Universal Germline Panel Testing for Individuals With Pheochromocytoma and Paraganglioma Produces High Diagnostic YieldHorton, Carolyn; LaDuca, Holly; Deckman, Ashley; Durda, Kate; Jackson, Michelle; Richardson, Marcy E; Tian, Yuan; Yussuf, Amal; Jasperson, Kory; Else, Tobias
doi: 10.1210/clinem/dgac014pmid: 35026032
BackgroundPractice guidelines to identify individuals with hereditary pheochromocytomas and paragangliomas (PPGLs) advocate for sequential gene testing strategy guided by specific clinical features and predate the routine use of multigene panel testing (MGPT).ObjectiveTo describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort.SettingCommercial laboratory based in the United States.MethodsClinical data and test results were retrospectively reviewed in 1727 individuals who had targeted MGPT from August 2013 through December 2019 because of a suspicion of hereditary PPGL.ResultsOverall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Most PVs were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.7%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, early age of onset, multiple tumors, and positive family history of PPGL. Individuals with extra-adrenal PGL and a positive family history were the most likely to have a PV (85.9%). Restricting genetic testing to SDHB/C/D misses one-third (32.8%) of individuals with PVs.ConclusionOur data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, and a substantial contribution to diagnostic yield from rare genes. These findings support universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.
Effect of Daily Vitamin D3 Supplementation on Muscle Health: An Individual Participant Meta-analysisBislev, Lise Sofie; Wamberg, Louise; Rolighed, Lars; Grove-Laugesen, Diana; Rejnmark, Lars
doi: 10.1210/clinem/dgac004pmid: 35018442
BackgroundThe role of vitamin D on muscle health is debated.MethodsAn individual participant metanalysis of 4 randomized placebo-controlled trials, investigating short-term (3-9months) effects of vitamin D3 in moderate (2800 IU) to high (7000 IU) daily oral doses on muscle health and quality of life (QoL). Inclusion criteria were either obesity (n = 52), newly diagnosed primary hyperparathyroidism (n = 41), Graves’ disease (n = 86), or secondary hyperparathyroidism (n = 81).ResultsOverall (n = 260) as well as in a subgroup analysis including only vitamin D insufficient [25(OH)D < 50 nmol/L] individuals (n = 176), vitamin D supplementation did not affect measures of muscle health (isometric muscle strength, Timed Up and Go test, chair rising test, body composition, and balance) or QoL. However, a beneficial effect was present on QoL (physical component score) in vitamin D deficient [25(OH)D < 25 nmol/L] individuals (n = 34). Overall, relative changes in 25(OH)D inversely affected maximum muscle strength in a dose-response manner. Stratified into body mass index </> 30 kg/m2, vitamin D supplementation had divergent effects on isometric muscle strength, with beneficial effects in obese individuals (n = 93) at knee flexion 90° (P = 0.04), and adverse effects in nonobese individuals (n = 167) at handgrip (P = 0.02), knee extension 60° (P = 0.03) and knee flexion 60° (P < 0.01).ConclusionOverall, short-term treatment with moderate to high daily doses of vitamin D did not affect muscle health or QoL. A potential beneficial effect was present on muscle strength in severely obese individuals and on QoL in vitamin D deficient individuals. Subgroup analyses, however, suggested negative effects of large relative increases in p-25(OH)D.
