ORPHA: 666; DO: 0112201;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p22.1 | Osteogenesis imperfecta, type XXI | 619131 | Autosomal recessive | 3 | KDELR2 | 609024 |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XXI (OI21) is caused by homozygous or compound heterozygous mutation in the KDELR2 gene (609024) on chromosome 7p22.
Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).
Van Dijk et al. (2020) reported 6 patients from 4 families with osteogenesis imperfecta (OI), all of whom had been given a clinical diagnosis of progressively deforming OI type 2B/3. Four patients (P1, P2-1, P2-2, and P3) showed disproportionate short stature and had experienced multiple fractures from early childhood, leading to progressive skeletal deformation and requiring recurrent surgical interventions. In P2-1, P2-2, and P3, progression led to wheelchair dependence, in childhood for P2-1 and P2-2 and at 18 years for P3. No bisphosphonate therapy was available in childhood. In P1, low bone density was seen to improve with bisphosphonate therapy, and mobility was maintained at 12 years. Prenatal ultrasound showed a suspicion of a severe skeletal dysplasia in patients P4-1 and P4-2 and both pregnancies were terminated, at 24 and 22 weeks' gestational age, respectively. X-rays of both fetuses showed slender ribs and malformed bowed tibiae and femora due to multiple fractures, compatible with OI type 2B/3. None of the patients exhibited blue sclerae or dentinogenesis imperfecta.
Efthymiou et al. (2021) reported a Pakistani brother and sister and a Turkish boy with progressively deforming OI and neurodevelopmental delay, who had mutations in the KDELR2 gene. All 3 exhibited motor delay, and 2 had speech delay. Common features among the affected children included short stature, failure to thrive, wormian bones, bowed limbs, chest deformity, hypotonia, joint hypermobility, and dysmorphic facies. In addition, the Pakistani girl and the Turkish boy had blue sclerae, dentinogenesis imperfecta, and scoliosis; the Turkish boy had a femoral fracture, and the Pakistani boy had vertebral compression fractures and platyspondyly. The Pakistani sibs could not walk at ages 6 years and 2.75 years, respectively. The sister had not yet experienced a fracture, and spoke her first word at age 2 years. The Turkish boy developed independent ambulation and speech at 2 years of age, and at age 4 was comparable to his neurotypical peers. The authors stated that it was unclear whether speech delay was associated with mutation in the KDELR2 gene.
The transmission pattern of OI21 in the families reported by Van Dijk et al. (2020) was consistent with autosomal recessive inheritance.
In 6 patients from 4 families with osteogenesis imperfecta, who were negative for mutation in known OI-associated genes, van Dijk et al. (2020) identified homozygosity or compound heterozygosity for mutations in the KDELR2 gene (609024.0001-609024.0004).
By family-based exome sequencing, Efthymiou et al. (2021) identified homozygous missense variants in the KDELR2 gene in 3 children with progressively deforming OI and neurodevelopmental delay: an R5W substitution (609024.0005) in 2 Pakistani sibs, and a Y162C change (609024.0006) in a Turkish boy. The mutations segregated with disease in each family, and were not found in the gnomAD database.
Efthymiou, S., Herman, I., Rahman, F., Anwar, N., Maroofian, R., Yip, J., Mitani, T., Calame, D. G., Hunter, J. V., Sutton, V. R., Yilmaz Gulec, E., Duan, R., and 10 others. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. (Letter) Am. J. Med. Genet. 185A: 2241-2249, 2021. [PubMed: 33964184] [Full Text: https://doi.org/10.1002/ajmg.a.62221]
van Dijk, F. S., Semler, O., Etich, J., Kohler, A., Jimenez-Estrada, J. A., Bravenboer, N., Claeys, L., Riesebos, E., Gegic, S., Piersma, S. R., Jimenez, C. R., Waisfisz, Q., and 26 others. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by bi-allelic variants in KDELR2. Am. J. Hum. Genet. 107: 989-999, 2020. [PubMed: 33053334] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.009]