expert in reporting PPGL screening scans. Areas of high signal on DWI were interrogated using other standard MRI sequences.

Patients: We reviewed the MRI scans for 18 SDHB mutation carriers with a total of 18 histologically proven SDHB-related tumours and 12 presumed PGLs/metastatic deposits.

Results: The DWI sequences identified all 30 lesions. False-positive lesions were excluded by standard sequences. The tumours detected by DWI ranged in size from 5 to 52 mm. PPGLs were identified on DWI in the abdomen (n = 14), adrenal gland (n = 1), thorax (n = 3), neck (n = 2) and bladder (n = 2). Additionally, other SDHB-related tumours (GIST, RCC) were also highlighted by DWI, as were metastatic deposits in the liver and bone.

Conclusions: These preliminary data suggest that DWI has high sensitivity and can identify even small SDHB-related tumours. If these findings are confirmed in larger series, for all SDH subunits, it will provide reassurance about identifying small SDH-related tumours, without exposing patients to the consequences of radiation-based imaging and will secure the role of MRI for surveillance imaging.
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http://dx.doi.org/10.1111/cen.13980DOI Listing
July 2019

An analysis of surveillance screening for SDHB-related disease in childhood and adolescence.

Endocr Connect 2019 Mar;8(3):162-172

Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Objective Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected. Method We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations. Results Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening. Conclusions Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.
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http://dx.doi.org/10.1530/EC-18-0522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391899PMC
March 2019

Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Clin Endocrinol (Oxf) 2019 01 28;90(1):31-46. Epub 2018 Nov 28.

Department of Endocrinology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.

Objective: With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers.

Design: A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance).

Results: The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%).

Conclusions: Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes.
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http://dx.doi.org/10.1111/cen.13877DOI Listing
January 2019

A prospective longitudinal study of Pasireotide in Nelson's syndrome.

Pituitary 2018 Jun;21(3):247-255

Department of Oncology and Metabolism, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.

Purpose: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome.

Methods: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly.

Results: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients.

Conclusions: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume.

Trial Registration: Clinical Trials.gov ID, NCT01617733.
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http://dx.doi.org/10.1007/s11102-017-0853-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942349PMC
June 2018

Radiological Surveillance Screening in Asymptomatic Succinate Dehydrogenase Mutation Carriers.

J Endocr Soc 2017 Jul 6;1(7):897-907. Epub 2017 Jun 6.

Department of Endocrinology, St. Bartholomew's Hospital, Barts Health National Health Service Trust, West Smithfield, London EC1A 7BE, United Kingdom.

There has been a significant increase in the availability of testing for pheochromocytoma and paraganglioma (PPGL) germline susceptibility genes. As more patients with genetic mutations are identified, cascade genetic testing of family members is also increasing. This results in identifying genetic predispositions at a much earlier age. With our current understanding of familial PPGL syndromes, lifelong surveillance is required. This review focuses on carriers of succinate dehydrogenase () mutations. For genetic testing to be proven worthwhile, the results must be used for patient benefit. For mutations, this should equate to a surveillance program that is safe and removes as much uncertainty around diagnosis as possible. Early identification of these tumors is the goal of any surveillance program, as surgical resection is the mainstay of treatment with curative intent to prevent the morbidity and mortality consequences associated with catecholamine excess, in addition to the risk of malignancy. Modality and frequency of surveillance imaging and how to engage individuals in the process of surveillance remain controversial questions. The data reviewed here and the cumulative advice supports the avoidance of using radiation-exposing imaging in this group of individuals that require lifelong screening.
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http://dx.doi.org/10.1210/js.2017-00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686572PMC
July 2017

Excluding the pheochromocytoma.

Int J Cardiol 2017 12;249:326-327

St Bartholomew's Hospital, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2017.08.061DOI Listing
December 2017

mutated paragangliomas may be at high risk of metastasis.

Endocr Relat Cancer 2017 07 12;24(7):L43-L49. Epub 2017 May 12.

Department of EndocrinologySt Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK

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http://dx.doi.org/10.1530/ERC-17-0030DOI Listing
July 2017

Adrenal Vein Catecholamine Levels and Ratios: Reference Intervals Derived from Patients with Primary Aldosteronism.

