Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta.

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1-16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.

Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta.

Abnormalities in the structure and/or processing of type I collagen cause osteogenesis imperfecta and result in bone fragility, abnormal bone growth and short stature. Type I collagen is expressed in the growth plate but the mechanisms by which abnormalities in collagen I contribute to growth plate dysfunction and growth retardation are unknown. The non-collagenous domain (NC1) of type X collagen (CXM) is released from the hypertrophic zone of active growth plates and is a marker for new endochondral bone formation. Serum CXM levels are strongly correlated with the rate of growth in healthy children. We hypothesized that CXM levels in children with OI would be abnormal when compared to normally growing children. Using participants from the Brittle Bone Disease Consortium Natural History Study we analyzed the distribution of CXM over the ages of 8 months to 40 years in 187 subjects with OI (89 type I and 98 types III/IV) as well as analyzed the relationship between growth velocity and CXM levels in a subset of 100 children <16 years old with OI (44 type I and 56 types III/IV). CXM levels in both control and OI children demonstrated a similar pattern of variation by age with higher levels in early life and puberty followed by a post-pubertal drop. However, there was greater variability within the OI cohort and the relationship with growth velocity was weaker. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. These results suggest that the relationship between hypertrophic zone function and the end point of skeletal growth is disrupted in OI.

Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates.

Chronic high caloric intake has contributed to the increased prevalence of pediatric obesity and related morbidities. Most overweight or obese children, however, do not present with frank metabolic disease but rather insulin resistance or subclinical precursors. The innate immune system plays a role in the pathophysiology of type 2 diabetes but how it contributes to early metabolic dysfunction in children on chronic high-fat diet (HFD) is unclear. We hypothesize that such inflammation is present in the pancreas of children and is associated with early insulin resistance. We used nonhuman primate (NHP) juveniles exposed to chronic HFD as a model of early pediatric metabolic disease to demonstrate increased pancreatic inflammatory markers before the onset of significant obesity or glucose dysregulation. Pancreata from 13-month-old Japanese macaques exposed to a HFD from in utero to necropsy were analyzed for expression of cytokines and islet-associated macrophages. Parameters from an intravenous glucose tolerance test were correlated with cytokine expression. Before significant glucose dysregulation, the HFD cohort had a twofold increase in interleukin 6 (IL6), associated with decreased first-phase insulin response and a sexually dimorphic (male) increase in IL1ß correlating with increased fasting glucose levels. The number of islet-associated macrophages was also increased. Pancreata from juvenile NHP exposed to HFD have increased inflammatory markers and evidence of innate immune infiltration before the onset of significant obesity or glucose dysregulation. Given the parallel development of metabolic disease between humans and NHPs, these findings have strong relevance to the early metabolic disease driven by a chronic HFD in children.