ESPE Abstracts (2018) 89 FC15.4


aUnidade de Endocrinologia-Genetica, LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), São Paulo, Brazil; bDepartamento de Pediatria da Irmandade da Santa Casa de São Paulo – Pediatric Diabetes Unit, São, Brazil; cLaboratorio de Hormonios e Genetica Molecular (LIM/42), Unidade de Endocrinologia do Desenvolvimento, Hospital das Clinicas, FMUSP, São Paulo, Brazil; dLaboratorio de Genetica e Cardiologia Molecular, Instituto do Coraçao (InCor), FMUSP, São Paulo, Brazil; eLaboratorio de Nutricao Humana e Doencas Metabolicas (LIM/25), Hospital das Clinicas, FMUSP, São Paulo, Brazil; fUnidade de Genetica, Instituto da Crianca, FMUSP, Sao Paulo, Brazil; gLaboratorio de Hormonios e Genetica Molecular (LIM/42), Unidade de Endocrinologia do Desenvolvimento, Hospital das Clinicas, FMUSP, Sao Paulo, Brazil; hDepartamento de Pediatria, Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brazil

Background: Noonan syndrome (NS) is a frequent autosomal dominant disorder characterized by facial dysmorphisms, heart defects, short stature and learning disabilities. It is caused by mutations in genes within the RAS/MAPK signaling pathway, thus called RASopathies. The RAS/MAPK pathway can also impact the signal transduction of hormones involved in body weight, carbohydrate, and lipid metabolism features scarcely studied only in animal models. This study aimed to describe metabolic profile in children with RASopathies.

Subjects and methods: We evaluated 102 prepubertal NS patients (40 males), 41 with identified PTPN11 mutation (PTPN11+) and 61 without PTPN11 mutation (PTPN11−). We accessed height and body mass index (BMI) expressed as SDS for age and sex. We compared fasting insulin, glycemic, HOMA-IR, triglycerides, HDL-cholesterol, and LDL-cholesterol levels between NS groups and with a eutrophic prepubertal control group. We excluded patients with family history of obesity, hypertension, and diabetes mellitus.

Results: Patients with NS were shorter than the control group. BMI–SDS were similar among groups NS groups and control. NS patients had overweight and obesity frequency of 8% and 1%, while in Brazilian population aged 5 to 9 this frequency is 33.4% and 14.3%, respectively. PTPN11+ patients had higher fasting insulin levels [median 4.6; (3 to 13.9)], than PTPN11− [2.9; (1.3 to 18.7)] and control [3.3; (2.5–7.3 μU/ml); P=0.01]. HOMA-IR were higher in PTPN11+[1.0;(0.4 to 3.2)], than PTPN11− [0.6;(0.3 to 4.4)], and control [0.6; (0.4 to 1.4); P=0.008]. The frequency of low HDL-C levels was higher in both NS groups 57% (21/37) in PTPN11+, and 54% (32/60) in PTPN11− than control group 20% (9/44); P<0.001. The LDL-C concentration was similar between groups. Frequency of elevated triglyceride levels were higher in NS groups, 57% (21/37) in PTPN11+ and 18% (11/60) PTPN11−, than control group 2% (1/44); P=0.007.

Conclusions: NS patients may have particular protection against obesity and overweight. Despite that, PTPN11+ patients seem to have an impaired insulin signaling (higher insulin fasting levels and higher HOMA-IR), that could be associated with SHP2/PTPN11 mutations. PTPN11+ patients also had low HDL and an increased triglycerides levels in comparison to control. To the best of our knowledge, this was the first report concerning metabolism in children with NS. More studies are necessary to expand the knowledge about possible consequences that this metabolic profile could have on the cardiovascular risk to these patients.

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