Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years

Abstract

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1-3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003-2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77-100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a "founder mutation" in Russia.

Keywords: SMARCAL1; Schimke immuno-osseous dysplasia (SIOD); genetics of rare disease; hereditary nephrotic syndrome; steroid-resistant nephrotic syndrome (SRNS); ultra-rare hereditary disease.

Figure 1

Common clinical features of patients with SIOD in our cohort. (A) Six-year-old boy with SIOD: short stature, disproportional short trunk, short neck, low auricles; (B) The spine X-ray of a child with SIOD. R—right side. In the lateral projection, the thoracic vertebrae are rounded, the anterior contours are smoothed, and the lumbar vertebrae are flattered. The height of the intervertebral spaces is significantly reduced in the thoracic region throughout and expanded in the lumbar region (due to deformation of the vertebral bodies).

Figure 2

Spectrum of disease manifestations in children with SIOD. CAKUT—congenital anomalies of kidney and urinary tract.

Figure 3

Survival of SIOD patients. (A) Overall and (B) renal survival. Kaplan–Meier curves.