Osteogenesis Imperfecta, Type X

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta X (OI10) is caused by homozygous mutation in the SERPINH gene (600943) on chromosome 11q13.

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 X is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010).

Clinical Features

Christiansen et al. (2010) reported a child with a severe deforming form of OI who was born to a clinically normal consanguineous Saudi Arabian couple and was the only affected member in the extended family. At birth he was noted to have a triangular face, relative macrocephaly, bitemporal narrowing, blue sclerae, micrognathia, and relatively short limbs with bowing at the thighs. Radiographs of the chest showed thin ribs with healing fractures, a fracture of the right humerus, a healing fracture of the left humerus, and platyspondyly. A skeletal survey at the age of 1 month was consistent with the diagnosis of osteogenesis imperfecta. There were multiple bone deformities and fractures that involved the upper and lower extremities and ribs and generalized osteopenia. When he was 1 year old, bilateral renal stones were noticed with left pelviureteric junction obstruction that ultimately required left nephrectomy because of hydronephrosis and loss of renal function. He had chronic lung disease of unclear etiology and from the age of 1.5 years he required continuous oxygen by nasal cannula to maintain adequate oxygenation. He had small opalescent teeth consistent with dentinogenesis imperfecta. At age 3 years and 6 months he had sudden unexplained respiratory distress at home and died soon after arrival at the hospital. No autopsy was performed.

Duran et al. (2015) studied a consanguineous family in which a sister and brother (cases R92-020A and B, International Skeletal Dysplasia Registry) were diagnosed with a moderately severe form of OI at ages 4 years and 6 months, respectively. No fractures occurred during their first few months of life, but radiographs showed generalized osteopenia, large anterior fontanel and wormian bones in the skull, coxa valga, mild femoral bowing, reduced thorax size, and scoliosis with compression fractures in the vertebrae. Hyperextensibility was noted in the fingers, knees, and hips. Blue sclerae were not observed, nor was there dentinogenesis imperfecta or hearing loss.

Molecular Genetics

Because the SERPINH1 gene encodes a collagen-binding protein that functions as a chaperone in the endoplasmic reticulum, Christiansen et al. (2010) screened for mutations in this gene in individuals with OI whose cells did not produce overmodified type I collagen. In a Saudi Arabian patient with severe deforming OI X, they identified a homozygous missense mutation (L78P; 600943.0002).

Using DNA from a 4-year-old girl with a moderately severe form of OI, Duran et al. (2015) analyzed the exon sequences of 9 known OI-associated genes and identified homozygosity for a missense mutation in the SERPINH1 gene (M237T; 600943.0003). Her unaffected third-cousin parents were heterozygous carriers of the mutation; DNA from her affected brother was not available. In experiments using cultured patient dermal fibroblasts, the authors demonstrated that protein levels of both HSP47 and FKBP65 (FKBP10, 607063; see OI11, 610968) were reduced and mislocalized, and proximity ligation assays indicated that the proteins interact in subcellular compartments. Duran et al. (2015) suggested that the similarity in phenotype between OI10 and OI11 might be explained by the similar consequences on type I procollagen synthesis.