Etiology and Treatment of Growth Delay in Noonan Syndrome.

Fernando Rodríguez,Fernando Cassorla,Ximena Gaete

doi:10.3389/fendo.2021.691240

Fernando Rodríguez, Fernando Cassorla + Show 1 more

Open Access

https://doi.org/10.3389/fendo.2021.691240

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Abstract

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

Highlights

Noonan syndrome (NS - MIM# 163950) is a congenital disorder with an estimated incidence of one in 1,000 to 2,500 live births [1, 2]
The spectrum of genes with germline pathogenic variants associated with Noonan syndrome exceeds 20 (PTPN11, SOS1, SOS2, KRAS, NRAS, RIT1, RRAS, RASA1, RASA2, MRAS, RAF1, BRAF, MAP2K1, MAP3K8, SHOC2, PPP1CB, SPRY1, LZTR1, MYST4, A2ML1, and CBL)
This study showed that long-term recombinant human growth hormone (rhGH) therapy accelerates growth in growth hormone deficiency (GHD) subjects affected by RASopathies, normalizing adult height for Ranke standards, most patients did not show the characteristic catch-up growth observed in patients with isolated GHD treated with rhGH [59]

Summary

INTRODUCTION

Noonan syndrome (NS - MIM# 163950) is a congenital disorder with an estimated incidence of one in 1,000 to 2,500 live births [1, 2]. The IGF-1 generation test, as reported by Bertelloni and co-workers in a well-defined pre-pubertal NS cohort with PTPN11 pathogenic variants, showed an impaired responsiveness to GH stimulation compared with patients with short stature and healthy children [26] This hormonal profile suggests that some of these patients may show evidence of partial GH insensitivity, possibly at a post-receptor level. Data from murine NS models provide evidence that the growth retardation in NS, at least in those cases associated with a specific Ptpn variant, may be due either to partial GH insensitivity at a post-receptor level, and/or to an effect on RAS/ MAPK activation This murine model (Ptpn D61G/+) reproduces several Noonan syndrome characteristics, and allows for the understanding of the molecular process involved in the development of these features, in a tissue specific context. These authors reported an increase in adult height from −2.9 to −1.2 SDS after completion of rhGH treatment in this uncontrolled study (Table 2)

24 KIGS world

Findings

CONCLUSION