Coexistence of NXF5 Mutation-Associated Nephrotic Syndrome and Williams Syndrome: Coincidence or a Shared Pathogenic Mechanism?

Dear Editor,

Focal segmental glomerulosclerosis (FSGS) is a primary cause of nephrotic syndrome, characterized by proteinuria, hypoalbuminemia, and kidney dysfunction. Its etiology is diverse, with genetic factors, especially mutations in podocytes, critical in steroid-resistant nephrotic syndrome (SRNS) in children.¹ The NXF5 gene encodes a protein involved in nuclear mRNA export, essential for gene expression. Rare mutations in NXF5 are linked to X-linked FSGS and may coexist with cardiac anomalies, arrhythmias, and neurodevelopmental disorders.² Williams syndrome (WS) is a genetic disorder caused by a 7q11.23 microdeletion, characterized by congenital heart disease, distinctive facial features, and developmental delay, with renal involvement being rare.³

We report a 13-year-old girl with genetically confirmed WS, followed for precocious puberty, intellectual disability, and long QT syndrome. The diagnosis of WS had previously been confirmed by fluorescence in situ hybridization, demonstrating a 7q11.23 microdeletion. She was referred to pediatric nephrology due to hypoalbuminemia and generalized edema. There was no consanguinity or family history of kidney disease. Laboratory evaluation showed preserved renal function, serum albumin of 2.5 g/dL, and a urine protein/creatinine ratio of 5.2 mg/mg. Complement levels were normal. Nephrotic syndrome was diagnosed, and corticosteroids were initiated. Proteinuria paersisted, and renal biopsy revealed FSGS. Genetic analysis subsequently revealed a heterozygous NXF5 mutation (Ex15.958C>T; p.Arg320Ter). Because this is an X-linked recessive gene, the phenotype in this girl can be explained by which X chromosome is inactivated. Partial remission was achieved under calcineurin inhibitor therapy.

In our patient, SRNS and FSGS were associated with an NXF5 mutation, which has been linked to glomerular, neurological, and cardiac abnormalities. The coexistence of FSGS, long QT syndrome, and intellectual disability suggests a multisystemic effect.^4,5 This case highlights the rare coexistence of WS and SRNS and underscores the importance of genetic evaluation in complex multisystem disorders.