Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10⁻⁸). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10⁻²⁵) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability (h²).

Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover. The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover. Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study. In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change. Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS.

Context: Visceral adipose tissue (VAT) is established as a risk factor for type 2 diabetes and cardiovascular disease, but the radiation exposure and cost of computed tomography (CT) measurements limits its daily clinical use. Objective: The main objective of this study was to compare the degree of agreement between VAT measurements by a new dual-energy X-ray absorptiometry (DXA) application and one of the standard methods, CT, in a population of patients with Prader-Willi syndrome (PWS) before and after GH treatment. Furthermore, we tested whether VAT estimations by these two methods are equivalent in assessing the metabolic risk in this population. Design and Patients: Data from the Norwegian population of a multicenter study in adults with genetically proven PWS were used. Subjects with complete anthropometry, biochemical, and imagistic measurements at all study visits (baseline and after 12 and 24 months of GH treatment) (n = 14, six men) were included. VAT was quantified both using CT scans (GE Lightspeed 16 Pro) of the abdomen at L2-L3 level and a total body DXA scan (GE Healthcare Lunar Prodigy). Results: VAT DXA was strongly associated with VAT CT at baseline (r = 0.97) and after 12 (r = 0.90) and 24 months (r = 0.89) of GH treatment (all P < .001). We found moderate to strong positive correlations between VAT by both methods, and blood pressure, weight, body mass index, waist circumference, glucose metabolism, and other fat depots (arms, legs, android, trunk, total body) but no association with age, gender, blood lipids, and IGF-I. Adiponectin was negatively associated with the amount of VAT. At baseline, the highest correlation with homeostasis model assessment of insulin resistance (HOMA-IR) was found for VAT DXA (r = 0.76, P = .001) and VAT CT (r = 0.75, P = .002), respectively. Conclusion: VAT can be accurately estimated by DXA, in patients with PWS, and might contribute to the assessment of the metabolic risk.

Context Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = –0.487; P < 0.001). Conclusion In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

Context: Prader-Willi syndrome (PWS) is a rare, genetic, multisymptom, neurodevelopmental disease due to lack of the expression of the paternal genes in the q11 to q13 region of chromosome 15. The main characteristics of PWS are muscular hypotonia, hyperphagia, obesity, behavioral problems, cognitive disabilities, and endocrine deficiencies, including growth hormone (GH) deficiency. Sleep apnea and abnormal sleep patterns are common in PWS. GH treatment might theoretically have a negative impact on respiration. Objective: Here we present the effect of GH treatment on polysomnographic measurements. Methods: Thirty-seven adults, 15 men and 22 women, with confirmed PWS were randomly assigned to 1 year of GH treatment (n = 19) or placebo (n = 18) followed by 2 years of GH treatment to all. Polysomnographic measurements were performed every 6 months. A mixed-effect regression model was used for comparison over time in the subgroup that received GH for 3 years. Results: At baseline median age was 29.5 years, body mass index 27.1, insulin-like growth factor 115 µg/L, apnea-hypopnea index (AHI) 1.4 (range, 0.0-13.9), and sleep efficiency (SE) 89.0% (range, 41.0%-99.0%). No differences in sleep or respiratory parameters were seen between GH- and placebo-treated patients. SE continuously improved throughout the study, also after adjustment for BMI, and the length of the longest apnea increased. AHI inconsistently increased within normal range. Conclusion: SE improved during GH treatment and no clinical, significantly negative impact on respiration was seen. The etiology of breathing disorders is multifactorial and awareness of them should always be present in adults with PWS with or without GH treatment.