Complicated ventricular arrhythmia and hematologic myeloproliferative disorder in RIT1-associated Noonan syndrome: Expanding the phenotype and review of the literature

Aly SA, Boyer KM, Muller BA, Marini D, Jones CH, Nguyen HH.Mol Genet Genomic Med. 2020 May 12:e1253. doi: 10.1002/mgg3.1253. Online ahead of print.PMID: 32396283 Free article.



Background: Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome.

Methods and results: We present a patient with RIT1-associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and “left-shifted” complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1.

Conclusion: We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1-associated Noonan syndrome can be extremely severe with poor outcome.


Figure 1 Wide complex tachycardia consistent with idioventricular rhythm associated with loss of pulse on arterial line (ART) tracing


Figure 2 Percentage of immature neutrophils (band neutrophils, blasts, myelocytes, metamyelocytes, and promyelocytes) and ratio of immature to total neutrophils (I/T) on serial complete white blood counts with manual differentiation. The red circles identify the tests where the immature to total neutrophils ratio is greater than 20%. The size of each circle is proportional to the magnitude of the ratio