Noonan syndrome and related disorders: Alterations in growth and puberty

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548–555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465–468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652–662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413–427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42–48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038–1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet,2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294–296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis

Five-year response to growth hormone in children with Noonan syndrome and growth hormone deficiency

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant disorder characterized by specific features including short stature, distinctive facial dysmorphic features, congenital heart defects, hypertrophic cardiomyopathy, skeletal anomalies and webbing of the neck. Molecular screening has shown that the majority of individuals with NS have a mutation in the PTPN11 gene. Noonan syndrome children may show an impaired growth hormone (GH)/insulin-like growth factor axis. Moreover, recombinant human GH (rhGH) has been shown to improve growth rate in patients with NS, although data are still limited. METHODS: In the present study, we assessed growth response following GH therapy (0.25 mg/Kg/week) in 5 (2 M and 3 F) GH-deficient NS patients (NSGHD, mean age 8.5 years) and in 5 (2 M and 3 F) idiopathic GH deficient (IGHD, mean age 8.6 years) patients. We also evaluated the safety of rhGH therapy in NS patients with GHD. RESULTS: At the beginning of GH treatment, height and growth rate were statistically lower in NSGHD children than in IGHD ones. During the first three years of rhGH therapy, NSGHD patients showed a slight improvement in height (from −2.71 SDS to −2.44 SDS) and growth rate (from −2.42 SDS to −0.23 SDS), although the values were always significantly lower than in IGHD children. After five years of rhGH treatment, height gain was higher in IGHD children (mean 28.3 cm) than in NSGHD patients (mean 23.6 cm). During the first five years of rhGH therapy, regular cardiological and haematological check-ups were performed, leading to the conclusion that rhGH therapy was safe. CONCLUSIONS: In conclusion, pre-pubertal NS children with GHD slightly increased their height and growth rate during the first years of GH therapy, although the response to rhGH treatment was significantly lower than IGHD children. Furthermore, the therapy appeared to be safe since no severe adverse effects were reported, at least during the first five years. However, a close follow-up of these patients is mandatory, especially to monitor cardiac function