Schimke immunoosseous dysplasia (SIOD): Delayed onset of rare disease and novel variant

TL;DR

A 15-year-old with a rare genetic disorder showed delayed symptoms and a new mutation, leading to kidney failure but mild immune issues.

Contribution

A novel SMARCAL1 mutation in a patient with juvenile-onset SIOD and milder immunodeficiency is reported.

Findings

The patient had a novel homozygous p.(R611C) SMARCAL1 mutation confirmed by whole-exome sequencing.

The patient progressed to end-stage kidney disease but had only mild immune dysfunction.

Kidney transplantation may be a feasible treatment option in similar cases with cautious immunosuppression.

Abstract

Schimke immunoosseous dysplasia (SIOD) is a condition marked by spondyloepiphyseal dysplasia (SED), leading to short stature, nephropathy, and T-cell immunodeficiency.

Case presentation: A 15-year-old male was referred to the nephrology clinic with a gradual onset of lower-limb swelling. Clinical examination revealed short stature. Laboratory studies revealed renal impairment and nephrotic-range proteinuria. Kidney biopsy showed global sclerosis in 3 of 28 glomeruli, segmental sclerosis in 16 of 28 glomeruli, and 90% foot-process effacement on electron microscopy. A skeletal survey showed flattened thoracolumbar vertebral bodies, a characteristic feature of SIOD. Flow cytometry revealed a low CD4 count. Whole-exome sequencing confirmed that the proband was homozygous for the p.(R611C) variant in the SMARCAL1 gene. The patient was treated with a calcineurin inhibitor (CNI), angiotensin receptor blockers (ARBs), and prophylactic anticoagulation. Initially, he experienced improvement in serum albumin levels and proteinuria. However, his urine protein and creatinine levels subsequently increased, prompting discontinuation of CNI. The patient progressed to end-stage kidney disease (ESKD) and required hemodialysis 18 months after the initial presentation.

Discussion: This report describes a case of SIOD, a rare multisystem disorder characterized by short stature due to SED and nephrotic syndrome, distinguishing it from other hereditary nephrotic syndromes. The patient presented unusually in adolescence with nephrotic-range proteinuria and skeletal abnormalities, representing a rarely reported juvenile variant. Genetic testing revealed a novel homozygous SMARCAL1 mutation, p.(R611C), which was confirmed in his younger sibling. However, the phenotypic expression differed, reflecting the weak genotype–phenotype correlation in SIOD. Unlike many SIOD cases, our patient did not experience recurrent infections despite abnormal immune parameters, suggesting a milder immunodeficiency and making kidney transplantation with cautious immunosuppression a feasible option. Current therapeutic challenges include the lack of effective disease-specific treatments, limited success with conventional transplantation due to infection and malignancy risks, and emerging but logistically complex approaches such as combined stem-cell and kidney transplantation.

SIOD is a rare genetic disorder with variable presentation and outcomes. Our patient, carrying a novel SMARCAL1 mutation and presenting with juvenile-onset disease, progressed to ESKD but had only mild immune dysfunction, making kidney transplantation a potential treatment option. Early recognition is essential to avoid unnecessary treatments, guide supportive care, and enable timely referral for advanced therapies. Clinicians should consider SIOD in patients presenting with short stature and nephrotic syndrome to optimize outcomes.

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