ESPE Abstracts

Background: Noonan Syndrome (NS) is a genetic disorder mainly inherited in an autosomal dominant manner, which prevalence is estimated to range from 1:1,000 to 1:2,500 live births. Characteristic features of NS include short stature, distinctive craniofacial dysmorphisms (e.g., hypertelorism, low-set ears, broad and short neck), skeletal anomalies and cardiovascular defects. The genetic basis involves, most commonly, mutations in the PTPN11 gene, KRAS gene and SOS1.

Presented Problem: We present 4 children (3 boys and 1 girl) with NS, who were referred to the Department of Endocrinology and Metabolic Diseases of the Polish Mother’s Memorial Hospital – Research Institute in Lodz, Poland. These patients demonstrated significant variability in the clinical presentation of NS, which was also influenced by the presence of overlapping comorbid conditions. One of the children presented with advanced resorption of the roots of the permanent incisors, for which no graspable cause could be determined. Genetic testing revealed not only a pathogenic allele of the PTPN11 gene, but also a pathogenic allele of the NBN gene associated with Nijmegen syndrome. This boy did not display typical NS features, and his growth was between the 10th and 25th percentiles on growth charts. Another patient had mitral valve insufficiency, along with bilateral undescended testes. Notable features included facial dysmorphisms and reduced muscle tone. Molecular NGS analysis revealed a pathogenic variant in the LZTR1 gene, associated with NS type 10, and karyotyping indicated Klinefelter syndrome (47, XXY), typically characterized by tall stature. Interestingly, his growth was harmonious between the 25th and 50th percentiles on growth charts. The third patient was consulted due to low bone mass and growth deficiency (-2,9 hSDS). Endocrinological causes of growth disorders were excluded, however NGS analysis identified a pathogenic variant in the PTPN11 gene. This case was unique because, aside from growth deficiency, the patient did not manifest any typical phenotypic features of NS. The last patient presented with significant growth deficiency (-4,43 hSDS). He exhibited facial dysmorphisms characteristic of NS, as well as cogenital pulmonary stenosis. Genetic testing confirmed NS by revealing a mutation in the PTPN11 gene. Two patients with short stature are being treated with growth hormone therapy, showing favorable therapeutic outcomes. The other two patients remain under close supervision.

Discussion: NS can present a wide range of manifestations, often lacking the characteristic features associated with the syndrome. Establishing the diagnosis may uncover previously undetected abnormalities or unveil new therapeutic opportunities.