Osteogenesis Imperfecta, Type Xviii

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XVIII (OI18) is caused by homozygous mutation in the FAM46A gene (611357) on chromosome 6q14.

Description

Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life (Doyard et al., 2018).

Clinical Features

Doyard et al. (2018) reported 2 sibs and 2 unrelated patients with osteogenesis imperfecta and mutations in the FAM46A gene. The first patient was an Italian boy who was born with bowing of the femora and tibia, but also experienced swallowing difficulties and hyperthermic episodes in the first 6 months of life. He was originally diagnosed with Stuve-Wiedemann syndrome (601559), but his symptoms later became more consistent with a diagnosis of OI, with 4 spontaneous fractures and vertebral collapses in the first 2 years of life. He also had blue sclerae and abnormal teeth. He died suddenly and inexplicably at 4 years of age. A French brother and sister, born to first-cousin parents, showed bowing of the femora, poor mineralization, thin cortical bone, and numerous wormian bones at birth. They sustained numerous fractures in the first years of life, and also exhibited blue sclerae and joint hyperlaxity. The girl and her mother both had a marfanoid habitus, with arachnodactyly and joint hyperlaxity, but no cardiovascular abnormalities; the mother had no ocular abnormalities. The fourth patient was an Egyptian girl born to double-first-cousin parents, who presented at 5 years of age with a history of recurrent spontaneous fractures, approximately 7 per year. Dysmorphic features included high broad forehead, long eyelashes, wide palpebral fissures, blue sclerae, grooved philtrum, broad nasal root, and micrognathia. She also had joint laxity and an umbilical hernia. X-ray examination showed generalized osteoporotic texture, collapse of the lower 3 thoracic and first lumbar vertebral bodies with biconcave endplates (codfish vertebrae), thin ribs, bowing of long bones, thin cortex, multiple fractures, and wormian bones at the skull base. An older sister who was born with severe bowing of upper and lower limbs died of pneumonia at 3 months of age. The French sibs showed developmental delay, with speech delay in the brother and global hypotonia and motor delay in the sister; the Egyptian girl had motor developmental delay.

Molecular Genetics

In an Italian boy who exhibited features of Stuve-Wiedemann syndrome but was negative for mutation in the LIFR gene (151443), and who later developed symptoms consistent with OI, Doyard et al. (2018) performed exome sequencing and identified homozygosity for a frameshift mutation in the FAM46A gene (611357.0001). Screening the FAM46A gene in 25 patients with OI who were negative for mutation in known OI-associated genes revealed homozygosity for missense mutations in a French brother and sister (H127R; 611357.0002) and an Egyptian girl (D231G; 611357.0003).