ESPE Abstracts

Introduction: The mechanisms underlying short stature in Noonan Syndrome (NS) are poorly understood and may include inadequate GH secretion or action, decreased IGF-1 production, growth plate dysfunction, or other factors. In this retrospective study, we aimed to evaluate the function of the GH-IGF-1 axis in NS.

Method: We took all patients with genetically proven Noonan syndrome among 1001 children and adolescents currently treated with GH in our center. We evaluated their birth length, standardized height, GH secretion and IGF-1 before GH therapy, IGF-1 within 3-6 months thereafter, and the first-year growth response to GH. Data are presented as median and IQR.

Results: We identified 42 patients with NS (25 males) in total, their current age is 10.5 years (median; IQR 7.5-12.8). Of them, 29 had a PTPN11 pathogenic variant, and 13 other gene variants (SOS1, RAF1, KRAS, SHOC2, or HRAS). GH secretion was tested in 32 patients. At birth, newborns with NS had a shorter median birth length of -1.19 SD for gestational age (IQR -0.59 to -1.77; P<0.0001) which correlated with both maternal height (r= 0.39; P=0.01) and mid-parental height (r= 0.32; P=0.04), and also predicted growth retardation later in childhood (r= 0.31; P=0.05). After birth, children with NS failed to catch-up and further deteriorated in height-SDS to -3.17 (IQR -2.71 to -3.87) by age 4.9 years (IQR 3.3 to 7.2). IGF-1 before GH therapy was low (-1.63 SD; IQR -1.21 to -2.20; P<0.0001). The life-minimum height was not predicted by GH secretory status but rather by IGF-1 (r= 0.32; P=0.04), suggesting that growth failure is due to limited GH sensitivity, and not GH deficiency. Following the first year of GH therapy (0.033 mg/kg/day), height-SDS increased by 0.65 (IQR 0.46 to 0.79; P<0.0001) to height-SDS -2.73 (IQR -2.23 to 3.26). IGF-1 following 3-6 months’ therapy increased to -0.91 SD (IQR +0.23 to -1.51). Those with a more profound initial IGF-1 deficiency had a better growth response (r= 0.35; P=0.04), regardless of GH secretory status. We observed no apparent differences between individuals with PTPN11 or other gene variants.

Conclusion: Our findings suggest that growth retardation in NS is due to both prenatal and postnatal factors and is not due to insufficient GH secretion but rather to limited GH sensitivity. Short-term GH treatment response is predicted by a more severe initial IGF-1 deficiency, indicating a mechanism of overcoming GH insensitivity. Individual gene variants have no apparent specific impact on growth pattern or response to therapy.