Bone Status in a Patient with Insulin-Like Growth Factor-1 Receptor Deletion Syndrome: Bone Quality and Structure Evaluation Using Dual-Energy X-Ray Absorptiometry, Peripheral Quantitative Computed Tomography, and Quantitative Ultrasonography

Abstract

Haploinsufficiency of the insulin-like growth factor (IGF)-1 receptor (IGF1R) gene is a rare, probably under-diagnosed, cause of short stature. However, the effects of IGF1R haploinsufficiency on glucose metabolism, bone status, and metabolism have rarely been investigated. We report the case of a patient referred to our center at the age of 18 months for short stature, failure to thrive, and Silver-Russell-like phenotype. Genetic analysis did not show hypomethylation of the 11p15.5 region or uniparental disomy of chromosome 7. Growth hormone (GH) stimulation tests revealed GH deficiency, whereas IGF-1 was 248 ng/mL. r-hGH treatment showed only a slight improvement (from -4.4 to -3.5 SDS). At 10 years of age, the child was re-evaluated: CGH-array identified a heterozygous de novo 4.92 Mb deletion in 15q26.2, including the IGF1R gene. Dual-energy X-ray absorptiometry showed a normal bone mineral density z-score, while peripheral quantitative computed tomography revealed reduced cortical and increased trabecular elements. A phalangeal bone quantitative ultrasonography showed significantly reduced amplitude-dependent speed of sound and bone transmission time values. The changes in bone architecture, quality, and metabolism in heterozygous IGF1R deletion patients, support the hypothesis that IGF-1 can be a key factor in bone modeling and accrual.

Keywords: bone metabolism; insulin-like growth factor-I; insulin-like growth factor-I receptor; peripheral quantitative computed tomography; quantitative ultrasonography.

Figure 1

Growth chart of the patient.

Figure 2

Molecular karyotyping was performed by array-CGH on the proband’s DNA using an Agilent 60 K array platform with a resolution of approximately 100 kb. Based on the physical mapping positions of the February 2009 Assembly (GRCh37/hg19) of the UCSC Genome Browser, this analysis showed a deletion of approximately 4,942 Mb that involved the 15q26.2-q26.3 region, with the breakpoint falling between 97,457,185 bp (first deleted oligomer) and 102,399,819 bp (last deleted oligomer).

Figure 3

Cross-sectional evaluation of trabecular bone mineral density (TrabBMD) (A), cortical bone mineral density (CrtBMD) (B), total density corrected for age (C), bone area corrected for height (D), muscle cross-sectional area (MuscleCSA) corrected for height (E), bone area corrected for MuscleCSA (F), fat cross-sectional area (FatCSA) corrected for height (G), and density-weighted polar section modulus (SSIp) (H). The gray squares in the panels (A,B,C,H) represent the bone age-adjusted values.