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

Objective. To compare growth and hormonal growth factors before and during rhGH therapy in patients with and without PTPN11 mutations (M+ and M-).

Setting, Design and Patients. 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, IGFBP-3, and ALS levels were evaluated before and during therapy.

Results. Molecular investigation of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20/35 (57%). Birth length was reduced (mean : -1.2 SDS, 6 M+ and 2 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+, 8 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 < - 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 post receptor signaling defect.