Osteogenesis Imperfecta, Type Xvi

A number sign (#) is used with this entry because of evidence that autosomal recessive osteogenesis imperfecta type XVI (OI16) is caused by homozygous mutation in the CREB3L1 gene (616215) on chromosome 11p11. Mildly affected heterozygous family members have been reported.

OI16 has also been reported in 1 family with a contiguous gene deletion including the CREB3L1 gene on chromosome 11p11.2.

Description

Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018).

Clinical Features

Symoens et al. (2013) reported a Turkish family in which 2 sibs had osteogenesis imperfecta. The first affected child had fractures in utero and was small for gestational age. He continued to have fractures after birth, and x-rays showed beaded ribs, callus formation, and multiple fractured tubular bones with an accordion-like broadened appearance. He was hospitalized several times due to recurrent constipation and bronchopneumonia, and developed cardiac insufficiency and hepatomegaly. He died at 9 months of age. A subsequent affected pregnancy was terminated at 19 weeks' gestation; postmortem showed thin ribs and fractures at the bowed humeri and femora. The parents, who were not known to be consanguineous but came from neighboring villages, had blue sclerae, soft velvety skin, and normal teeth; the mother also had small joint hypermobility, and the father had conductive hearing loss. There was a healthy daughter with blue sclerae who had not experienced any fractures, and the mother also had had 1 miscarriage of unknown cause.

Keller et al. (2018) studied a large Lebanese family in which the proband had shortened and angulated humeri, multiple fractures of the long bones of both legs, and apparently reduced skull mineralization at 12 weeks' gestation by ultrasound. Imaging at 14 weeks confirmed micromelia and angulated long bones, as well as ribs of normal length that were angulated, consistent with fractures. The pregnancy was terminated at 16 weeks due to suspected OI. Two prior pregnancies had been terminated due to in utero findings consistent with severe skeletal dysplasia, including severe long bone deformity with crumpling, angulation, and marked rhizomelic and mesomelic shortening. Calvarial bones were paper-thin and soft, with almost no ossification of the cranial vault, and severe demineralization was noted. In addition, there were 3 mildly affected family members, including the proband's brother, who was born with a fractured right femur but otherwise had normal long bones, ribs, thorax, and skull. At age 6 years, x-ray of his pelvis showed osteopenia. At age 15 years, he was osteopenic with blue sclerae but had no additional fractures. An affected sister also had blue sclerae and mild osteopenia, but no history of fractures. Their mother had blue sclerae and a history of recurrent fractures in childhood, including a fractured pelvis with minimal trauma at age 1 year, and a spiral fracture of 1 femur at age 16 years. Their maternal grandfather and great-grandfather, as well as a maternal granduncle, had recurrent fractures and were suspected to be mildly affected but were not available for clinical assessment. Their reportedly unaffected father declined clinical assessment.

Lindahl et al. (2018) reported a Somali family in which an 11-year-old boy with severe OI had experienced 27 major fractures despite bisphosphonate treatment. He was born with a femur fracture, and neonatal x-rays showed curved femora and humeri with suspected healed intrauterine fractures, multiple vertebral compression fractures, and rib fractures, as well as wormian bones. He had bluish-gray sclerae. In infancy he had an increased bleeding time, and during early childhood showed a tendency to bruise easily. At age 11, he exhibited marked short stature and hyperextensibility of small and large joints, with ambulation primarily by manual wheelchair. Skin turgor, elasticity, and healing were normal. Audiometry was normal. There were no signs of dentinogenesis imperfecta, but he had tooth agenesis, with 6 missing teeth. His parents and 4 sibs were healthy, with normal sclerae, no hyperextensibility, and no history of fractures.

Cytogenetics

Using DNA from an affected fetus from a Turkish family with OI, Symoens et al. (2013) screened 14 known OI-associated genes but found no mutations. PCR amplification of the candidate gene CREB3L1 failed, and array CGH revealed a homozygous deletion (chr11:46,268,141-46,359,490) encompassing the CREB3L1 gene and the first exon of neighboring gene DGKZ (601441). Both parents and a healthy sib were heterozygous for the deletion. Expression analysis of dermal fibroblasts from the affected fetus showed complete absence of the CREB3L1 transcript; in addition, using primer pairs specific for DGKZ isoforms 1 and 2, in which exon 1 is present or absent, respectively, Symoens et al. (2013) found evidence for lack of expression of isoform 1 and normal expression of isoform 2 in cultured patient fibroblasts. The authors noted that no known function in bone formation had been associated with the DGKZ gene, and it was unclear what role it might play in the bone phenotype of the affected individuals. They also found that type I procollagen (see COL1A1, 120150) production was normal in patient fibroblasts, indicative of a tissue-specific effect of CREB3L1 on type I procollagen production.

Molecular Genetics

In a large Lebanese family segregating an apparently recessive form of severe OI, Keller et al. (2018) performed exome sequencing and identified a 3-bp deletion in the CREB3L1 gene (616215.0001) for which the severely affected proband was homozygous. His mildly affected sibs and mother were heterozygous for the deletion, as was his reportedly unaffected father, who had declined clinical assessment.

In an 11-year-old Somali boy with severe OI, who was negative for mutation in the COL1A1 and COL1A2 (120160) genes, Lindahl et al. (2018) screened known OI-associated genes and identified homozygosity for a nonsense mutation in the CREB3L1 gene (Y428X; 616215.0002). His unaffected parents and 2 unaffected sibs were heterozygous for the mutation. The authors noted that the proband was the first child with recessive OASIS deficiency-associated OI to survive infancy.