Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

Late Ebola virus relapse causing meningoencephalitis: a case report.

BACKGROUND: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2). METHODS: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. FINDINGS: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. INTERPRETATION: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. FUNDING: Royal Free London NHS Foundation Trust.

Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

CONTEXT: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. OBJECTIVE: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. METHODS: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. RESULTS: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. CONCLUSION: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia.

OBJECTIVE: Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. DESIGN: We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. METHODS: Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. RESULTS: The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L-1 (IQR 8.3) versus 10.5 nmol L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L-1 s-1 (IQR 1.0) to 0.48 ng L-1 s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L-1 s-1 (IQR 0.66) to 0.52 ng L-1 s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L-1 to 139.3 ± 1.8 mmol L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L-1 to 139.3 ± 1.9 mmol L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. CONCLUSION: 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Withdrawn as duplicate: Expanding the phenotypic spectrum of Kenny-Caffey syndrome: a case series and systematic literature review.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Disorders of blood pressure regulation-role of catecholamine biosynthesis, release, and metabolism.

Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia.

CONTEXT: Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. OBJECTIVE: We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. METHODS: A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. RESULTS: The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). CONCLUSION: MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

Gender-Affirming Hormone Therapy, Vascular Health and Cardiovascular Disease in Transgender Adults.

Gender-affirming or cross-sex hormone therapy is integral to the management of transgender individuals yet our appreciation of the effects of such hormones on cardiovascular health is limited. Insights into vascular pathophysiology and outcomes in transgender people receiving sex steroids could be fundamental in providing better care for this population through the management of cardiovascular risk and more broadly advance our understanding of the role of sex and gender in vascular health and disease. In addition, there is a need to understand how gender-affirming hormone therapy impacts cardiovascular disease risk and events as transgender individuals age. This review explores the available evidence on the associations between gender-affirming hormones and cardiovascular events such as coronary artery disease, stroke, hypertension, thrombosis, lipid abnormalities, and diabetes mellitus. Current research about vascular outcomes in adults receiving hormonal therapy is limited by the absence of large cohort studies, lack of appropriate control populations, and inadequate data acquisition from gender identity services. Existing epidemiological data suggest that the use of estrogens in transgender females confers an increased risk of myocardial infarction and ischemic stroke. Conversely, transgender males receiving testosterone lack any consistent or convincing evidence of increased risk of cardiovascular or cerebrovascular disease. Further studies are required to confirm whether such risk exists and the mechanisms by which they occur.

Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic Acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma.

CONTEXT: Recent evidence suggests that plasma-free metanephrines provide a highly sensitive test in patients requiring exclusion of pheochromocytoma. The diagnostic efficacy of urinary free metanephrines, however, has not been evaluated. OBJECTIVE, DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: We compared retrospectively the diagnostic efficacy of 24-h urinary free metanephrines with our currently available measurements of 24-h urinary vanillyl mandelic acid (VMA), urinary catecholamines, and plasma catecholamines in 159 outpatients tested in a tertiary referral center for pheochromocytoma over a 4-yr period. RESULTS: The sensitivity of urinary free metanephrines was 100% [25 of 25 patients; 95% confidence interval (CI) 86-100%)] compared with the sensitivity of 84% (21 of 25; 95% CI 64-95%) for urinary catecholamines; 72% (18 of 25; 95% CI 51-88%) for urinary VMA; and 76% (16 of 21; 95% CI 53-92%) for plasma catecholamines. The specificity of urinary free metanephrines was 94% (116 of 123; 95% CI 89-98%), compared with the specificity of 99% (127 of 129; 95% CI 96-100%) for urinary catecholamines; 96% (130 of 134; 95% CI 91-98%) for urinary VMA; and 88% (66 of 75; 95% CI 78-94%) for plasma catecholamines. Receiver operating characteristic curves for all test groups were generated. Pairwise comparisons of the area under the receiver operating characteristic curve for urinary free metanephrines with that of each of the other three test groups individually were: 0.993 (95% CI 0.962-0.999) vs. 0.919 (95% CI 0.862-0.957, P = 0.032) for urine catecholamines; 0.993 (95% CI 0.962-0.999) vs. 0.846 (95% CI 0.778-0.900, P = 0.002) for urine VMA; and 0.992 (95% CI 0.945-0.998) vs. 0.852 (95% CI 0.762-0.918, P = 0.009) for plasma catecholamines. Testing with urinary free metanephrines failed to misidentify a single case of pheochromocytoma, compared with four missed cases for urinary catecholamines, seven missed cases for urinary VMA, and five missed cases for plasma catecholamines. CONCLUSION: Urinary free metanephrines were superior to urinary VMA, urinary catecholamines, and plasma catecholamines and can provide a valuable test for diagnosis of pheochromocytoma in adults.

Functioning paraganglioma and gastrointestinal stromal tumor of the jejunum in three women: syndrome or coincidence.

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome. Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST. The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.

Review of growth hormone therapy in adolescents and young adults with Prader-Willi syndrome.

Consensus guidelines from the Growth Hormone Research Society Workshop recommend growth hormone therapy in all children with genetically confirmed Prader-Willi syndrome (PWS) in combination with dietary, lifestyle and environmental interventions. As yet, however, there are limited published data regarding the use of growth hormone therapy in adolescents and young adults with PWS. This review focuses on the advantages and disadvantages of growth hormone therapy in this particular group. The risk of complications, challenges with consent for therapy, the need for contraception in females with PWS and the appropriate monitoring required are all factors which must be carefully considered in this challenging patient group. Transition from paediatric to adult services can be difficult for most adolescents, but especially so for PWS adolescents and should be undertaken under the care of experienced paediatric and adult endocrinologists and a multidisciplinary team approach. Further research is, however, still required in the management of PWS patients during adolescence.

