Spondylometaphyseal Dysplasia, Corner Fracture Type

A number sign (#) is used with this entry because of evidence that the corner fracture type of spondylometaphyseal dysplasia (SMDCF) is caused by heterozygous mutation in the fibronectin gene (FN1; 135600) on chromosome 2q35.

Description

The corner fracture type of spondylometaphyseal dysplasia is characterized by flake-like, triangular, or curvilinear ossification centers at the edges of irregular metaphyses that simulate fractures. These 'corner fractures,' which involve the distal tibia, the ulnar aspect of the distal radius, the proximal humerus, and the proximal femur, represent irregular ossification at the growth plates and secondary ossification centers. They become larger in older children and disappear after growth has stopped. In addition, severe scoliosis has been observed in FN1-associated SMDCF, whereas developmental coxa vara is less often seen, and odontoid abnormalities have not been reported (Lee et al., 2017).

Clinical Features

In 11 patients, including a father and daughter and a mother and 2 children, Langer et al. (1990) described an apparently unique skeletal dysplasia associated with short stature and developmental coxa vara. Progressive hip deformity usually resulted in a significant disability requiring surgical correction. The diagnostic constellation comprised coxa vara, simulated 'corner fractures' of long tubular bones, and vertebral body abnormalities. They pictured x-rays of patients with large triangular fragments situated laterally in the distal tibial metaphyses on the ulnar aspect of the distal radius and in the proximal humerus. The vertebral body endplates were more convex than usual for the patient's age. Some hypoplasia of the anterior part of the bodies created an appearance of anterior wedging. By the time a gait disturbance was identified, at about 2 years of age, characteristic radiographic changes were present in the hips. Continued slippage of the femoral capital epiphysis resulted in an angle between the long axis of the femoral capital epiphysis and the femoral shaft of 90 degrees or less. This type of deformity is referred to as developmental coxa vara.

Also called the Sutcliffe type of spondylometaphyseal dysplasia (SMD) (Sutcliffe, 1966), cases of SMD 'corner fractures' type were described by Felman et al. (1974), Langer et al. (1990), Kozlowski et al. (1992), and Currarino et al. (2000). The features of these cases were proportional short stature, mild vertebral abnormalities, developmental coxa vara in most cases, metaphyseal abnormalities that included flakelike, triangular, or curvilinear ossification centers at the edges of the metaphyses (corner fractures), and deficiency or absence of ossification of the odontoid process. Mild short stature in childhood was a feature. This type of SMD differs from the Kozlowski type (184252) by the presence of corner fractures, absence of marked platyspondyly, absence of kyphoscoliosis, and milder involvement of short tubular bones (Langer et al., 1990).

Sutton et al. (2005) reported a mother and 2 sons with a dominantly inherited SMD with corner fractures and severe, congenital scoliosis but neither coxa vara nor odontoid abnormalities, which are usually found with the corner fracture type of SMD. Severe congenital scoliosis and short stature were present in all members of this family, suggesting that the disorder may represent a different dominantly inherited SMD.

Lee et al. (2017) studied patients from 7 families with SMD and corner fractures who had mutations in the FN1 gene (see MOLECULAR GENETICS), including the family originally reported by Sutton et al. (2005). Noting that 7 of the 9 mutation-positive patients exhibited severe scoliosis and that developmental coxa vara was only observed in 3, Lee et al. (2017) suggested that these patients might represent a subtype of the classic Sutcliffe-type SMD.

Molecular Genetics

Using exome sequencing, Lee et al. (2017) identified heterozygous variants in the FN1 gene in 3 of 13 individuals with SMD and corner fractures (SMDCF). Mutations included C87P (135600.0004) in a mother a 2 sons (family 1), originally reported by Sutton et al. (2005), and Y240D (135600.0005) in a mother and daughter (family 4). Subsequently, they identified 4 more patients with de novo FN1 mutations, including C123R (135600.0006) in 2 patients (families 2 and 7). All of the FN1 variants involved highly conserved residues, and none was found in the ExAC database. Noting that FN1 mutations had previously been associated with glomerulopathy (GFND2; 601894), Lee et al. (2017) stated that none of the SMDCF patients showed any evidence of renal disease.