# Exploring the clinical and genetic spectrum of Steel syndrome: two case reports and review of the literature

## TL;DR

This paper explores two new cases of Steel syndrome in Russian and Uzbek patients, expanding the genetic and clinical understanding of this rare skeletal disorder.

## Contribution

The study reports two novel genetic variants in non-Puerto Rican populations and explores genotype-phenotype correlations in Steel syndrome.

## Key findings

- Two novel compound heterozygous and homozygous variants in COL27A1 were identified in non-Puerto Rican patients with Steel syndrome.
- Phenotypic variability was observed depending on variant type and population origin.
- Biallelic Gly substitutions are linked to the classic skeletal phenotype, while frameshift/nonsense variants correlate with extraskeletal features and severe short stature.

## Abstract

Steel syndrome (STLS, OMIM# 615155) is a rare skeletal dysplasia associated with biallelic pathogenic variants in COL27A1 gene. To date, more than 60 patients with STLS have been reported in the literature, the majority of whom are Puerto Rican. STLS in all individuals from this population is associated with the homozygous p.Gly697Arg missense variant, confirming the founder effect. Meanwhile, just 17 cases from 14 unrelated non-Puerto Rican families have been reported, including two fetuses. Here we present two pediatric cases of STLS from Russian and Uzbek populations, associated with two novel compound heterozygous splice variants c.2673 + 4A > G, c.2619 + 1G > A and a novel homozygous missense variant c.3988G > C p. (Gly1330Arg). Splicing assay was performed to investigate the novel donor splice site variants' effects on mRNA structure and expression. Both cases demonstrated skeletal features characteristic of STLS, including acetabular dysplasia or hip dislocation, carpal coalition, radial head dislocation, with additional extraskeletal manifestations observed in one patient. A review of 63 STLS cases revealed key diagnostic criteria present in the majority of individuals, though phenotypic variability was observed depending on variant type and population origin. It is proposed that biallelic Gly substitutions within the triple-helical domain associated with the ‘classic' skeletal phenotype of STLS initially characterized in Steel's study. In contrast, patients with homozygous or compound heterozygous frameshift or nonsense variants more frequently demonstrate a higher prevalence of extraskeletal manifestations and severe short stature. Our study expands the genetic and clinical spectrum of STLS in non-Puerto Rican populations and explores potential genotype-phenotype correlations, which will contribute to early disease diagnosis and the selection of optimal patient management strategies, avoiding unnecessary interventions.