Craniotubular Dysplasias

Craniometaphyseal dysplasia is a genetic disorder of bone density characterized by progressive thickening (hyperostosis) and increased mineral density of craniofacial bones and by abnormalities in the metaphyses of long bones.

This disorder is typically an autosomal dominant disorder caused by mutations in the ANKH gene; however, autosomal recessive forms due to mutations in the GJA1 gene are known to occur (1).

Craniometaphyseal dysplasia is a very rare disorder, and its prevalence is estimated to be < 1/1,000,000 people (2).

Paranasal bossing develops during infancy, and progressive expansion and thickening of the skull and mandible distort the jaw and face. The encroaching bone entraps cranial nerves, causing dysfunction. Malocclusion of the teeth may be troublesome; partial sinus obliteration predisposes to recurrent nasorespiratory infections. Height and general health are normal, but progressive elevation of intracranial pressure is a rare, serious complication.

The diagnosis of craniometaphyseal dysplasia is suspected when typical craniofacial abnormalities occur, which are at times coupled with increased susceptibility to upper respiratory infections. The disorder may be found during an evaluation for cranial nerve dysfunction that may result from nerve entrapment at the skull base. Typically, plain radiographs are done. Radiographic changes are age-related and usually evident by 5 years of age. Sclerosis is the main feature in the skull. Long bones have widened metaphyses, appearing club-shaped, particularly at the distal femur. However, these changes are much less severe than those in Pyle disease. The spine and pelvis are unaffected.

Treatment of craniometaphyseal dysplasia consists of surgical decompression of entrapped nerves and remodeling of severe bony abnormalities; however, regrowth does occur. Upper respiratory infections should be treated when they occur.

Frontometaphyseal dysplasia is a genetic disorder of bone density characterized by abnormalities in skeletal development.

This disorder has distinct autosomal dominant and X-linked dominant forms. The X-linked dominant form is caused by mutations in the FLNA gene, and the autosomal dominant form is caused by variants in the MAP3K7 or TAB2 gene (1). The X-linked variant is an otopalatodigital spectrum disorder (2).

The exact population prevalence is unknown; however, > 100 cases have been reported (1).

Frontometaphyseal dysplasia becomes evident during early childhood. The supraorbital ridge is prominent, resembling a knight’s visor. The mandible is hypoplastic with anterior constriction; dental anomalies are common. Hearing loss develops during adulthood because sclerosis narrows the internal acoustic foramina and middle ear or may cause deformities of the ossicles. Long leg bones are moderately bowed. Progressive contractures in the digits may simulate arthritis. Extraskeletal manifestations such as ureteral obstruction and heart defects may be present. Bronchial constriction may lead to dyspnea. Height and general health are normal.

The diagnosis of frontometaphyseal dysplasia is suspected when hearing loss is present in a patient with features of the skeletal abnormalities described previously. Typically, plain radiographs are taken and show obvious bony overgrowth of the frontal region; patchy sclerosis is also visualized in the cranial vault. Vertebral bodies are dysplastic but not sclerotic. Iliac crests are abruptly flared, and the pelvic inlet is distorted. The femoral capital epiphyses are flattened, with expansion of the femoral heads and coxa valga (hip deformity). Finger bones are undermodeled, with erosion and loss of joint space.

Treatment options are primarily supportive and symptomatic. However, corrective surgery is indicated for severely disfiguring deformities, including severe micrognathia, or those causing orthopedic problems. Hearing loss is treated with hearing aids.

Metaphyseal dysplasia is characterized by broad metaphyses resembling a boat oar or paddle due to the enlargement of the trabecular bone and thinning of the cortical bone.

This rare, autosomal recessive disorder is caused by defects in the SFRP4 gene; > 25 cases have been described (1).

Metaphyseal dysplasia is often confused semantically with craniometaphyseal dysplasia.

Affected people are clinically (phenotypically) normal, apart from genu valgum, although scoliosis and bone fragility occasionally occur.

The diagnosis of metaphyseal dysplasia is usually made when radiographs are taken for an unrelated reason. Radiographic changes are striking. Long bones are undermodeled, and bony cortices are generally thin. Tubular leg bones have gross Erlenmeyer flask flaring, particularly in the distal femur. The pelvic bones and thoracic cage are expanded. However, the skull is essentially spared.

Treatment of metaphyseal dysplasia is often not necessary but may involve orthodontic treatments for dental malformations or orthopedic surgery for clinically significant skeletal deformities or fractures.