Noonan syndrome: relationships between genotype, growth, and growth factors

J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. doi: 10.1210/jc.2005-0983. Epub 2005 Nov 1.


Context: Half of the patients with Noonan syndrome (NS) carry mutation of the PTPN11 gene, which plays a role in many hormonal signaling pathways. The mechanism of stunted growth in NS is not clear.

Objective: The objective of the study was to compare growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations (M+ and M-).

Setting, design, and patients: This was a prospective multicenter study in 35 NS patients with growth retardation. Auxological data and growth before and during 2 yr of GH therapy are shown. GH, IGF-I, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels were evaluated before and during therapy.

Results: Molecular investigation of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of 35 (57%). Birth length was reduced [mean -1.2 sd score (SDS); six m+ and two m- were < -2 SDS] but not birth weight. M+ vs. M- patients were shorter at 6 yr (P = 0.04). In the prepubertal group (n = 25), GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M- patients (P < 0.03). The mean peak GH level (n = 35) was 15.4 +/- 6.5 ng/ml. Mean blood IGF-I concentration in 19 patients (11 m+, eight m-) was low (especially in M+) for age, sex, and puberty (-1.6 +/- 1.0 SDS) and was normalized after 1 yr of GH therapy (P < 0.001), without difference in M+ vs. M- patients. ALS levels (n = 10) were also very low. By contrast, the mean basal IGFBP-3 value (n = 19) was normal.

Conclusions: In NS patients with short stature, some neonates have birth length less than -2 SDS. Growth of M+ is reduced and responds less efficiently to GH than M- patients. The association of low IGF-I and ALS with normal IGFBP-3 levels could explain growth impairment of M+ children and could suggest a GH resistance by a late postreceptor signaling defect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anthropometry
  • Birth Weight / physiology
  • Carrier Proteins / blood
  • Child
  • DNA Mutational Analysis
  • Female
  • Genotype
  • Glycoproteins / blood
  • Growth / physiology*
  • Growth Disorders / genetics
  • Growth Disorders / pathology
  • Growth Hormone / therapeutic use
  • Growth Substances / metabolism*
  • Human Growth Hormone / blood
  • Humans
  • Infant, Newborn
  • Insulin-Like Growth Factor Binding Protein 3 / blood
  • Insulin-Like Growth Factor I / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Mutation, Missense / genetics
  • Noonan Syndrome / drug therapy
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / pathology*
  • Prospective Studies
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / genetics
  • Puberty / physiology
  • Stimulation, Chemical


  • Carrier Proteins
  • Glycoproteins
  • Growth Substances
  • Insulin-Like Growth Factor Binding Protein 3
  • Intracellular Signaling Peptides and Proteins
  • insulin-like growth factor binding protein, acid labile subunit
  • Human Growth Hormone
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases