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. 2021 Mar;185(3):774-780.
doi: 10.1002/ajmg.a.62039. Epub 2020 Dec 31.

Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile

Renata M Noronha  1   2 , Sandra M F Villares  3 , Natalia Torres  4 , Elisangela P S Quedas  1 , Thais Kataoka Homma  1 , Edoarda V A Albuquerque  1 , Michelle B Moraes  1   5 , Mariana F A Funari  6 , Debora R Bertola  5 , Alexander A L Jorge  1   6 , Alexsandra C Malaquias  1   2
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Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile

Renata M Noronha et al. Am J Med Genet A. 2021 Mar.

Abstract

Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.

Keywords: Noonan syndrome; PTPN11; RASopathy; glucose; insulin; metabolism.

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