Bruck syndrome in 13 new patients: Identification of five novel FKBP10 and PLOD2 variants and further expansion of the phenotypic spectrum

Abstract

Bruck Syndrome (BS) is a very rare disorder characterized by osteogenesis imperfecta (OI) associated with congenital contractures and is caused by mutations in FKBP10 or PLOD2 genes. Herein, we describe 13 patients from 9 unrelated Egyptian families with BS. All patients had white sclerae, recurrent fractures, kyphoscoliosis and osteoporosis with variable degrees of severity. Large joint contractures were seen in 11 patients, one patient had contractures of small interphalangeal joints, and one patient had no contractures. Unusual findings noted in individual patients included microcephaly, dental malocclusion, enamel hypoplasia, unilateral congenital dislocation of knee joint, prominent tailbone, and myopathy. Nine different variants were identified in FKBP10 and PLOD2 including five novel ones. FKBP10 variants were found in six families (67%) while PLOD2 variants were identified in three families (33%). The four families, with two affected sibs each, showed inter-and intrafamilial phenotypic variability. In conclusion, we report five novel variants in FKBP10 and PLOD2 thus, expanding the mutational spectrum of BS. In addition, our results expand the phenotypic spectrum, describe newly associated orodental findings, and further illustrate the phenotypic overlap between OI and Bruck syndrome supporting the suggestion of considering BS as a variant of OI rather than a separate entity.

Bruck syndrome – description of the first Polish infant with FKBP10 gene mutation

“…In 2022, an article was published describing five new variants in the FKBP10 and PLOD2 genes, thus expanding the mutational spectrum of BS. Moreover, these data illustrate a phenotypic overlap between OI and BS, supporting the suggestion that BS should be considered a variant of OI rather than a separate disease entity (7) . The characteristics of BS include multiple recurrent fractures, congenital joint contractures, joint hypermobility, spinal deformities, craniofacial deformities, osteoporosis, blue sclerae, and others (5) .…”

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).…”