Higher Free Triiodothyronine Is Associated With Higher HDL Particle Concentration and Smaller HDL Particle SizePost, Adrian; Garcia, Erwin; Gruppen, Eke G; Kremer, Daan; Connelly, Margery A; Bakker, Stephan J L; Dullaart, Robin P F
doi: 10.1210/clinem/dgac044pmid: 35106588
ContextThyroid function status has effects on the development of atherosclerotic cardiovascular disease by affecting lipid metabolism, but associations of high-density lipoprotein (HDL) particle concentrations and subfractions with thyroid hormone levels within the reference range remain elusive.ObjectiveThe aim of the present study was to determine the associations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels with HDL particle characteristics in euthyroid individuals.MethodsThis cross-sectional study on the associations of thyroid hormones with HDL particle concentrations, HDL subfractions, and HDL particle size included 5844 euthyroid individuals (FT3, FT4, and TSH levels within the reference range and no medication use affecting thyroid function), participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. HDL particles and subfractions were measured by nuclear magnetic resonance using an optimized version of the NMR LipoProfile Test (LP4).ResultsIn multivariable linear regression analyses, FT3 was positively associated with total HDL particle concentration (std.β = 0.14; P < 0.001) and with small (std.β = 0.13; P < 0.001) and medium-sized HDL particles (std.β = 0.05; P = 0.001). Conversely, FT3 was inversely associated with large HDL particles (std.β = −0.07; P < 0.001) and with HDL particle size (std.β = −0.08; P < 0.001). Such associations with FT4 or reciprocally with TSH were less pronounced or nonsignificant.ConclusionIn euthyroid individuals, higher FT3 is cross-sectionally associated with higher total HDL particle concentration and with lower HDL particle size. These associations may be relevant to better understand the role of HDL in thyroid function–associated atherosclerotic cardiovascular disease.
Sex-specific Effect of Maternal Thyroid Hormone Trajectories on Preschoolers’ Behavioral Development: A Birth Cohort StudyLi, Peixuan; Teng, Yuzhu; Ru, Xue; Liu, Zijian; Han, Yan; Tao, Fangbiao; Huang, Kun
doi: 10.1210/clinem/dgab887pmid: 34999790
ContextMaternal thyroid hormone trajectories are a better predictor of offspring’s neurodevelopment than hormone levels in single trimester of pregnancy. Programming effect of uterine hormonal environment on offspring’s health is usually sex-specific.ObjectiveTo examine the sex-specific effect of thyroid hormone trajectories on preschoolers’ behavioral development.DesignBased on Ma’ anshan Birth Cohort in China, pregnant women were recruited at their first antenatal checkup from May 2013 to September 2014.SettingMa’ anshan Maternal and Child Health Hospital in China.Patients or Other Participants1860 mother-child pairs were included in the analysis. Children were followed up at age of 4.Main Outcome MeasuresMaternal thyroid hormones [thyroid-stimulating hormone (TSH), free thyroxine (FT4)] and thyroid peroxidase antibody in the first, second, and third trimesters of pregnancy were retrospectively assayed. Preschoolers’ behavioral development was assessed by Achenbach Child Behavior Checklist/1.5~5.ResultsMaternal TSH and FT4 levels were respectively fitted into high, moderate, and low trajectories. In boys, maternal high TSH trajectory was related to withdrawn [odds ratio (OR) = 2.01, 95% CI: 1.16, 3.50) and externalizing problems (OR = 2.69, 95% CI: 1.22, 5.92), and moderate TSH trajectory was associated with aggressive behavior (OR = 3.76, 95% CI: 1.16, 12.23). Maternal high FT4 trajectory was associated with anxious/depressed (OR = 2.22, 95% CI: 1.08, 4.56) and total problems (OR = 1.74, 95% CI: 1.13, 2.66), and low FT4 trajectory was associated with aggressive behavior (OR = 4.17, 95% CI: 1.22, 14.24).ConclusionsMaternal thyroid hormone trajectories impact preschool boys’ behavioral development.
Surveillance Improves Outcomes for Carriers of SDHB Pathogenic Variants: A Multicenter StudyDavidoff, Dahlia F; Benn, Diana E; Field, Michael; Crook, Ashley; Robinson, Bruce G; Tucker, Katherine; De Abreu Lourenco, Richard; Burgess, John R; Clifton-Bligh, Roderick J
doi: 10.1210/clinem/dgac019pmid: 35037935
ContextCarriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers.ObjectiveThe purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands.MethodsThis was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years.Results181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (P = .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (P = .029).ConclusionSDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.