BSPED2012 Poster Presentations (1) (66 abstracts)
The effect of homozygosity versus heterozygosity for IGFALS gene mutations on growth, bone strength and insulin resistance
Wolfgang Hogler 1 , David Martin 2 , Nicola Crabtree 3 , Timothy Barrett 1 , Jan Frystyk 4 , Jeremy Tomlinson 5 , Lou Metherell 6 , Ron Rosenfeld 7 , Vivian Hwa 7 , Stephen Rose 8 , Joanna Walker 9 & Nick Shaw 1
1Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK; 2University Children’s Hospital, Paediatric Endocrinology and Diabetology, Tuebingen, Germany; 3Department of Nuclear Medicine, Birmingham Children’s Hospital, Birmingham, UK; 4Medical Research Laboratories, University Hospital Aarhus, Aarhus, Denmark; 5Institute of Biomedical Research, Centre of Endocrinology, University of Birmingham, Birmingham, UK; 6Barts and the London School of Medicine, William Harvey Research Institute, London, UK; 7Department of Pediatrics, Oregon Health Sciences University, Portland, USA; 8Department of Paediatrics, Heartlands Hospital, Birmingham, UK; 9Department of Paediatrics, Portsmouth Hospital, Portsmouth, UK.
Background: Acid-labile subunit (ALS) deficiency inhibits ternary complex formation leading to primary IGF1 deficiency and short stature. Potential metabolic consequences such as diabetes and low bone mass are not well studied.
Objective: This study measured insulin sensitivity, lipid profile, bone density and structure in members of 4 affected families and explore possible gene-dose effects.
Methods: Four patients (7–21 years) with homozygous IGFALS gene mutations and 12 heterozygous carriers had i.v. glucose tolerance tests performed. Dual-energy X-ray absorptiometry of spine, hip and total body, peripheral quantitative computer tomography of the radius and metacarpal (MC) radiogrammetry were performed.
Results: Height z-scores in patients (median −3.75 (range −4.25 to −0.62)) were lower compared to carriers (−1.77 (−2.21 to +0.26), P<0.001), a reflection of their significantly lower IGF1, ALS and IGFBP3 levels (P<0.005). Glucose disappearance rate (k), HOMA-IR, fasting insulin, glucose and lipid levels were similar between the two groups. Three carriers (age 29, 53 and 55 years) had k rates below 1%, and elevated fasting glucose levels, indicating diabetes mellitus.
Lumbar spine BMD was lower in patients (z-score −2.0 (−2.6 to −1.1)) compared to carriers (−0.7 (−2.5 to 0.9), P=0.04), likely influenced by their short stature since size-corrected spine BMAD as well as radial total and trabecular BMD were not different between groups. Structurally, MC bone width (−2.67 (−3.5 to −2.56) vs −1.28 (−1.92 to −0.54), P=0.004) and length (−1.72 (−2.83 to −0.11) vs 0.33 (−0.6 to 2.65), P=0.015) were lower in patients compared to carriers but the MC bone health index was similar.
Conclusions: 3/12 IGFALS gene carriers had type 2 diabetes and there was some evidence of insulin resistance in this cohort. ALS deficiency affects bone lengthening and widening (growth). There is sufficient evidence for a gene-dose effect on bone size but insufficient evidence for a true reduction in bone density and strength.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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