Atelosteogenesis, Type I

A number sign (#) is used with this entry because atelosteogenesis type I (AO1) is caused by heterozygous mutation in the FLNB gene (603381), which encodes filamin B, on chromosome 3p14.

Description

Atelosteogenesis is the name given by Maroteaux et al. (1982) to a lethal chondrodysplasia characterized by distal hypoplasia of the humeri and femurs, hypoplasia of the midthoracic spine, occasionally complete lack of ossification of single hand bones, and the finding in cartilage of multiple degenerated chondrocytes encapsulated in fibrous tissue. Rimoin et al. (1980) termed it 'giant cell chondrodysplasia.' Patients with AO1 exhibit severe short-limbed dwarfism and dislocated elbows, hips, and knees (Jeon et al., 2014).

Genetic Heterogeneity of Atelosteogenesis

Atelosteogenesis type II (AO2; 256050) is caused by mutation in the SLC26A2 gene (606718) on chromosome 5q32. AO3 (108721) is also caused by mutation in the FLNB gene (603381).

Clinical Features

Sillence et al. (1982) reported 2 sporadic cases of atelosteogenesis. The fibulae were absent. Only the distal phalanges of the hands were ossified. They termed the disorder 'spondylohumerofemoral hypoplasia.' Hypocellular areas of growth plate cartilage contained occasional multinuclear giant cells. The genetics is unclear.

Maroteaux et al. (1982) pointed to a case reported by Kozlowski et al. (1981). Clubfoot and elbow or knee subluxation may be present. Cleft palate has been observed. The patients are stillborn or die very early of respiratory distress.

Yang et al. (1983) reported an infant in whom the findings were consistent with atelosteogenesis. A second case also with giant chondrocytes on histologic examination of bone, severe laryngeal stenosis and lethal outcome appeared to have some other skeletal dysplasia, an as yet unclassified form of spondyloepiphyseal dysplasia. Yang et al. (1983) concluded, and Sillence and Kozlowski (1983) agreed on the basis of further observations, that giant chondrocytes are not specific to one lethal skeletal dysplasia.

According to Whitley et al. (1986), the possible case of de la Chapelle dysplasia (256050) reported by Salonen (1982) has been reclassified as atelosteogenesis type I.

Temple et al. (1990) reviewed 10 reported cases, all of which had been sporadic, and reported an eleventh case, that in an infant with first-cousin Bengali parents. Polyhydramnios had been a complication of pregnancy. Multiple joint dislocations and radiological features, of which the most characteristic were short, distally tapering humeri, absent or hypoplastic fibulae, deficient vertebral ossification with coronal clefting, and anarchic ossification of phalanges, were described.

Hunter and Carpenter (1991) reported a case of atelosteogenesis type I. They concluded that boomerang dysplasia (112310) and AO1 are 'part of a spectrum, probably reflecting a common etiology.' In a male fetus with a lethal chondrodysplasia, Greally et al. (1993) documented clinical and radiologic overlap between AO1 and boomerang dysplasia. From histologic examination, they suggested a defect of cartilage and bone formation as the basic abnormality.

Jeon et al. (2014) studied a female infant, born of a twin pregnancy that was the result of in vitro fertilization, who died of respiratory failure 3 hours after birth. Facial dysmorphism in the affected infant included a depressed nasal bridge, hypertelorism, micrognathia, and low-set ears. Her thoracic cage was small and the abdomen protuberant. She had markedly short limbs, with talipes equinovarus deformities and spatulated short fingers. Radiographs showed incomplete ossification and hypoplasia of the vertebrae, humeri, femora, tarsals, phalanges, and pelvis, as well as other skeletal abnormalities, including elongated clavicles, small bell-shaped thorax, and several vertebrae with scoliosis and coronal clefting. The humeri were severely shortened and distally hypoplastic, the ulnae, radii, and tibiae were bowed, and both fibulae were completely absent. The elbows, knees, and ankles were dislocated.

Molecular Genetics

In 3 unrelated individuals with sporadically occurring AO1, Krakow et al. (2004) identified heterozygous point mutations in the FLNB gene (see, e.g., 603381.0006 and 603381.0007) that predicted single-residue substitutions in the N-terminal actin-binding domain of the protein. They also found 1 individual with AO3 (108721) who was heterozygous for the same point mutation, 604A-G (603381.0007), that had been identified in an individual with AO1.

In a female infant with atelosteogenesis who died 3 hours after birth due to respiratory failure, Jeon et al. (2014) performed postmortem exome sequencing and identified heterozygosity for a de novo A173T mutation in the FLNB gene (603381.0015) that was not found in 50 healthy controls. The authors noted that most lethal FLNB-related disorders are caused by de novo mutations, and thus there is a low risk of recurrence in subsequent pregnancies.