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Steroid Resistant nephrotic syndrome (SRNS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia, with an absence of response to an initial trial of six weeks of corticosteroids. It is an important cause of chronic kidney disease in the paediatric population. There are more than 60 monogenic variants causing SRNS and most are expressed in the glomerular podocytes. DAAM2 variants are implicated in causing Type 24 SRNS probably through actin dysregulation. Here, we describe a child with SRNS, found to have a novel mutation at c.1993c>T in exon 16 of the DAAM2 gene who responded well to Rituximab therapy.
Four-year-old girl, a second child of distantly related healthy parents and healthy seven-year-old brother was admitted for evaluation for the 3rd dose of Rituximab therapy. She first presented with steroid resistant nephrotic syndrome with microscopic haematuria and hypertension at the age of two year and two months. She had initially shown some response to calcineurin inhibitor, cyclosporin, but subsequently developed frequent relapses instead, with a cyclosporin level of more than 80 ng/dl.
At the age of 3 years, she underwent whole exome sequencing and found to have a novel heterozygous variant of uncertain significance (VUS), c.1993C>T in exon 16 of the DAAM2 gene located in chromosome 6. She was treated with two doses of Rituximab 750mg/m2 each two weeks apart at the age of 3 years. Following that she had achieved a long-term remission, nearly one year to date. The renal biopsy was not performed due to parental concerns.
One third of cases with Steroid Resistant Nephrotic Syndrome (SRNS) has a genetic basis and is implicated in hereditary podocytopathies. It includes Nephrotic syndrome type 24 (NPHS24), a very rare autosomal recessive steroid resistant nephrotic syndrome (OMIM#606627).
NPHS24 is characterized by early onset oedema, hypoalbuminemia, and proteinuria. Some shown to have a response to second line immunosuppressive drugs and others were shown to have multidrug resistant nephrotic syndrome. Renal biopsy has shown nonspecific changes with most shown to have focal segmental glomerulosclerosis and diffuse mesangial proliferation. It is slowly progressive and eventually lead to end stage renal disease in most cases.
NPHS24 is reported to be caused by DAAM2 variants in the homozygous or compound heterozygous state. The DAAM2 gene, located in chromosome 6 codes for disheveled-associated activator of morphogenesis 2 protein which maintains the function of the podocyte foot processes and podocyte migration through an intact actin network.
The single nucleotide variant (SNV) found in this patient through whole exome sequencing, whose parents are distant relatives, is in the heterozygous state. There are no previous reports to date of the disease manifesting in the heterozygous state. It would be better to test the parents for the variant to determine if it occurred de novo, including copy number variant analysis of the DAMM2 gene, whole genome sequencing and functional studies in this child to give us further insight on her unique genetic makeup.
Our patient with this novel mutation at c.1993c>T in exon 16 of the DAAM2 gene has shown very good response to Rituximab therapy and is currently in remission for one year duration whilst maintaining normal renal functions.