CHST3‐related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum

Abstract

Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.

Indian patients with CHST3‐related chondrodysplasia with congenital joint dislocations

“…None of the patients had hearing loss. Seven patients reported in this study had supernumerary carpal ossification centers which were observed in only six previously reported patients and most of them were above 10 years of age (Albuz et al, 2020;Otaify et al, 2023;Tuysuz et al, 2009;van Roij et al, 2008). The other two affected individuals were of ages 3 and 6 years, suggesting the possibility of observing this feature later in life.…”

“…It appears that mitral, tricuspid, and aortic valves are commonly affected in that order with thickened leaflets, stenosis, and insufficiency. In recent study by Otaify et al, severe cardiac valvular insufficiencies were reported in three individuals (Otaify et al, 2023). Considering this observation, a cardiac evaluation is warranted in patients with CHST3 deficiency.…”

“…This report provides further evidence for the cardiac involvement in this condition. First reported by Kozlowski et al (1974), cardiac defects including hypertrophy of both atria and ventricle, thickening of mitral valve leaflet, aortic regurgitation, and stenosis were noted in several reports (Hall, 1997;Otaify et al, 2023;Rajab et al, 2004;Srivastava et al, 2017;Tuysuz et al, 2009;Unger et al, 2010;Yan et al, 2017). It appears that mitral, tricuspid, and aortic valves are commonly affected in that order with thickened leaflets, stenosis, and insufficiency.…”

“…There are 52 disease‐causing variants identified till date, including our four novel variants (Otaify et al, 2023). Most of the pathogenic variations are substitutions (Unger et al, 2010).…”