# Recurrent cellulitis associated with lymphoedema in Noonan syndrome: case reports with RIT1 variants and literature review

## TL;DR

The paper reports on patients with Noonan syndrome and RIT1 gene mutations who experience severe lymphoedema and recurring cellulitis, highlighting the need for early treatment.

## Contribution

The study identifies a higher frequency of RIT1 mutations in Noonan syndrome patients with lymphoedema and cellulitis, suggesting a genetic link to these complications.

## Key findings

- Eighteen patients with Noonan syndrome and RIT1 or PTPN11 mutations showed early-onset lymphoedema and cellulitis.
- Four patients with sepsis had congenital heart defects, indicating a higher prevalence than typically reported.
- RIT1 mutations were more common in this subgroup than previously observed in Noonan syndrome.

## Abstract

Noonan syndrome (NS) is a RASopathy, a disorder caused by genetic alterations involving the Ras/mitogen-activated protein kinase pathway. It causes characteristic clinical manifestations, including facial dysmorphism and congenital cardiac defects. Occasionally, lymphoedema and recurrent cellulitis occur in patients with NS, potentially escalating to lethal conditions. Despite the frequent association of cellulitis with lymphoedema in NS, features susceptible to these complications have not been fully characterized. We encountered two patients with NS carrying RIT1 pathogenic variants, who were treated for recurrent lower leg cellulitis since their teenage years, which occasionally progressed to sepsis. Here we retrospectively examined these patients with NS and recurrent cellulitis on the background of lymphoedema and reviewed published cases of NS with lymphoedema and cellulitis up to March 2024 to elucidate the clinical and genetic features of this subgroup. Our literature review identified 16 additional patients with NS with similar complications. Among the 18 patients (15 men), genetic analyses revealed pathogenic variants in PTPN11 and RIT1 in 4 patients each, with the latter occurring more frequently than commonly observed. The patients developed lymphoedema by 15 years of age, predisposing them to cellulitis by 23 years of age. Notably, four of the five patients with sepsis had congenital heart defects, with a higher prevalence than that generally reported in NS. This study highlights the characteristics of genetic variants, congenital cardiac anomalies and heightened risk of recurrent cellulitis in patients with NS, emphasizing the need for early intervention with prophylactic antibiotics and surgical treatment to mitigate these risks.

Noonan syndrome (NS) is a genetic disorder that affects various parts of the body, often leading to heart defects and unique facial features. Researchers have identified several genes linked to NS, but the connection between these genes and certain complications, such as cellulitis and lymphoedema, is not well understood. In this study, two patients with NS and recurrent cellulitis were examined. Researchers collected clinical data from these patients and conducted genetic testing to identify any mutations. They also reviewed 15 similar cases from existing literature. The study found that both patients had a mutation in the RIT1 gene, which is known to be associated with NS. This mutation may increase the risk of developing lymphoedema and cellulitis. The findings suggest that specific genetic mutations in patients with NS could lead to recurrent infections and swelling.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.