Abstract
Children with Noonan Syndrome (NS) present variable growth impairment associated to facial dysmorphology and cardiovascular anomalies. Mutations in several genes of RAS/MAPK signaling pathway have been identified, likely impairing Growth Hormone (GH) sensitivity. If untreated, these patients often remain short in adulthood. Although Recombinant Human GH (rhGH) treatment improves short-term linear growth, poor data on the Final Height (FHt) of rhGH-treated subjects with NS are available. After thorough search of the published literature for pertinent studies, a meta-analysis evaluation of the efficacy and safety of rhGH treatment in NS patients were performed. In total sample (n=885; 70.0% males), administration of rhGH progressively improved height pattern, but relevant catch-up growth was not shown. The rhGH-induced growth improvement appeared until FHt [n=168; –2.151 SDS (95%CI –2.792 to –1.511)]. During 1st year of rhGH treatment, height velocity gain meta-correlated with serum insulin-like growth factor 1 (IGF1) increment [n=31; r=0.685 (95%CI 0.419 to 0.843); P<0.0001] while negative meta-correlation was detected between age at rhGH start and height velocity [n=48; r=–0.608 (95%CI –0.765 to –0.383); P<0.0001]. Height gain after 1-yr rhGH treatment (dosage range 0.35-0.46 mg/kg/wk) was higher in NS patients without protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene mutation [n=33; 0.903 SDS (95%CI 0.552 to 1.254)] than that observed in subjects positive for PTPN11 mutations [n=62; 0.606 SDS (95% CI 0.274 to 0.938); P<0.0001]. While few serious adverse events were reported during rhGH treatment, causal relationship to rhGH therapy was unlikely. In conclusion, this meta-analysis indicates that rhGH treatment progressively improved height outcome of short children with NS. Future studies using carefully titrated rhGH protocols are need to optimize treatment protocols and establish possible risks, if any, leading to clear indications for practice and regulatory agencies.
Highlights
Noonan syndrome (NS) is a rare genetic disorder, characterized by specific facial features associated to cardiovascular anomalies, mild mental retardation, deafness, visual problems, hypogonadism with cryptorchidism, clotting disorders, and short stature [1]
Seven casereports were excluded from our analysis because used statistical software needs at least 2 patients for each groups while one study which reported NS height data including Turner syndrome ones
From the 27 selected studies, 885 Recombinant Human GH (rhGH)-treated children with NS were selected with male sex prevalence (n=808; 69.4% males; 30.6% females)
Summary
Noonan syndrome (NS) is a rare genetic disorder, characterized by specific facial features associated to cardiovascular anomalies, mild mental retardation, deafness, visual problems, hypogonadism with cryptorchidism, clotting disorders, and short stature [1]. The best-defined function of SHP2 is its positive role in the activation of the RAS/MAPK (mitogen-activated protein kinase) ERK1/2 pathway [5]. Biochemical studies have revealed that NS causing PTPN11 mutations result in hyperactivation of SHP2 catalytic activity by disrupting the inhibitory interaction between its catalytic and SH2 domains [6]. In this view, SHP2 binds to and dephosphorylates signaling molecules that are positive regulators of the cellular response to growth factors such as growth hormone (GH). Six other genes (i.e. KRAS, NRAS, SOS1, RAF1, BRAF, SHOC2) of RAS/MAPK signaling pathway were recently identified as causative for NS [8,9,10,11,12]
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