Novel IGF1R Variants in Short Stature: Lessons from Two Patients and Outcome of Growth Hormone Therapy

The growth hormone (GH) - insulin-like growth factor 1 (IGF1) axis is essential for the regulation of growth. IGF1 exerts its effects through the IGF1 receptor (<i>IGF1R</i>) that plays a pivotal role in fetal and postnatal growth. Pathogenic monoallelic <i>IGF1R</i> variants are known to cause pre- and postnatal growth restriction, often accompanied by normal or elevated serum IGF1 levels. Herein, the clinical and genetic characteristics of two cases with <i>IGF1R</i> novel variants, emphasizing their growth patterns, endocrinological findings, and response to recombinant human growth hormone (rhGH) therapy. The first case, a 6.3-year-old boy, had a birth weight of 2,500 g (-2.5 SDS) and a current height of 101.5 cm (-3.2 SDS). Laboratory investigations revealed IGF1 and IGFBP3 levels of 117.8 ng/ml (0.9 SDS) and 4.55 µg/ml (1.3 SDS), respectively. Clinical exome sequencing (CES) identified a novel heterozygous c.3722+1G>A/p.(?) variant in the <i>IGF1R</i> (NM_000875.5) inherited from the mother. At 6.9 years of age, rhGH treatment was initiated at a dose of 0.035 mg/kg/day. The patient has been receiving rhGH for two years, achieving a height gain of +0.3 SDS per year, with an uneventful follow-up. The second case features a 3-year-old male with short stature and a history of being born small for gestational age (SGA) (-2.6 SDS). His height and weight were 70.0 cm (-2.1 SDS) and 8.8 kg (-1.1 SDS), respectively. He had a history of frequent respiratory infections. Pituitary hormone levels were normal, and he had no evidence of GH deficiency. CES revealed a novel heterozygous variant c.2275_2278 dup/p.(Ala760Glyfs*21) in the <i>IGF1R</i>. Uncovering the genetic causes of idiopathic short stature with SGA is crucial, as it facilitates more precise diagnoses, reduces unnecessary testing, and potentially enables targeted therapies. Our experience with rhGH therapy in one patient suggests a modest growth response, consistent with previous studies. However, elevated IGF1 levels during treatment highlight the importance of balancing therapeutic doses to optimize height gains without causing side effects.