Abstract
<b><i>Introduction:</i></b> The clinical features of bi-allelic <i>IGF1</i> 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 <i>IGF1</i> 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. <b><i>Methods:</i></b> Retrospective case series of patients with pathogenic heterozygous <i>IGF1</i> variants. <b><i>Results:</i></b> 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 (<i>n</i> = 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 (<i>n</i> = 7), and GH peak range 5–31 μg/L (<i>n</i> = 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 2 patients was −2.8 and −1.3 SDS, which was, respectively, 1.3 and 2.9 SDS taller than predicted before start of treatment. <b><i>Conclusion:</i></b> Haploinsufficiency of <i>IGF1</i> 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 2 years of treatment, and in 2 patients adult height after treatment was higher than predicted at treatment initiation.