IGF1 haploinsufficiency in children with short stature: a case series

in European Journal of Endocrinology
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  • 1 Division of Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
  • | 2 Division of Pediatric Endocrinology, Department of Pediatrics, Ghent University Hospital and Ghent University, Ghent, Belgium
  • | 3 Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED), Brussels, Belgium
  • | 4 Division of Pediatric Endocrinology, Department of Pediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
  • | 5 Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Charleroi, Belgium
  • | 6 Department of Pediatrics, Clinique CHC MontLégia, Liège, Belgium
  • | 7 Division of Pediatric Endocrinology, Department of Pediatrics, Université Catholique de Louvain, CHU UCL Namur, Yvoir, Belgium

Correspondence should be addressed to D Beckers; Email: dominique.beckers@uclouvain.be

*(W Staels and N Alev contributed equally to this work)

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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 four out of five 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.

 

     European Society of Endocrinology

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