Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.

Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS.

Dosage of hydrocortisone during late infancy is positively associated with changes in body mass index during early childhood in patients with 21-hydroxylase deficiency.

Obesity is a major complication in children with 21-hydroxylase deficiency (21-OHD). There is evidence to show that higher body mass index (BMI) during infancy and early childhood is associated with an increased risk for the subsequent development of obesity in the general population; however, limited information is currently available on this issue in 21-OHD patients. Additionally, despite the frequent use of supraphysiological dosages of hydrocortisone in 21-OHD, the association between BMI and hydrocortisone dosage during these periods remains largely unclear; therefore, we retrospectively investigated BMI at approximately 1 and 3 years old and its association with hydrocortisone dosage in 56 children with 21-OHD. The median BMI-standard deviation score (SDS) was 0.28 (Interquartile range [IQR]: -0.53 to 1.09) and 0.39 (IQR: -0.44 to 1.14) at approximately 1 and 3 years old, respectively, and no association was observed between hydrocortisone dosage and BMI-SDS at either time-point; however, multivariate analysis revealed that hydrocortisone dosage at approximately 1 year old was positively associated with changes in BMI (ß = 0.57, p = 0.013) and BMI-SDS (ß = 0.59, p = 0.011) between approximately 1 and 3 years old after adjustment for age, sex, and changes in hydrocortisone dosage during the same period. The average dosage of hydrocortisone between approximately 6 months and 1 year old also showed similar results. These results indicate that a higher dosage of hydrocortisone during late infancy is associated with a higher BMI at approximately 3 years old, which may lead to the development of obesity later in life in children with 21-OHD.