T A FORBES1,2,3, C D’ARCY1,2, P BLOMBERY3,4, D EFRON1,2,3, E WILKINS1,5, T COLE1,2, S L KHAW1,2,3, C QUINLAN1,2,3, S M WHITE2,3,5
1Murdoch Children’s Research Institute, Parkville, Australia, 2Royal Children’s Hospital, Parkville, Australia, 3University of Melbourne, Parkville, Australia, 4Peter MacCallum Cancer Centre, Parkville, Australia, 5Victorian Clinical Genetics Service, Parkville, Australia
Background: Focal segmental glomerulosclerosis (FSGS) describes a histological glomerular appearance frequently associated with genetic forms of steroid resistant nephrotic syndrome (SRNS) in children and adults. Only one third of patients with SRNS will have a pathogenic variant found on genomic sequencing. Sterile alpha motif domain-containing protein 9 (SAMD9) encodes for a protein expressed in diverse cell types, which has been observed to suppress cell proliferation. Pathogenic, germline, gain of function variants give rise to MIRAGE syndrome characterised by myelodysplasia, recurrent infections, growth retardation, adrenal hypoplasia, genitourinary anomalies and enteropathy.
Case Report: We present a 7-year-old girl with MIRAGE syndrome who presented with recurrent fever and pancytopenia in early infancy and was found to have myelodysplasia associated with mosaic monosomy 7 on bone marrow aspirate. She later developed severe proteinuria (3.2 g/mmol creatinine) and hypoalbuminaemia (21g/L) without oedema. Renal function was normal (eGFR 98 mL/min/1.73sqm). Histology on renal biopsy was consistent with FSGS without glomerular immune deposits. Electron microscopy revealed podocyte hypertrophy with segmental foot process effacement and no glomerular basement membrane changes or deposits. She demonstrated a remarkable response to empiric ACE inhibitor therapy (>300mg/mmol creatinine, albumin 35g/L). We present a complex diagnostic genomic odyssey, which culminated in trio whole exome sequencing of DNA from fibroblasts showing a de novo, germline SAMD9 variant (NM_017654.3:c.4057A>G, p.Lys1353Glu). We review two previous reports of glomerular disease (with and without glomerular basement membrane deposits) in MIRAGE syndrome.
Conclusions: FSGS is an evolving phenotype of MIRAGE syndrome due to SAMD9 variants. We propose that SAMD9 should be added to genomic panels for FSGS or undiagnosed proteinuria and illustrate the profound effect of lisinopril in reducing proteinuria in our case.
Dr Tom Forbes is a Paediatric Nephrologist at the Royal Children’s Hospital in Melbourne, with an interest in genetic kidney diseases. He completed his clinical training at the Royal Children’s Hospital in 2015, also training at Birmingham Children’s Hospital and Nottingham University Hospital in the UK. He completed his PhD with Prof Melissa Little’s Kidney Regeneration laboratory at MCRI examining the capabilities and limitations of patient-iPSC derived kidney organoids as functional genomic models of kidney disease. He holds an MCRI Clinician Scientist Fellowship continuing his research in novel gene discovery and functional genomic disease modelling with kidney organoids.