Impaired Bone Health in Inflammatory Bowel Disease: A Case-Control Study in 80 Pediatric Patients

Peer reviewe

Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study

Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders

Vitamin D Deficiency in Children with a Chronic Illness-Seasonal and Age-Related Variations in Serum 25-hydroxy Vitamin D Concentrations

Peer reviewe

Lipocalin-2 is associated with FGF23 in WNT1 and PLS3 osteoporosis

Abstract Background: The pathogenic mechanisms of early-onset osteoporosis caused by WNT1 and PLS3 mutations are incompletely understood and diagnostic biomarkers of these disorders are limited. Recently, lipocalin-2 has been recognized as an osteokine involved in bone development and homeostasis. However, the role of lipocalin-2 in WNT1 and PLS3 osteoporosis is unknown. Objective: We aimed to investigate if plasma lipocalin-2 could be utilized as a biomarker for WNT1 and PLS3 osteoporosis and to evaluate the association between lipocalin-2 and other parameters of bone metabolism. Methods: We measured plasma lipocalin-2 in 17 WNT1 and 14 PLS3 mutation-positive patients and compared them to those of 34 mutation-negative (MN) healthy subjects. We investigated possible associations between lipocalin-2 and several bone biomarkers including collagen type I cross-linked C-telopeptide (CTX), alkaline phosphatase (ALP), type I procollagen intact N-terminal propeptide (PINP), intact and C-terminal fibroblast growth factor 23 (FGF23), dickkopf-1 (DKK1) and sclerostin as well as parameters of iron metabolism (iron, transferrin, transferrin saturation, soluble transferrin receptor and ferritin). Results: We found no differences in plasma lipocalin-2 levels in WNT1 or PLS3 patients compared with MN subjects. However, lipocalin-2 was associated with C-terminal FGF23 in WNT1 patients (r=0.62; p=0.008) and PLS3 patients (r=0.63, p=0.017), and with intact FGF23 in PLS3 patients (r=0.80; p<0.001). In addition, lipocalin-2 correlated with serum transferrin in WNT1 patients (r=0.72; p=0.001). Conclusion: We conclude that plasma lipocalin-2 is not altered in WNT1 or PLS3 mutation-positive subjects but is associated with FGF23 in abnormal WNT1 or PLS3 signaling and with iron status in abnormal WNT1 signaling

Bone mineral density in very low birthweight adults:a sibling study

Abstract Background: Children and adults born very low birthweight (VLBW, <1500 g) at preterm gestations have lower bone mineral density (BMD) and/or bone mineral content (BMC) than those born at term, but causality remains unknown. Objectives: Our aim was to assess BMD and BMC in adults born at VLBW in a sibling comparison setting to account for shared genetic and environmental confounders. Methods: We conducted a cohort study of 77 adults born VLBW and 70 same-sex term-born siblings at mean age of 29 years. The primary outcome variables were BMD Z-scores, and BMC, of the femoral neck, lumbar spine, and whole body, measured using dual-energy X-ray absorptiometry. We analysed data by linear mixed models. Results: The VLBW adults had a 0.25 (95% CI 0.02, 0.47) Z-score unit lower femoral neck BMD, and 0.35 (95% CI 0.16, 0.54) grams lower femoral neck BMC than their term-born siblings, after adjustment for sex, age, and maternal smoking. Additional adjustment for adult body size attenuated the results. Lumbar spine, and whole body BMC were also lower in the VLBW group. Conclusions: Individuals born at VLBW had lower BMC values at all three measurement sites, as well as lower femoral neck BMD Z-scores, compared to term-born siblings, partly explained by their smaller adult body size, but the differences were smaller than those reported previously with unrelated controls. This suggests that genetic or environmental confounders explain partly, but not exclusively, the association between preterm VLBW birth and adult bone mineralisation

Targeted exome sequencing of genes involved in rare CNVs in early-onset severe obesity

Abstract Context: Rare copy number variants (CNVs) have been associated with the development of severe obesity. However, the potential disease-causing contribution of individual genes within the region of CNVs is often not known. Objective: Screening of rare variants in genes involved in CNVs in Finnish patients with severe early-onset obesity to find candidate genes linked to severe obesity. Methods: Custom-made targeted exome sequencing panel to search for rare (minor allele frequency <0.1%) variants in genes affected by previously identified CNVs in 92 subjects (median age 14 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0). Results: We identified thirteen rare heterozygous variants of unknown significance in eleven subjects in twelve of the CNV genes. Two rare missense variants (p.Pro405Arg and p.Tyr232Cys) were found in SORCS1, a gene highly expressed in the brain and previously linked to diabetes risk. Four rare variants were in genes in the proximal 16p11.2 region (a frameshift variant in TAOK2 and missense variants in SEZ6L2, ALDOA and KIF22) and three rare missense variants were in genes in the 22q11.21 region (AIFM3, ARVCF and KLHL22). Conclusion: We report several rare variants in CNV genes in subjects with childhood obesity. However, the role of the individual genes in the previously identified rare CNVs to development of obesity remains uncertain. More studies are needed to understand the potential role of the specific genes within obesity associated CNVs

Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants

Abstract Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood. Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013–2016), in which healthy term infants born to mothers of Northern European origin received vitamin D₃ supplementation of 10 or 30 μg/day from 2 weeks to 24 months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24 months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770. Results: Rs7955866 minor allele homozygotes had lowest cFGF23 at both time-points (mixed model for repeated measurements, pvariant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (pinteraction = 0.038) from 12 to 24 months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24 months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (pinteraction lt;0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD. Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24 months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood

Iron status in early childhood is modified by diet, sex and growth:secondary analysis of a randomized controlled vitamin D trial

Abstract Background and aims: During early childhood the risk of iron deficiency (ID) is high. Serum ferritin serves as a marker of iron status. We explored prevalence of ID and iron deficiency anemia (IDA), and identified determinants of iron status in infants and toddlers. Methods: We performed a secondary analysis of the Vitamin D intervention in infants (VIDI) study in Finnish healthy term infants. According to study protocol, at 12- and 24-months of age iron status, growth and dietary intakes were evaluated. ID was defined as serum ferritin <10 μg/L and IDA as serum ferritin <10 μg/L and Hb <112 g/L. For the present study, altogether 766 children provided data (N = 498 infants at 12 months, N = 508 toddlers at 24 months). Results: ID prevalence increased from 14% in infants to 20% in toddlers. IDA prevalence was 3% at both time points. In infants, ID and IDA were more common in boys than in girls (19% vs. 9%, p = 0.001 and 5% vs. 1%, p = 0.039) but no sex-difference in toddlers was observed. Of infants, 30% had daily iron intake below average requirement of 5 mg/day. Higher daily iron intake per body weight (mg/kg) independently associated with higher infant serum ferritin (B (95% CI) 0.30 (0.04, 0.56), p = 0.026). Correlation between iron intake and ferritin was stronger in infants with ID than in infants without ID. Breastfeeding was more common (63% vs. 35%, p < 0.001) among ID infants than in infants without ID. In toddlers, frequent consumption of milk products independently associated with lower ferritin (B (95% CI) −0.03 (−0.05, −0.01), p = 0.001). Consumption of meat and fish associated with better iron status. Serum ferritin at both time points associated with duration of gestation and growth. The association of growth and ferritin was age-dependent in boys, while in girls, faster growth associated consistently with lower ferritin. Conclusions: In Northern European healthy infants and toddlers ID is common. The intake of iron remains below recommendations and food consumption and iron intake associate with iron status. Further studies are warranted to assess significance of ID on child development and clinical health outcomes