Deficits in Trabecular Bone Microarchitecture in Young Women With Type 1 Diabetes Mellitus.

The pathophysiological mechanism of increased fractures in young adults with type 1 diabetes mellitus (T1DM) is unclear. We conducted a case-control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Thirty women with T1DM with a median age (range) age of 22.0 years (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7 years (0.46, 14.8) were compared with 28 age-matched healthy women who acted as controls. Measurements included MRI-based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA), and abdominal adipose tissue and biochemical markers of GH/IGF-1 axis (IGF-1, IGFBP3, ALS) and bone turnover. Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n = 15) compared with 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5733 mm(3) (2030, 11,144) and 3460 mm(3) (1808, 6832), respectively (p = 0.012), there was no difference in median BMA, which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF-1 and ALS were also lower in cases, and the latter showed an inverse association to appTbSp (r = -0.30, p = 0.04). Detailed MRI studies in young women with childhood-onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy.

Insulin-sensitising agents: beyond thiazolidinediones.

The global prevalence of Type 2 diabetes mellitus is increasing rapidly, at least in part as a function of obesity. The results of the United Kingdom Prospective Diabetes Study emphasise the importance of developing safe, efficacious new agents for the treatment of Type 2 diabetes. The pharmaceutical industry has recently focused on strategies to improve insulin resistance, particularly modulation of PPAR-gamma. Here we review current thinking on the mechanism of action of these agents, and consider future directions that may arise as a result of increasing understanding of the biology of these receptors and of insulin action. Studies of thiazolidinedione action in adipose tissue have revealed several novel adipocyte-derived hormones that may also be future pharmacological targets for increasing insulin sensitivity. The role of other hormones, such as cortisol and dehydroepiandrosterone, are also discussed in a therapeutic context, as are other novel approaches to the pharmacological management of patients with insulin resistance and Type 2 diabetes.

Euglycemic clamp insulin sensitivity and longitudinal systolic blood pressure: role of sex.

Insulin resistance may be an independent risk factor for the development of hypertension, but change in blood pressure (BP) over time has not been adequately studied in healthy individuals fully characterized for insulin sensitivity. In the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study, we measured insulin sensitivity (M/I) using the euglycemic clamp technique in 1073 healthy European adults (587 women, 486 men) aged 30 to 60 years followed up 3 years later. Systolic BP (SBP) at baseline was higher in insulin-resistant women (ie, those in the low sex-specific M/I tertile) compared with those in the intermediate (P<0.001) or high tertiles (P=0.06; mean ± SD: 117 ± 13, 111 ± 12, 114 ± 12 mm Hg, respectively). It did not differ across M/I tertiles in men. After adjustment for age, body mass index, baseline SBP, and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not in men; M/I was not associated with change in diastolic BP. SBP rose over time in both sexes and within all M/I tertiles (P<0.05), except in women with high insulin sensitivity. Therefore, in women (but not in men), low insulin sensitivity was associated with higher SBP at 3 years, and high insulin sensitivity was associated with a lower rise in SBP over time.

Urinary free (unconjugated) metadrenalines in different hereditary forms of catecholamine-secreting phaeochromocytoma/paraganglioma.

BACKGROUND: Catecholamine-producing neuroendocrine tumours are found in chromaffin cells of the adrenal medulla (phaeochromocytoma) or extra-adrenal paraganglia (paraganglioma), known collectively as PPGLs. In approximately a quarter or more of cases of PPGL, these rare tumours arise as a result of germline mutations of several tumour susceptibility genes. At the Crosshouse laboratory, urine tests include free metadrenalines (fMAs) (also known as free metanephrines) which demonstrate superior sensitivity over that obtained by urinary vanillyl mandelic acid, catecholamines or plasma catecholamines in the diagnosis of PPGL. This retrospective audit was to determine if urinary fMAs offered discrimination among the hereditary forms of PPGL. METHODS: Retrospective biochemical and genetic data were gathered from 1997 to 2011. The identified urine specimens were those obtained at the time of first diagnosis or recurrence of PPGL. Results of catecholamines and metabolites were standardized as multiples of their respective relevant upper reference limits (URLs). RESULTS: Results were available for 29 affected patients (15 females and 14 males), median age 26 (range 9-63) years, comprising three mutation groups: succinate dehydrogenase subunit B or D ([SDHB/D] 16 patients), multiple endocrine neoplasia type 2 ([MEN 2] 6 patients) and von Hippel-Lindau disease ([VHL] 7 patients). The parent catecholamines exhibited increased values for noradrenaline (NA) and/or adrenaline (AD) for 25/29 (86.2%) patients. Either or both free normetadrenaline (fNMA) and fMA were elevated in 29/29 (100%) patients. CONCLUSIONS: The ratio of the multiples of URL for fMA/fNMA displayed a clearer separation of MEN 2 patients from those with SDHB/D or VHL than did the equivalent AD/NA ratio.

Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.

CONTEXT: Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable. OBJECTIVE: We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation. DESIGN: The design of the investigation was the study of a three-generation family with SDHD c.242C>T (p.Pro81Leu) mutation. RESULTS: The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene. CONCLUSIONS: Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.