Context: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. Objective: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. Design, Setting, and Participants: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. Main Outcome Measures: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. Results:SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). Conclusions: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

Context: IL-1, IL-6, and TNF-α play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. Objective: Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. Methods: A total of 168 randomly selected subjects (mean 63 yr, range 52–78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: −0.18 to −0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-α, and the urinary PYR/Cr ratio were measured on both occasions. Results: The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-α, as well as change in hs-CRP (β: −0.41%/U, 95% confidence interval −0.68%, −0.15%) and IL-6 (β: −0.62%/U, 95% confidence interval −1.01%, −0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-α (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. Conclusions: Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.

Severe iodine deficiency (ID) during gestation is associated with neurocognitive sequelae. The long-term impact of mild ID, however, has not been well characterized. The purpose of this study was to determine whether children born to mothers with urinary iodine concentrations (UICs) <150 μg/L during pregnancy have poorer educational outcomes in primary school than peers whose mothers did not have gestational ID (UIC ≥150 μg/L). This was a longitudinal follow-up (at 9 years old) of the Gestational Iodine Cohort. Pregnancy occurred during a period of mild ID in the population, with the children subsequently growing up in an iodine-replete environment. Participants were children whose mothers attended The Royal Hobart Hospital (Tasmania) antenatal clinics between 1999 and 2001. Australian national curriculum and Tasmanian state curriculum educational assessment data for children in year 3 were analyzed. Children whose mothers had UIC <150 μg/L had reductions of 10.0% in spelling (-41.1 points, 95% confidence interval [CI], -68.0 to -14.3, P = .003), 7.6% in grammar (-30.9 points, 95% CI, -60.2 to -1.7, P = .038), and 5.7% in English-literacy (-0.33 points, 95% CI, -0.63 to -0.03, P = .034) performance compared with children whose mothers' UICs were ≥150 μg/L. These associations remained significant after adjustment for a range of biological factors (maternal age at birth of child, gestational length at time of birth, gestational age at time of urinary iodine collection, birth weight, and sex). Differences in spelling remained significant after further adjustment for socioeconomic factors (maternal occupation and education). This study provides preliminary evidence that even mild iodine deficiency during pregnancy can have long-term adverse impacts on fetal neurocognition that are not ameliorated by iodine sufficiency during childhood.

Purpose: A reliable method for diagnosing parathyroid carcinoma has remained elusive over the years, resulting in its under-recognition and suboptimal therapy. Obtaining an accurate diagnosis has become an even more pressing matter with recent evidence that germline HRPT2 gene mutations are found in patients with apparently sporadic parathyroid carcinoma. There is a high prevalence of HRPT2 gene mutations and biallelic inactivation in parathyroid carcinoma. We hypothesize that loss of parafibromin, the protein product of the HRPT2 gene, would distinguish carcinoma from benign tissue.