Gnathodiaphyseal Dysplasia

A number sign (#) is used with this entry because of evidence that gnathodiaphyseal dysplasia (GDD) is caused by heterozygous mutation in the ANO5 gene (608662) on chromosome 11p14.

Description

Gnathodiaphyseal dysplasia is an autosomal dominant generalized skeletal syndrome characterized by cementoosseous lesions of the jawbones, in conjunction with bone fragility, bowing/cortical thickening of tubular bones, and diaphyseal sclerosis of long bones (summary by Marconi et al., 2013).

Clinical Features

Akasaka et al. (1969) described a large Japanese family in which 21 individuals exhibited frequent bone fractures in adolescence and purulent osteomyelitis of the jaws during adult life, with autosomal dominant inheritance. Affected individuals experienced frequent bone fractures caused by trivial accidents in childhood; however, the fractures healed normally without bone deformity. The jaw lesions replaced the tooth-bearing segments of the maxilla and mandible with fibrous connective tissues, including various amounts of cementum-like calcified mass, sometimes causing facial deformities. The patients also had a propensity for jaw infection and often suffered from purulent osteomyelitis-like symptoms, such as swelling of and pus discharge from the gums, mobility of the teeth, insufficient healing after tooth extraction, and exposure of the lesions into the oral cavity. Extragnathic skeletal changes consisted of generalized coarse bony trabeculae and gross thickening of the diaphyseal cortices of long bones. Akasaka et al. (1969) called the condition hereditary gnathodiaphyseal sclerosis because it was distinguished from known systemic bone diseases by coincidence of bone fragility, sclerosis of tubular bones, cementoosseous lesions of the jaw bone, and no abnormalities of nonskeletal tissues.

Sporadic cases with similar clinical manifestations were reported by Colavita et al. (1984) and Nishimura et al. (1996).

Levin et al. (1985) described 13 patients in 3 families with osteogenesis imperfecta (OI) who had multilocular radiolucent, radiopaque, or radiolucent-radiopaque lesions of the maxilla and mandible. In most patients, the lesions involved the tooth-bearing areas, but in 2, the rami also were involved. Teeth were normal. Radiologically the rest of the skeleton showed marked coarseness of trabeculae and diffuse osteopenia. Levin et al. (1985) proposed that these patients had a distinct form of autosomal dominant OI. Male-to-male transmission occurred 3 times in 1 family with 4 affected males. In a second family 8 persons in 5 sibships in 3 generations were affected. A propensity for jaw infection was observed.

Riminucci et al. (2001) reported a patient who had been diagnosed previously with polyostotic fibrous dysplasia (see 174800). Cementoossifying fibroma of the jawbones occurred within the context of a complex skeletal syndrome of bone fragility and bowing with diaphyseal sclerosis of the long bones. The patient presented at 13 months of age with bilateral, relatively symmetric, expansile lesions in the maxillary bones associated with a sinus infection. In addition to their remarkable symmetry and expansile nature, the maxillary lesions exhibited a degree of lucency with occasional mineralized areas upon radiographic examination. Pathologic studies revealed participation of myofibroblasts, occurrence of psammomatoid bodies, and aberrant mineralization within walls of blood vessels. Riminucci et al. (2001) proposed the use of the term gnathodiaphyseal dysplasia (GDD), as opposed to gnathodiaphyseal sclerosis (Akasaka et al., 1969) or OI with unusual skeletal lesions (Levin et al., 1985), to refer to the disorder, as osteosclerosis was not a feature of the jaw lesions and bone fragility was the only possible association to OI, a link Riminucci et al. (2001) deemed 'tenuous at best.'

Tsutsumi et al. (2004) noted that the patients reported by Colavita et al. (1984) and Nishimura et al. (1996) had clinical manifestations similar to those in GDD; however, Pekkinen et al. (2019) reported these patients as having calvarial doughnut lesions with bone fragility (CDL; 126550).

Marconi et al. (2013) reported an Italian family in which multiple members had GDD. Two patients were examined in detail. The patients had onset of multiple spontaneous bone fractures at ages 11 and 8 years. Bones affected included the femur, vertebrae, and radius/ulna. Radiologic studies of 1 patient showed generalized decreased bone density. At age 25 years, 1 patient developed a gradual increase in the volume of the alveolar processes of the mandible and jaw, resulting in facial deformity. The lesions were removed at age 40, and studies of the material showed abundant fibroblasts in a fibrous stromal tissue with foci of calcification surrounded by a thick fibrous layer and a subtle fibroblast layer. The other patient had healing problems after extraction of wisdom teeth. Radiologic studies showed a cotton-wool-like pattern of the bony structure of the mandible, and biopsy showed similar histologic findings to the first patient. Other family members had similar features, including sclerosis of the jawbones, purulent osteomyelitis, and spontaneous fractures with slow healing.

Inheritance

The transmission pattern of GDD in the family reported by Marconi et al. (2013) was consistent with autosomal dominant inheritance.

Mapping

By linkage analysis of the Japanese family reported by Akasaka et al. (1969), Tsutsumi et al. (2003) mapped the disease locus to an 8.7-cM interval on 11p15.1-p14.3.

Molecular Genetics

Tsutsumi et al. (2003) found no mutations in 8 genes shown by genome sequence data to be located in the GDD critical region.

In a further search for GDD candidate genes, Tsutsumi et al. (2004) investigated uncharacterized ESTs that mapped to the critical region. One of these represented a novel gene (ANO5), which they designated GDD1. Screening of GDD1 DNA in the Japanese family of Akasaka et al. (1969) revealed that 14 affected members were heterozygous for a missense mutation in exon 11 (608662.0001). A different missense mutation in the same codon (608662.0002) was found in 2 affected members of another family of African American origin.

Marconi et al. (2013) identified a heterozygous missense mutation in the ANO5 gene (608662.0009) in affected members of an Italian family with gnathodiaphyseal dysplasia. The mutation segregated with the disorder in the family and was not found in several large control databases. Functional studies were not performed.