IGF1 haploinsufficiency: phenotype and response to growth hormone treatment in nine patients

Lauren D Punt, Daniëlle C M van der Kaay, Petra A van Setten, Kirsten de Groote, Anne R Kruijsen, Gianni Bocca, Sonja A de Munnik, Judith S Renes, Christiaan de Bruin, Monique Losekoot, Hermine A van Duyvenvoorde, Jan M Wit, Sjoerd D Joustra*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    Introduction: The clinical features of bi-allelic IGF1 defects are well established, i.e. severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants.

    Methods: Retrospective case series of patients with pathogenic heterozygous IGF1 variants.

    Results: Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n=7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n=7) and GH peak range 5-31 μg/L (n=4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in two patients was -2.8 and -1.3 SDS, which was respectively 1.3 and 2.9 SDS taller than predicted before start of treatment.

    Conclusion: Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first two years of treatment, and in two patients adult height after treatment was higher than predicted at treatment initiation.

    Original languageEnglish
    JournalHormone Research in Paediatrics
    DOIs
    Publication statusE-pub ahead of print - 28-Jun-2024

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