Horm Metab Res 2017 Jun 26;49(6):418-423. Epub 2017 Apr 26.

Department of Endocrinology, St Bartholomew's Hospital, London, UK.

Phaeochromocytoma localisation is generally reliably achieved with modern imaging techniques, particularly in sporadic cases. On occasion, however, there can be diagnostic doubt due to the presence of bilateral adrenal abnormalities, particularly in patients with mutations in genes predisposing them to the development of multiple phaeochromocytomas. In such cases, surgical intervention is ideally limited to large or functional lesions due to the long-term consequences associated with hypoadrenalism. Adrenal venous sampling (AVS) for catecholamines has been used in this situation to guide surgery, although there are few data available to support diagnostic thresholds. Retrospective analyses of AVS results from 2 centres were carried out. A total of 172 patients (88 men, 84 women) underwent AVS under cosyntropin stimulation for the diagnosis of established primary aldosteronism (PA) with measurement of adrenal and peripheral venous cortisol, aldosterone and catecholamines. Six patients (3 men, 3 women) with phaeochromocytoma underwent AVS for diagnostic purposes with subsequent histological confirmation. Reference intervals for the adrenal venous norepinephrine to epinephrine ratio were created from the PA group. Using the 97.5th centile (1.21 on the left, 1.04 on the right), the false negative rate in the phaeochromocytoma group was 0%. In conclusion, this study describes the largest dataset of adrenal venous catecholamine measurements and provides reference intervals in patients without phaeochromocytoma. This strengthens the certainty with which conclusions related to adrenal venous sampling for catecholamines can be drawn, acknowledging the procedure is not part of the routine diagnostic workup and is an adjunct for use only in difficult clinical cases.
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http://dx.doi.org/10.1055/s-0042-124419DOI Listing
June 2017

Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

Exp Clin Endocrinol Diabetes 2017 Jun 6;125(6):365-367. Epub 2017 Feb 6.

Centre for Endocrinology, WHRI, Barts & the London School of Medicine and Dentistry, Queen Mary University of London.

Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m, ANOVA p=0.034, B vs. C p<0.01). Groups A and B had EDVi and ESVi values at the top of published reference range values; Group C had values in the middle of the range.Acromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension.
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http://dx.doi.org/10.1055/s-0042-123710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193280PMC
June 2017

Long-term outcomes of children treated for Cushing's disease: a single center experience.

Pituitary 2016 Dec;19(6):612-624

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, First Floor, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.

Purpose: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients.

Methods: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2).

Results: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients.

Conclusions: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.
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http://dx.doi.org/10.1007/s11102-016-0756-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080319PMC
December 2016

Outcomes of annual surveillance imaging in an adult and paediatric cohort of succinate dehydrogenase B mutation carriers.

Clin Endocrinol (Oxf) 2017 Feb 24;86(2):286-296. Epub 2016 Oct 24.

Department of Endocrinology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.

Objective: For 'asymptomatic carriers' of the succinate dehydrogenase subunit B (SDHB) gene mutations, there is currently no consensus as to the appropriate modality or frequency of surveillance imaging. We present the results of a surveillance programme of SDHB mutation carriers.

Design: Review of clinical outcomes of a surveillance regimen in patients identified to have an SDHB gene mutation, based on annual MRI, in a single UK tertiary referral centre.

Patients: A total of 92 patients were identified with an SDHB gene mutation. a total of 27 index patients presented with symptoms, and 65 patients were identified as asymptomatic carriers.

Measurements: Annual MRI of the abdomen, with alternate year MRI of the neck, thorax and pelvis. Presence of an SDHB-related tumour included paraganglioma (PGL), phaeochromocytoma (PCC), renal cell carcinoma (RCC) and gastrointestinal stromal tumour (GIST).

Results: A total of 43 PGLs, eight PCCs and one RCC occurred in the 27 index patients (23 solitary, four synchronous, five metachronous). A further 15 SDHB-related tumours (11 PGLs, three RCCs, one GIST) were identified in the asymptomatic carriers on surveillance screening (25% of screened carriers): 10 on the first surveillance imaging and five on subsequent imaging 2-6 years later. A total of 11 patients had malignant disease.

