What question did this study set out to answer?

To explore the genetic basis of severe short stature and resistance to growth hormone therapy in a child born small for gestational age.

March 29, 2026Open Access

Severe Short Stature and rhGH Resistance in a Child Born SGA: The Role of a Novel IGF1R Mutation, Case Report and Narrative Review

Puntos clave

To explore the genetic basis of severe short stature and resistance to growth hormone therapy in a child born small for gestational age.
Case report of a 9-year-old boy with severe short stature born SGA
Evaluation of growth parameters and hormonal levels due to growth hormone therapy
Next-generation sequencing analysis to identify genetic mutations
Literature review on growth outcomes and glucose metabolism in IGF1R variant cases
Child exhibited severe short stature and poor response to growth hormone therapy with only 0.5 SDS height gain over three years
Novel heterozygous mutation in IGF1R gene identified
At 12 years, child showed impaired glucose metabolism, leading to discontinuation of rhGH therapy
The case highlights genetic testing's critical role for growing children with short stature.

Resumen

Background: Genetic causes of growth failure should be suspected in patients born small for gestational age (SGA) who fail to show postnatal catch-up growth, present with severe short stature (SS), and exhibit a poor or absent response to growth hormone (rhGH) therapy. Mutations in the insulin-like growth factor 1 receptor (IGF1R) gene are associated with impaired growth, intrauterine growth restriction (IUGR), low birth weight and/or length, and postnatal SS. Case Description: A 9-year-old boy, born SGA for birth length, was evaluated for severe SS. Common causes of SS were excluded. At 9 years and 7 months of age, his height was 112.6 cm (−3.99 SDS), weight 18 kg (−3.79 SDS), and BMI 14.2 kg/m2 (−1.8 SDS); pubertal development was Tanner stage 1. The target height was 158 cm (−2.62 SDS). Bone age was delayed by approximately one year compared with chronological age. Serum IGF-1 levels were within the upper-normal range for age. GH therapy (0.035 mg/kg/day) was initiated due to the lack of catch-up growth in an SGA subject. After three years of treatment, the height gain was only 0.5 SDS. IGF-1 levels showed a transient treatment-related increase, followed by persistent normalization during ongoing therapy. Next-generation sequencing (NGS) analysis identified novel heterozygous paternal nonsense variant in the IGF1R gene: c.3498C>G (p.Tyr1166Ter). At 12 years of age, impaired fasting glucose and reduced glucose tolerance were detected; consequently, it was decided to discontinue rhGH therapy, also in light of the IGF1R mutation and the lack of height recovery. Conclusions: This case underlines the critical role of genetic testing in the evaluation of patients born SGA. The coexistence of SGA status and an IGF1R gene mutation may provide a clear explanation for both the poor response to rhGH therapy and the increased risk of alterations in glucose metabolism. An extensive narrative review of the literature on growth outcomes and glucose metabolism abnormalities during GH treatment in SGA patients carrying IGF1R variants was also performed.

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