ESPE Abstracts

Background: Noonan syndrome (NS) is a rare genetic disease characterized by facial dysmorphism, short stature, heart defects, chest deformities, and variable developmental delay/learning disabilities. Almost 80% of patients have a mutation in the genes encoding components of the RAS/MAPK pathway. Puberty was described as delayed in NS patients, but few studies are focusing on this subject and genotype-phenotype correlations so far.

Objective: To evaluate puberty in patients clinically and molecularly diagnosed with NS.

Methods: This study was a retrospective analysis 84 NS patients (37 females) with mutations in the RAS/MAPK pathway genes (56 PTPN11, 5 RAF1, 5 SOS1/2, 4 KRAS, 3 BRAF, 3 RIT1, 3 LZTR1, 2 SHOC2, 1 NRAS, 2 MAP2K1/2). Genotype-phenotype correlations were analyzed between patients with PTPN11 mutations (n=56) and patients with mutations in other NS related genes (n=28).

Results: Age at puberty onset and menarche in girls was 11.8±1.9 years and 14.5±1.9 years (n=17), respectively. Eight out of 37 girls (22%) had delayed puberty. Age at puberty onset was 12.8±2.1 years in boys, and 16 out of 47 boys had delayed puberty (34%). Frequency of delayed puberty was similar in boys and girls. Patients with delayed puberty were shorter than patients with normal puberty (height-SDS of -3.9±1.0 vs. -2.0±1.0, respectively; P<0.001). BMI-SDS was lower in patients with delayed puberty in comparison with those with normal puberty (-0.6±1.1 vs. -1.7±1.4; P<0.001). Age at menarche was higher in delayed puberty girls (16.0±1.7 vs. 13.8±1.7; P=0.017). Height-SDS (P<0.001) and BMI-SDS (P=0.05) can negatively predict age at puberty onset in a multiple linear regression model (R²=0.40). No difference was observed concerning the frequency of delayed puberty, puberty onset, age at menarche, height-SDS, and BMI-SDS between patients with or without mutations in the PTPN11 gene.

Conclusions: Delayed puberty was observed in 29% of NS patients. Patients with delayed puberty were shorter and thinner than patients with normal puberty resembling constitutional delay of growth and puberty. Prospective studies are required to further investigate the link between metabolism and puberty in NS patients.