Objective:

To report a rare case of neonatal Noonan syndrome (NS) caused by a RIT1 c.247A>C (p.Thr83Pro) variant.

Approach:

• Clinical Data Collection: Clinical data of a neonate with NS were retrospectively analyzed.
• Genetic Analysis: Whole-exome sequencing was performed to identify potential pathogenic variants.
• Functional Validation: In vitro studies were conducted to investigate the pathogenic mechanism of the variant.
• Literature Review: A review of RIT1-NS cases reported between 2014 and 2025 was performed, identifying 54 cases for analysis.

Key Findings:

• The proband presented with progressive acute kidney injury (AKI), systemic capillary leak syndrome (SCLS), refractory chylothorax, and a large patent ductus arteriosus.
• Whole-exome sequencing identified a de novo heterozygous RIT1:c.247A>C p.(Thr83Pro) variant.
• Functional studies indicated that the variant enhanced phosphorylation of ERK, JNK, and p38, and upregulated IL-1β, IL-6, and TNF-α mRNA expression.
• Among 54 reported RIT1-NS cases, the p.Thr83Pro variant accounted for 3.7% (2/54), with this case being the only one presenting with AKI and SCLS.

Interpretation:

The RIT1:c.247A>C p.(Thr83Pro) variant may contribute to life-threatening NS in the neonatal period, highlighting the importance of early genetic testing for diagnosis and prognostic assessment.

Limitations:

• The study is based on a single case report, which may limit the generalizability of the findings.
• The literature review may not capture all relevant cases due to potential publication bias.

Conclusion:

The findings suggest that early genetic testing may facilitate diagnosis and prognostic assessment in neonatal RIT1-NS.