ESPE Abstracts

Introduction: Patients carrying homozygous IGF1 loss-of-function mutations are extremely rare and show severe pre- and postnatal growth failure, microcephaly, developmental delay, retrognathia and sensorineural deafness. Heterozygous variants in IGF1 appear to be more common in short stature, but only few cases have been reported in detail. Therefore, clinical features and growth response to recombinant human growth hormone (rhGH) therapy are still incompletely defined. We aimed to perform an extensive characterization of patients with IGF1 haploinsufficiency in terms of phenotype and their response to rhGH treatment.

Methods: We present the largest case series to date of patients with heterozygous variants in IGF1. Ten patients are included (four girls), with either ACMG class 5 (n=5 whole gene deletions, n=3 frameshift variants) or class 4 (partial gene deletion or base substitution) variants. Eight patients had received rhGH for 1 to 12 years. Height, sitting height/height (SH/H) ratio, head circumference and weight for height were expressed as standard deviation score (SDS) for Dutch references. Predicted adult height was determined with the validated software program Bonexpert. Serum IGF-I was expressed as SDS for national standards.

Results: Mean birth length and weight were -1.3 and -1.5 SDS, respectively, and five (of ten) children were born small for gestational age. A history of feeding difficulties or low BMI was present in seven. At an median age of six years (range 1.1-11.9 yr and one adult), height was -3.7±0.7 SDS with a normal SH/H ratio, weight for height was -1.7±1.1 SDS, and average bone age delay 1.8 years (range 0.4-4.0 years). Head circumference was -2.5±0.6 SDS. Mild developmental delay was present in six patients. Serum IGF-I was -1.6±1.3 SDS while serum IGFBP-3 and the GH response to stimulation testing were normal. In six children a predicted adult height could be calculated with a mean of -3.2±0.9 SDS. In the eight rhGH-treated patients, height increased by +0.3-1.2 SDS (median 0.7 SDS) after one year and +0.5-2.0 SDS (median 1.7 SDS, n=5) after two years of treatment. One patient has reached adult height and gained a total of +1.4 SDS compared to height SDS at start.

Conclusion: The phenotype of children with IGF1 haploinsufficiency consists of borderline low birth size, feeding problems and mild developmental delay, proportionate short stature, and low head circumference and serum IGF-I. RhGH therapy significantly increases growth velocity in a majority of patients and may increase adult height.