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

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.

SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

“…However, given the effect, albeit transient, of MEK inhibitor, one cannot exclude that glucose intolerance will be found in other RASopathies, although a mouse model of Costello syndrome seems to display improved glucose tolerance (48). Supporting our results, an unfavorable metabolic profile was recently reported in patients with NS, including impaired glucose tolerance despite a lean phenotype (49). This study further demonstrates that NS and other RASopathies are associated with defects in systemic glucose management.…”

Feeding Problems in Patients with Noonan Syndrome: A Narrative Review

“…Additionally, it is possible that a need for greater energy intake is initially masked by feeding problems. Both energy supply and energy demand (metabolism, energy expenditure, and the storage of energy in muscle, adipose and bone tissue) participate in the regulation of energy homeostasis [28][29][30]. It is important to evaluate all of the nutritional and feeding aspects involved not only in length growth but also in maintaining a healthy weight for length (BMI) and a healthy body composition.…”

Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling

“…Nevertheless, multiple experiments support that inhibition of SHP2 activity in the liver (but not in the skeletal muscle or pancreas) can ameliorate insulin resistance in mouse models 5 , 38 – 40 . In accordance with animal experiments, individuals with hereditary SHP2 gain-of-function mutations (Noonan syndrome) display insulin resistance more frequently than the generic population, despite their overall leaner phenotype 41 .…”