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Growth Defects in Noonan Syndrome

  • Alexsandra C. Malaquias
  • Alexander A.L. Jorge
Chapter

Abstract

Noonan syndrome is one of the most common syndromes transmitted by a Mendelian mode and is mainly characterized by dysmorphic facial features, congenital heart disease, and proportionate postnatal short stature. In recent years, germline mutations that affect components of the RAS/MAPK (mitogen-activated protein kinase) pathway as PTPN11, KRAS, SOS1, and RAF1 genes were shown to be involved in the pathogenesis of Noonan syndrome as well as of four rare syndromes with phenotype overlapping with Noonan syndrome: LEOPARD syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and neurofibromatosis type 1. These mutations are predicted to be gain-of-function defects increasing signaling down the RAS/MAPK pathway. Some genotype–phenotype correlation has been reported in Noonan syndrome patients, allowing screening for mutations in Noonan syndrome-related genes based on clinical signs. Several hormones act through receptors that stimulate the RAS/MAPK pathway, and therefore, Noonan syndrome and related disorders represent a remarkable opportunity to study the implication of the RAS/MAPK pathway in different endocrine systems, including the GH/IGF-1 system. Additionally, similarly to Turner syndrome, growth velocity and final height of Noonan syndrome patients can be improved by recombinant human growth hormone treatment. In this chapter, we review the diagnostic, clinical, and molecular aspects of Noonan syndrome and rhGH treatment of short stature in these patients.

Keywords

Short Stature Noonan Syndrome rhGH Therapy rhGH Treatment PTPN11 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CFC

Cardiofaciocutaneous syndrome

EGF

Epidermal growth factor

ERK

Extracellular signal-regulated kinase

FGF

Fibroblast growth factor

GAP

GTPase-activating proteins

GH

Growth hormone

GNEF

Guanosine nucleotide exchange factor

IGF-1

Insulin-like growth factor 1

IL-1

Interleukin-1

ISS

Idiopathic short stature

JAK

Janus kinase

JMML

Juvenile myelomonocytic leukemia

KRAS

Kirsten rat sarcoma viral oncogene homolog

MAPK

Mitogen-activated protein kinase

MEK

Mitogen-activated protein kinase kinase 1-interacting protein 1

MGCLs

Multiple giant cell lesions

NF1

Neurofibromin

NS

Noonan syndrome

OMIM

Online Mendelian inheritance in man

PTP

Protein tyrosine phosphatase

PTPN11

Protein tyrosine phosphatase, non-receptor type 11

RAF1

Murine leukemia viral oncogene homolog 1

rhGH

Recombinant human growth hormone

SH

Src homology

SHP-2

Src homology region 2-domain phosphatase 2

SOS1

Son of sevenless, drosophila, homolog 1

STAT

Signal transducers and activators of transcription

TNF-1

Tumor necrosis factor 1

TS

Turner syndrome

Notes

Acknowledgments

This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (05/04726-0 and 07/59555-0 to A.C.M.) and from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) (307951/06-5 to A.A.L.J).

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Alexsandra C. Malaquias
    • 1
  • Alexander A.L. Jorge
    • 2
    • 3
  1. 1.Hospital das Clínicas, Labaratório de Hormonios e Genetica MolecularSao PauloBrazil
  2. 2.Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25São PauloBrazil
  3. 3.Disciplina de Endocrinologia da, Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil

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