Osteogenesis Imperfecta, Type Xii

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XII (OI12) is caused by homozygous mutation in the SP7 gene (606633) on chromosome 12q13.

Description

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XII is an autosomal recessive form characterized by recurrent fractures, mild bone deformations, generalized osteoporosis, delayed teeth eruption, progressive hearing loss, no dentinogenesis imperfecta, and white sclerae (summary by Lapunzina et al., 2010).

Clinical Features

Lapunzina et al. (2010) reported an 8-year-old Egyptian boy with osteogenesis imperfecta and normal sclerae, who was born to consanguineous parents related as second cousins. Clinical features included recurrent fractures beginning at 3 months of age, mild bone deformities, delayed tooth eruption, and normal hearing. The family had a history of a similarly affected sib who, in addition to OI, was diagnosed with a congenital heart condition and died at the age of 4 years.

Fiscaletti et al. (2018) studied 3 sibs with osteogenesis imperfecta who were born to consanguineous Iraqi parents. The proband was a 14-year-old boy who presented for evaluation of profound sensorineural hearing loss, but who also had a history of recurrent low-trauma fractures starting at age 13 years. Examination revealed short stature, white sclerae, mild facial asymmetry, high prominent forehead, prominent supraorbital ridges, midface hypoplasia, prominent ears, depressed nasal bridge, microstomia, and high-arched palate. He had a history of delayed tooth eruption but no evidence of dentinogenesis imperfecta. In addition, there was bilateral knee joint hyperlaxity with valgus deformity and mild scoliosis. Temporal bone CT scan revealed significant bilateral otospongiosis (osteosclerosis) and poor mineralization of the ossicles and petrous temporal bone. Spine x-rays showed thoracic platyspondyly and reduced vertebral body height at all levels, with pronounced vertebral crush fractures at the thoracolumbar junction. Skeletal survey showed generalized osteopenia and striking undertubulation of long bones, metatarsals, and metacarpals, with associated thickening of cortices; bone densitometry confirmed diffuse low bone mineral density. Transiliac bone biopsy revealed high cortical porosity, with long canals that traversed the cortex parallel to the periosteal surface. A younger brother, who presented at age 12 years with a femur fracture after minimal trauma, also exhibited short stature and similar craniofacial features and had moderately severe mixed hearing loss. A 9-year-old sister had a history of low-trauma fractures and low bone density, but did not have short stature or hearing loss.

Mapping

By homozygosity mapping in the Egyptian family segregating OI, Lapunzina et al. (2010) identified several regions of homozygosity, including a region on chromosome 12 containing the candidate gene SP7. They considered SP7 to be a good candidate because it encodes an osteoblast-specific transcription factor that had been shown in mice to be indispensable for bone formation (Nakashima et al., 2002).

Molecular Genetics

In an 8-year-old Egyptian boy with osteogenesis imperfecta and normal sclerae, Lapunzina et al. (2010) identified a homozygous single basepair deletion in the SP7/OSX gene (606633.0001). The parents were heterozygous for the mutation.

In a consanguineous Iraqi family in which 3 sibs had osteogenesis imperfecta, 2 of whom also had severe to profound hearing loss, Fiscaletti et al. (2018) performed massively parallel sequencing analysis of 13 known OI-associated genes and identified homozygosity for a missense mutation in the SP7 gene (R316C; 606633.0002). The proband was negative for mutation in 2 common deafness genes. Their consanguineous parents were heterozygous for the SP7 mutation, as were 3 unaffected sibs. The father met the criteria for adult osteoporosis, but had no craniofacial or skeletal anomalies or history of low-trauma fractures, and had normal hearing.

Nomenclature

The form of OI caused by mutation in the SP7 gene was originally designated OI type XI (OI11) in OMIM.