IGF1 haploinsufficiency in children with short stature: a case series

Abstract

Context: Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/ insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). Case descriptions: We describe five patients presenting with short stature, microcephaly, and in 4 out of 5 born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. Conclusions: This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency - unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.

New developments and therapies in pediatric endocrinology

“…GH deficiency may be overdiagnosed, and there is a move to re-testing of GH deficiency in puberty [25]. Genetic variants or deletions in the GH signalling pathway such as those in GHR (growth hormone receptor) [26], STAT5B (signalling transducer and activator of transcription 5B) [27], IGF1 (insulin-like growth factor 1) [28] and IGF1R (IGF1 receptor) [29] may be more common than initially thought, but seem to be still far rarer than variants in genes involved in bone or cartilage development as a cause for short stature. Examples of such relatively frequent causes for short stature are mutations/deletions of SHOX (short stature gene on the X chromosome), ACAN (aggrecan), NPR2 (natriuretic peptide receptor 2) and CUL7/OBSL (leading to 3M syndrome) [30].…”