DO: 0111849;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q25.1 | Osteogenesis imperfecta, type XX | 618644 | Autosomal recessive | 3 | MESD | 607783 |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XX (OI20) is caused by homozygous or compound heterozygous mutation in the MESD gene (607783) on chromosome 15q25.
Osteogenesis imperfecta type XX (OI20) is a progressive deforming bone disorder characterized by osteopenia, skeletal deformity, and both healed and new fractures on radiography. Several patients have died due to respiratory failure (Moosa et al., 2019).
Moosa et al. (2019) reported 5 probands from consanguineous families who were clinically diagnosed with a progressive deforming type of osteogenesis imperfecta. Fractures were observed prenatally in 2 patients, and all had a fracture within the first 2 years of life. Treatment with bisphosphonates, undertaken in 4 of the patients, was unsuccessful. Three patients died of respiratory failure, 2 before 18 months of age and 1 at age 17 years. The oldest affected individuals, when assessed at ages 10 years and 16 years, respectively, were nonambulatory. Bluish sclerae were noted in the youngest individuals, but not in the older ones. None had dentinogenesis imperfecta, but the 3 older individuals had disorganized dentition and/or oligodontia. Global developmental delay or evidence of intellectual disability was present in 3 individuals.
Sturznickel et al. (2021) reported 3 stillborn sibs, born to nonconsanguineous parents of German origin, with osteogenesis imperfecta type XX. Gestational age of the stillbirths was 26, 22, and 14 weeks. All 3 stillbirths occurred after prenatal diagnosis of a skeletal disorder was made during the second trimester. Findings included a triangular face, blue sclerae, retrognathia, micromelia, angulated long bones, and bilateral clubfeet. The thorax was narrow, resulting in severe lung hypoplasia and congestion of the venous inflow tract of the heart, with consequent hepatomegaly and fetal hydrops. Multiple rib fractures and overtubulation of the long bones were seen on fetal autopsy. One of the stillbirths had a double kidney. Histologic evaluation showed impaired osseous development with altered osteocyte morphology and reduced canalicular connectivity. Examination of bone mineral density distribution showed an impaired and more heterogeneous matrix mineralization in the patients.
The transmission pattern of OI20 in the families reported by Moosa et al. (2019) was consistent with autosomal recessive inheritance.
In 5 probands with a progressive deforming type of osteogenesis imperfecta, who were negative for mutation in known OI-associated genes, Moosa et al. (2019) performed whole-exome sequencing and identified homozygosity for mutations in the MESD gene (607783.0001-607783.0004). The unaffected parents were heterozygous for the mutations, which were not common polymorphisms in public variant databases.
In 3 stillborn sibs with OI20, who were born to nonconsanguineous parents of German origin, Sturznickel et al. (2021) identified compound heterozygous mutations in the MESD gene, the previously identified 5-bp deletion (c.607_611del; 607783.0004) and a novel 1-bp deletion (c.265del; 607783.0005). Each parent was heterozygous for one of the disease-causing variants. Sequencing of the mRNA from the parents revealed a complete loss of the mRNA harboring the c.265del mutation, whereas the mRNA with the c.607_611del mutation was readily detected. The authors suggested that the prenatally lethal phenotype in this family was likely related to complete functional loss of one MESD allele, which could not be compensated by the residual function of the second allele.
Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C.-A., and 21 others. Autosomal-recessive mutations in MESD cause osteogenesis imperfecta. Am. J. Hum. Genet. 105: 836-843, 2019. [PubMed: 31564437] [Full Text: https://doi.org/10.1016/j.ajhg.2019.08.008]
Sturznickel, J., Jahn-Rickert, K., Zustin, J., Hennig, F., Delsmann, M. M., Schoner, K., Rehder, H., Kreczy, A., Schinke, T., Amling, M., Kornak, U., Oheim, R. Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX. J. Bone Miner. Res. 36: 1077-1087, 2021. [PubMed: 33596325] [Full Text: https://doi.org/10.1002/jbmr.4277]