A novel compound heterozygous variation in the FKBP10 gene causes Bruck syndrome without congenital contractures: A case report

Abstract

Background: Bruck syndrome (BS) is an extremely rare autosomal-recessive connective tissue disorder mainly characterized by bone fragility, congenital joint contracture, and spinal deformity. It is also considered as a rare form of osteogenesis imperfecta (OI) due to features of osteopenia and fragility fractures. Its two forms, BS1 and BS2, are caused by pathogenic variations in FKBP10 and PLOD2, respectively.

Objective: We aimed to improve the clinical understanding of BS by presenting a case from China and to identify the genetic variants that led to this case.

Methods: OI was suspected in a Chinese boy with a history of recurrent long bone fractures, lumbar kyphosis, and dentinogenesis imperfecta (DI). Whole-exome sequencing (WES) was performed to identify pathogenic variations. Sanger sequencing was used to confirm the results of the WES. In silico analysis was used to predict the pathogenicity of genetic variants.

Results: WES and Sanger sequencing revealed a compound heterozygous variation in the FKBP10 gene (NM_021939, c.23dupG in exon 1, and c.825dupC in exon 5). Both variants resulted in a frameshift and premature stop codon. Of these two variants, c.23dupG has not been previously reported. The patient's parents were heterozygous carriers of one variant. In addition, zoledronic acid treatment improved the vertebral deformity and bone mineral density (BMD) significantly in this patient.

Conclusions: A novel compound heterozygous variation of FKBP10, c.23dupG/c.825dupC, was identified in a patient with moderately severe OI. Based on these findings, the patient was diagnosed with BS1 without congenital joint contractures or OI type XI. This study expands the spectrum of FKBP10 genetic variants that cause BS and OI.

Keywords: Bruck syndrome; Case report; FKBP10; Osteogenesis imperfecta; Whole-exome sequencing.

Fig. 1

Clinical presentations of an OI case. (A) The pedigree. II:3 is the patient. (B, C) X-radiographs and CT scanning demonstrated a lumbar kyphosis deformity centered on L1. Multiple lumbar vertebrae became flattened and wedge-shaped, especially L1 and L3. The X-ray film also showed mild osteoporosis in the spine. (D) No obvious limb deformities or joint contractures were found. (E) The enamel of multiple maxillary incisors was partially exfoliated, indicating DI. (F) The patient experienced multiple recurrent long bone fractures beginning in infancy. The X-ray film showed that he had bilateral tibial fractures (indicated by white arrows) at the age of 2 and a half. (G) Treatment with zoledronic acid improved the vertebral deformity significantly. Compared to before treatment (B), the height of lumbar vertebrae became normal.

Fig. 2

Identification of a novel compound heterozygous variation in FKBP10 gene. (A) Schematic representation of the filtering process of WES data. (B) Sanger sequencing. A novel compound heterozygous variation in FKBP10 gene, c.23dupG/c.825dupC, were identified in the patient (II:3). The patient's father (II:1) carries heterozygous c.825dupC and mother (II:2) carries heterozygous c.23dupG. (C) Representation of FKBP65 protein with the location of variants. FKBP65 protein contains four peptidyl-prolyl-isomerase domains (PPIase), two EF Hand domains, and a putative ER-retention sequence (ER Target).