Conclusions: SDHB-related tumours are picked up as early as 2 years after initial negative surveillance scan. We believe the high malignancy rate and early identification rate of tumours justifies the use of 1-2 yearly imaging protocols and MRI-based imaging could form the mainstay of surveillance in this patient group thereby minimizing radiation exposure.
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http://dx.doi.org/10.1111/cen.13246DOI Listing
February 2017

Alpha blockade-not to be underdone.

Clin Endocrinol (Oxf) 2017 02 21;86(2):306-308. Epub 2016 Nov 21.

Department of Endocrinology, St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London.

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http://dx.doi.org/10.1111/cen.13262DOI Listing
February 2017

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

Hum Mutat 2017 01 4;38(1):78-85. Epub 2016 Oct 4.

Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1002/humu.23121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215436PMC
January 2017

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

Eur J Endocrinol 2016 Nov 25;175(5):485-498. Epub 2016 Aug 25.

Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science

Objective: To determine if functional imaging using C-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).
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http://dx.doi.org/10.1530/EJE-16-0639DOI Listing
November 2016

Succinate Dehydrogenase B (SDHB)-Associated Bladder Paragangliomas.

Clin Genitourin Cancer 2017 02 23;15(1):e131-e136. Epub 2016 Jun 23.

Department of Endocrinology, St Bartholomew's Hospital, West Smithfield, London, UK.

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http://dx.doi.org/10.1016/j.clgc.2016.06.006DOI Listing
February 2017

Characterisation of myocardial structure and function in adult-onset growth hormone deficiency using cardiac magnetic resonance.

Endocrine 2016 Dec 17;54(3):778-787. Epub 2016 Aug 17.

Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Growth hormone (GH) can profoundly influence cardiac function. While GH excess causes well-defined cardiac pathology, fewer data are available regarding the more subtle cardiac changes seen in GH deficiency (GHD). This preliminary study uses cardiac magnetic resonance imaging (CMR) to assess myocardial structure and function in GHD. Ten adult-onset GHD patients underwent CMR, before and after 6 and 12 months of GH replacement. They were compared to 10 age-matched healthy controls and sex-matched healthy controls. Left ventricular (LV) mass index (LVMi) increased with 1 year of GH replacement (53.8 vs. 57.0 vs. 57.3 g/m, analysis of variance p = 0.0229). Compared to controls, patients showed a trend towards reduced LVMi at baseline (51.4 vs. 60.0 g/m, p = 0.0615); this difference was lost by 1 year of GH treatment (57.3 vs. 59.9 g/m, p = 0.666). Significantly reduced aortic area was observed in GHD (13.2 vs. 19.0 cm/m, p = 0.001). This did not change with GH treatment. There were no differences in other LV parameters including end-diastolic volume index (EDVi), end-systolic volume index, stroke volume index (SVi), cardiac index and ejection fraction. There was a trend towards reduced baseline right ventricular (RV)SVi (44.1 vs. 49.1 ml/m, p = 0.0793) and increased RVEDVi over 1 year (70.3 vs. 74.3 vs. 73.8 ml/m, p = 0.062). Two patients demonstrated interstitial expansion, for example with fibrosis, and three myocardial ischaemia as assessed by late gadolinium enhancement and stress perfusion. The increased sensitivity of CMR to subtle cardiac changes demonstrates that adult-onset GHD patients have reduced aortic area and LVMi increases after 1 year of GH treatment. These early data should be studied in larger studies in the future.
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http://dx.doi.org/10.1007/s12020-016-1067-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107200PMC
December 2016

Investigation for Paediatric Cushing's Syndrome Using Twenty-Four-Hour Urinary Free Cortisol Determination.

Horm Res Paediatr 2016 10;86(1):21-6. Epub 2016 Jun 10.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Objective: Paediatric Cushing's syndrome (CS) remains a challenge to diagnose and exclude. We assessed the accuracy of 24-hour urinary free cortisol (UFC) determination in children referred for suspected CS.

