Abstract


Introduction: Noonan syndrome (NS) and Noonan-like syndromes (NLS) are autosomal dominant disorders caused by heterozygous mutations in genes of the RAS/MAPK pathway. Noonan syndrome related proteins, such as SHP2, may regulate insulin signaling and could have an influence on metabolism and control of energy storage. It is of great interest to understand the glucose metabolism in patients with NS and NLS.

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Introduction: Noonan syndrome (NS) and Noonan-like syndromes (NLS) are autosomal dominant disorders caused by heterozygous mutations in genes of the RAS/MAPK pathway. Noonan syndrome related proteins, such as SHP2, may regulate insulin signaling and could have an influence on metabolism and control of energy storage. It is of great interest to understand the glucose metabolism in patients with NS and NLS.

Objectives: To estimate the insulin sensitivity, using plasma glucose and insulin responses derived from the OGTT, in NS and NLS patients. Subjects and Methods: We selected 53 patients (31 females; from 14.5 to 61.2 years) clinically diagnosed with NS/NLS, 40 of them harboring mutation in RAS/MAPK-related genes (29 PTPN11, 4 BRAF, 3 SOS1, 2 SOS2, 1 SHOC2 and 1 LZTR1) to undergo a standard 75g OGTT. Demographic parameters for age, height, weight, and BMI were expressed as SDS for age and sex. To estimate insulin sensitivity, we used indexes from fasting- or OGTT-derived measurements.

Results: Height-SDS was -2.5 ± 1.3 and BMI-SDS was -0.5 ± 1.4 in all patients. Fasting glucose levels were normal in patients with NS/NLS. In contrast, 4 patients disclosed fasting insulin levels > 15 µUI/mL; 5 showed Insulin Sensitivity Index (ISI)-composite < 2.5 and 2 showed HOMA-IR > 2.71. Nine patients (17%) had impaired glucose tolerance (IGT), 6 with previously identified pathogenic mutation (4 PTPN11, 1 LZTR1 and 1 SHOC2), and would have been missed if only fasting glucose level, ISI and/or HOMA-IR had been considered alone as diagnostic criteria. IGT and normal glucose tolerance (NGT) patients were similar in relation to age, gender, BMI-SDS, fasting glucose and insulin levels, HOMA-IR, ISI-composite and HOMAβ%. The glucose area under the curve (AUCglu) was higher in IGT than NGT patients (1013 ± 154 vs 791 ± 154, p<0,001) whereas the ratio insulin AUC (AUCins) to AUCglu was lower in IGT patients (67 ± 45 vs 40 ± 17, p=0,047).

Conclusion: It is worth noting that impaired glucose tolerance was diagnosed in 17% of patients with NS or NLS despite BMI SDS within the normal range along with fasting glucose and insulin levels. Since RAS/MAPK-related proteins seem to have a role in insulin signaling through PI3K/AKT pathway, patients with NS or NLS should be considered at risk for developing insulin resistance and its complications.

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