Phenotype-genotype correlation in a familial IGF1R microdeletion case.

BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment.

CONTEXT: Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children. OBJECTIVES: To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function. PATIENTS: A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient. MEASUREMENTS: Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment. RESULTS: Baseline mean TSH was higher in preterm short SGA children than in age-matched controls (P < 0.05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment. CONCLUSION: Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.

CONTEXT: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. OBJECTIVE: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. PATIENTS: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. INTERVENTION: Short prepubertal SGA children received GH 1mg/m(2)/day. OUTCOME MEASURES: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. RESULTS: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. CONCLUSION: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.