The Fetal Phenotype of Noonan Syndrome Caused by Severe, Cancer-Related PTPN11 Variants

Abstract

Case series Patients: Female, 37-year-old • Female, 31-year-old Final Diagnosis: Noonan syndrome Symptoms: Fetal nuchal fold thickening Medication: — Clinical Procedure: Chorionic villi sampling Specialty: Genetics • Obstetrics and Gynecology Objective: Rare disease Background: The nuchal translucency measurement is the major focus of an early fetal ultrasound scan, with the goal to identify various inherited conditions, such as chromosomal aberrations and others. The diagnostic strategy for fetuses with increased nuchal translucency and normal karyotype is not clearly defined and may vary between countries. Case Reports: We describe 2 cases of Noonan syndrome diagnosed prenatally by ultrasound scanning and genetic testing. The prenatal ultrasound scans showed abnormal nuchal translucencies, cystic lymphangioma/cystic hygroma, and other findings. Both fetuses had normal karyotype; however, after additional analysis, pathogenic variants of the PTPN11 gene (encoding SH2 domain-containing protein tyrosine phosphatase) were found, previously frequently described as somatic variants in hematological malignancies in postnatal life, but not previously described with severe prenatal phenotype of Noonan syndrome. Conclusions: Our case reports confirm the hypothesis that severe, cancer related PTPN11 variants cause severe Noonan syndrome prenatal phenotype, when inherited in the germline. Analysis of pathogenic variants associated with Noonan syndrome should be included in the prenatal diagnostics for fetuses with increased nuchal translucency and normal karyotype.

First prenatal case of Noonan syndrome with SOS2 mutation: Implications of early diagnosis for genetic counseling

“…However, SOS2 mutation is a rare cause of NS (< 2% of cases), without any data on the overall outcome of fetuses with SOS2 pathogenic variants, which are prenatally identified. We cannot exclude a more severe prognosis in cases with severely increased NT or with significant and/or early prenatal signs, as described by Malniece et al (2020) in a PTPN11 NS case diagnosed prenatally. Therefore, great caution should be taken regarding any genotype–phenotype correlation in prenatal counseling for NS.…”

Improving prenatal diagnosis through standards and aggregation

“…Terms were added to specify the time of onset of a particular phenotype, with new terms added to describe embryonal, late first trimester, second trimester, and third trimester onset. An example of HPO terms related to a particular case is shown in Figure 2 74 . It is estimated that the current HPO covers roughly 85% of the terms required for comprehensive annotation, and efforts continue to revise and augment the HPO.…”

“…An example of HPO terms related to a particular case is shown in Figure 2. 74 It is estimated that the current HPO covers roughly 85% of the terms required for comprehensive annotation, and efforts continue to revise and augment the HPO.…”

“…Expansion of the prenatal HPO: Since 2020, over 90 new prenatal-relevant terms have been added to the HPO. This is demonstrated in the evolving fetal phenotype of a fetus with a PTPN11 variant, adapted from Malniece, et al 74 Newly added HPO terms, including onset terms, are bolded and italicized. HPO, human phenotype ontology.…”