Paternally Inherited Noonan Syndrome Caused by a Variant May Exhibit Mild Symptoms: A Case Report and Literature Review.

BACKGROUND

Noonan syndrome (NS)/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case.

METHODS

In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of were searched from 2000 to 2022.

RESULTS

We present a case of a proband with a variant (c.1492C > T/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the p.Arg498Trp variant, cardiac abnormalities (6/11), facial dysmorphism (7/11), skin pigmentation (4/11), growth problems (4/11), and sensorineural hearing loss (2/11) have been observed. NS/NSML patients with the p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated .

CONCLUSIONS

Paternally inherited NS/NSML caused by a p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene-gene interactions, gene-environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype.