Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib.

BACKGROUND: Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. OBJECTIVE: To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. DESIGN AND METHODS: In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. RESULTS: A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. CONCLUSION: Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.

Physical activity is associated with improved bone health in children with inflammatory bowel disease.

BACKGROUND & AIMS: Bone health is an important concern in patients with inflammatory bowel disease (IBD). Low bone mineral density (BMD) is a powerful predictor of fracture risk in IBD patients. Physical activity (PA) plays an important role in bone health. However, PA data for children and adolescents with IBD are scarce. The primary aim is to evaluate the relationship between PA and BMD in children with IBD. The secondary aim was to assess the relationship between PA and quality of life. METHODS: Eighty-four IBD paediatric patients (45 boys) aged 14.3 ± 2.7 years were included (disease activity: (i) remission, n = 62; (ii) mild, n = 18; (iii) severe disease, n = 1). BMD was measured using dual-energy X-ray absorptiometry and expressed as age- and sex-based Z-scores. Each patient wore a triaxial accelerometer for seven consecutive days for objective PA quantification. Quality of life was assessed using the PedsQL™ and energy intake was assessed prospectively for three days using a dietary diary. RESULTS: BMD Z-score was -0.96 ± 1.11. Only five patients (6%) fulfilled the recommendation of 60 min of daily moderate-to-vigorous PA (MVPA). The proportion of children with osteopenia and osteoporosis was 51% and 4%, respectively. After adjustment for confounders (pubertal status and body mass index), total PA and time in MVPA were positively associated with BMD (regression coefficient per one standard deviation increase in PA parameters = 0.26; P < 0.05). There was no association between time spent in MVPA and total PA, and total quality of life score. CONCLUSIONS: PA likely is associated with improved bone health in IBD children. Intervention studies investigating a causal relationship between PA and BMD in paediatric patients with IBD are warranted.