PTPN11 variants in four Chinese patients: a case series and genotype-phenotype analysis

Noonan syndrome (NS) and LEOPARD syndrome (LS) are well-characterized RAS/MAPK pathway-related disorders with strong genotype-phenotype correlations. Most cases of both syndromes are caused by variants in the PTPN11 gene, with specific sites predisposing to either NS or LS. The association between PTPN11 and granular cell tumours (GCTs) remains largely unexplored. To further investigate the phenotypic spectrum of patients with PTPN11 variants. We performed whole-exome sequencing on four Chinese children who presented with café-au-lait macules as the initial cutaneous manifestation. To confirm the mutation, Sanger sequencing was performed on DNA samples obtained from the patient and both parents. Histopathological examination and immunohistochemical staining were performed on a subcutaneous nodule from patient 1 to characterize the lesion. Three PTPN11 variants were identified: c.1391G>C (p. Gly464Ala), c.1403C>T (p. Thr468Met), and c.1493G>T (p. Arg498Leu). Notably, patient 1, who carried the PTPN11 c.1391G>C variant, presented with coexisting granular cell tumours -an association that has not previously been reported for this specific variant. The association with granular cell tumours highlights the clinical importance of long-term surveillance of neural crest-derived neoplasms in PTPN11 variant carriers and broadens our understanding of the diverse phenotypic outcomes associated with PTPN11 variants.