Richard Lifton and colleagues identify somatic and germline mutations in the CACNA1D calcium channel gene in aldosterone-producing adenomas and primary aldosteronism. Their functional studies show that these mutations result in channel activation at more hyperpolarized membrane potentials, implicating increased Ca2+ influx in disease pathogenesis. Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca2+ influx cause ∼40% of these tumors1. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca2+ channel mutations in APAs and primary aldosteronism.

Background: Rickets and vitamin D deficiency appeared to increase in Alaskan children starting in the 1990s. We evaluated the epidemiology of rickets and vitamin D deficiency in Alaska native (AN) children in 2001–2010. Methods: We analyzed 2001–2010 visits with rickets or vitamin D deficiency diagnosis for AN and American Indian children and the general US population aged <10 years. We conducted a case-control study of AN rickets/vitamin D deficient cases and age- and region-matched controls. Results: In AN children, annual rickets-associated hospitalization rate (2.23/100,000 children/year) was higher than the general US rate (1.23; 95% CI 1.08–1.39). Rickets incidence increased with latitude. Rickets/vitamin D deficiency cases were more likely to have malnutrition (OR 38.1; 95% CI 4.9–294), had similar breast-feeding prevalence, and were less likely to have received vitamin D supplementation (OR 0.23; 95% CI 0.1–0.87) than controls. Conclusions: Our findings highlight the importance of latitude, malnutrition, and lack of vitamin D supplementation as risk factors for rickets.

Introduction Diabetes distress (DD) describes the unrelenting emotional and behavioral challenges of living with, and caring for someone living with, type 1 diabetes (T1D). We investigated associations between parent-reported and child-reported DD, T1D device use, and child glycated hemoglobin (HbA1c) in 157 families of school-age children. Research design and methods Parents completed the Parent Problem Areas in Diabetes-Child (PPAID-C) and children completed the Problem Areas in Diabetes-Child (PAID-C) to assess for DD levels. Parents also completed a demographic form where they reported current insulin pump or continuous glucose monitor (CGM) use (ie, user/non-user). We measured child HbA1c using a valid home kit and central laboratory. We used correlations and linear regression for our analyses. Results Children were 49% boys and 77.1% non-Hispanic white (child age (mean±SD)=10.2±1.5 years, T1D duration=3.8±2.4 years, HbA1c=7.96±1.62%). Most parents self-identified as mothers (89%) and as married (78%). Parents’ mean PPAID-C score was 51.83±16.79 (range: 16–96) and children’s mean PAID-C score was 31.59±12.39 (range: 11–66). Higher child HbA1c correlated with non-pump users (r=−0.16, p<0.05), higher PPAID-C scores (r=0.36, p<0.001) and higher PAID-C scores (r=0.24, p<0.001), but there was no association between child HbA1c and CGM use. A regression model predicting child HbA1c based on demographic variables, pump use, and parent-reported and child-reported DD suggested parents’ PPAID-C score was the strongest predictor of child HbA1c. Conclusions Our analyses suggest parent DD is a strong predictor of child HbA1c and is another modifiable treatment target for lowering child HbA1c.

Objective: This paper reports on the initial outcomes of a new mHealth intervention to reduce diabetes distress (DD) in families of school-age children living with type 1 diabetes (T1D) entitled, ‘Remedy to Diabetes Distress’ (R2D2). Methods: We randomized 34 families (mean child age = 10 ± 1.4 years; 53% male, 85% White, mean HbA1c = 7.24 ± 0.71%) to one of three delivery arms differing only by number of telehealth visits over a 10-week period: zero visits = self-guided (SG), three visits = enhanced self-guided (ESG), or eight visits = video visits (VV). All families had 24 × 7 access to digital treatment materials for 10 weeks. We examined the feasibility and acceptability of R2D2. We used the Problem Areas in Diabetes-Child (PPAIDC and PAIDC, parent and child, respectively) to examine treatment effects by time and delivery arm. We performed sensitivity analyses to characterize families who responded to R2D2. Results: It was feasible for families to access R2D2 mHealth content independently, though attendance at telehealth visits was variable. Parents and children reported high satisfaction scores. There were significant pre-post reductions in PPAIDC (p = 0.026) and PAIDC (p = 0.026) scores but no differences by delivery arm. There were no differences in child age, sex, race, or pre-treatment HbA1c for responders versus non-responders, though families who responded reported higher PPAID-C scores pre-treatment (p = 0.01) and tended to report shorter diabetes duration (p = 0.08). Conclusions: Initial results support the acceptability and treatment effects of R2D2 regardless of the frequency of adjunctive virtual visits. Characterizing responders may help to identify families who could benefit from R2D2 in the future.