Design: We conducted a retrospective study of paediatric patients referred to our centre with suspected CS between 1982 and 2014.

Patients: Of 66 subjects (mean age 12.9 years; range 4.4-16.9), there were 47 cases of CS (29 males), which included Cushing's disease (CD; 39 patients, 25 males), primary pigmented nodular adrenocortical disease (8 patients, 4 males) and 19 'controls' (6 males) in whom the diagnosis of CS was excluded.

Measurements: The subjects had between one and five 24-hour UFC collections analysed by radioimmunoassay, chemiluminescent immunoassay or liquid chromatography-mass spectrometry. The data were normalised, corrected for body surface area (m2) and assessed using receiver operating characteristic analysis and an independent two-tailed t test.

Results: The diagnostic accuracy of 24-hour UFC for CS was excellent (area under the curve 0.98, 95% CI 0.946-1.00, sensitivity 89%, specificity 100%).

Conclusions: Twenty-four-hour UFC is a reliable and practical investigation with high diagnostic accuracy for paediatric CS. However, further investigations may be required if the UFC is normal but there is a high diagnostic suspicion of CS.
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http://dx.doi.org/10.1159/000446913DOI Listing
April 2017

Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation.

J Clin Endocrinol Metab 2014 Apr 1;99(4):1122-31. Epub 2013 Jan 1.

Regional Center for Endocrinology and Diabetes (F.W., S.H., A.B.A.), Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland, United Kingdom; Department of Medical Genetics (L.B., P.J.M.), Belfast Health and Social Care Trust, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Endocrinology (H.S.C., H.L.S., S.A.A., M.K.), Barts and London School of Medicine, Queen Mary University of London, London EC1A 6BQ, United Kingdom; North East Thames Regional Genetics Service (A.V.K.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Endocrinology (S.M.O.), St James University Hospital, Leeds LS9 7TF, United Kingdom; Department of Radiology (J.E.), St Bartholomew Hospital, London EC1A 7BE, United Kingdom; and Department of Endocrinology (N.A.), Royal Belfast Hospital for Sick Children, Belfast, BT12 6BA, United Kingdom.

Context: Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues.

Objective: The aim of the study was to identify and screen mutation carriers in the family.

Patients: Forty-three family members participated in the study.

Setting: The study was performed in university hospitals.

Outcome: We conducted genetic and endocrine screening of family members.

Results: We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives.

Conclusions: Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.
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http://dx.doi.org/10.1210/jc.2013-2868DOI Listing
April 2014

Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling.

Clin Endocrinol (Oxf) 2014 Jul 28;81(1):25-30. Epub 2013 Dec 28.

Department of Endocrinology, St. Bartholomew's Hospital, London, UK.

Context: In patients with primary aldosteronism (PA), adrenalectomy is potentially curative for those correctly identified as having unilateral excessive aldosterone production. It has been suggested that a recently developed and published clinical prediction score (CPS) may correctly identify some patients as having unilateral disease, without recourse to adrenal venous sampling.

Objective: We have applied the CPS to a large cohort of PA patients with defined and documented outcomes. We also incorporated a minor modification to the CPS and a radiological grading score (RGS) into our analysis to assess whether its performance could be augmented.

Results: A total of 75 patients with a robust diagnosis following bilateral adrenal venous cannulation and/or strictly defined surgical outcome were analysed. Applying the CPS to this group of patients produced a sensitivity of 38·8% and a specificity of 88·5% of correctly identifying unilateral aldosterone production. Using a suggested modification to the CPS, in which different levels of hypokalaemia were given different weightings, the sensitivity rose to 40·8%, with an identical specificity. Using the RGS alone improved sensitivity to 91·7%, but specificity was reduced to 62·5%.

Conclusion: Applying the recently developed CPS to this cohort of patients, it was not possible to reproduce the 100% specificity reported in the original publication. Using the modified score or incorporating the RGS did not improve its performance. In this cohort, we were unable to show superiority of the CPS over an imaging-based strategy. CPS may have a role in guiding clinical decision-making, especially in those whose adrenal venous sampling (AVS) has been unsuccessful.
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http://dx.doi.org/10.1111/cen.12374DOI Listing
July 2014
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