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

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.

Fig. 1. Flow diagram outlining study inclusion for NS complicated with lymphoedema and cellulitis.

The literature search across PubMed with the MeSH term ‘Noonan syndrome’ combined with text words such as ‘cellulitis’, ‘bacteraemia’, ‘septic shock’, ‘sepsis’ or ‘lymphoedema’ resulted in 85 hits. Based on the title, abstract and full text, 68 records were excluded because they did not meet the eligibility criteria or were not available in full text, and 8 duplicates were removed. In total, 9 articles (7 case reports and 2 case series) were identified, involving 16 patients with NS complicated by lymphoedema and cellulitis.

Fig. 2. Clinical features of patient 1.

a Physical examination reveals bilateral lower limb swelling, more severe in the right leg, with accompanying redness extending to the right inguinal region. b Computed tomography showing multiple enlarged pelvic lymph nodes. c Swelling and redness improved after antibacterial treatment.

Fig. 3. Clinical features of patient 2.

a, b Facial dysmorphism, including ptosis and low-set posteriorly rotated ears (a Frontal view b Lateral view). c, d Physical examination reveals bilateral limb lymphoedema, more severe in the left leg (c), accompanied by exudate (d). e Lymphoedema improved after vascularized lymph node transplantation, and no further recurrence was observed for 3 years.