Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height.

Annachiara Libraro,Marco Cappa,Antonietta Spinuzza,Vito D’Ascanio,Malgorzata Gabriela Wasniewska,Mariangela Chiarito,Alessandro Mussa,Giovanni Battista Ferrero,Mohamad Maghnie,Laura Mazzanti,Maria Cristina Digilio,Anna Grandone,Giuseppa Patti,Silvia Vannelli,Emanuela Scarano,Silvia Einaudi,Maria Felicia Faienza

doi:10.3389/fendo.2021.761171

Abstract

ObjectivesGrowth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children.MethodsRetrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement.ResultsANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (p<0.001), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from −3.10 ± 0.84 to −2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH.ConclusionsrhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes.

Highlights

Noonan syndrome (NS) is a multisystem disorder characterized by facial and skeletal dysmorphisms, short stature, congenital heart diseases, organ dysfunction, and mild-to-moderate developmental/learning delay [1, 2]
The outcome ΔHSDS can be predicted from a linear combination of the following variables: sex (R2 = 0.431, p
The postnatal growth in our cohort showed a significant difference between birth length (BL) standard deviation scores (SDS) and height SDS (HSDS) at the different key ages, while no differences in terms of HSDS were found starting from the age of 2 until adult height (AH)

Summary

Introduction

Noonan syndrome (NS) is a multisystem disorder characterized by facial and skeletal dysmorphisms, short stature, congenital heart diseases, organ dysfunction, and mild-to-moderate developmental/learning delay [1, 2]. Short stature is a common feature in NS subjects, and adult height (AH) is variably affected [12,13,14,15,16,17]. The mean AH is about −2 standard deviation scores (SDS) compared to normal population [18]. Long-term rhGH therapy ranging from 4.2 to 11.8 years determines a normalization of AH as for Ranke standards, with height gains varying from 0.6 to 2.0 SDS [19, 20]; NS patients do not show the typical catch-up growth of subjects with isolated growth hormone deficiency (GHD) [25]. The response to rhGH treatment in NS can be affected by several factors, such as age at the treatment start, genotype, dose, and treatment duration [26]

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