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Atelosteogenesis Disorders
Introduction
Atelosteogenesis (AO) refers to a group of lethal short-limb skeletal dysplasias characterized by an abnormal, characteristic facies and hypoplastic or dysplastic tubular bones. Specific radiographic abnormalities, distinct histopathology, and differing inheritance patterns distinguish the three well-recognized types of AO. All three forms have abnormal facies and short limbs, but associated findings help distinguish them from each other; for example, synpolydactyly, omphalocele, and frontal encephalocele are seen in AO I, increased nuchal thickness and hitchhiker thumbs in AO II, and multiple joint dislocations and abnormal hands in AO III.
AO is caused by defects in genes involved in skeletal development. AO I and AO III result from heterozygosity for mutations in the gene coding for filamin B (FLNB). AO II, which is recessively inherited, is caused by mutations in the diastrophic dysplasia sulfate transporter ( DTDST, also referred to as SLC26A2 ) gene. Neonates with all forms of AO frequently succumb, usually in infancy, as a result of respiratory problems (pulmonary insufficiency, laryngeal hypoplasia, and recurrent infections), although some individuals with AO III survive into adulthood.
Disease
Definition
AO disorders are a group of chondrodysplasias with short limbs, unique forms of brachydactyly, and underdeveloped bones. The forms can also be distinguished based on cartilage growth plate histology. The diagnosis is suspected by skeletal findings, usually noted on routine prenatal ultrasound (US) and confirmed with molecular genetic testing, or postnatal radiology findings.
Prevalence and Epidemiology
AO I and III are autosomal dominant disorders, and germ line mosaicism has been reported. AO II is recessively inherited. Infants with AO I or AO II usually die in the immediate neonatal period from respiratory compromise. AO III is considered semilethal, but there have been long-term survivors.
Etiology and Pathophysiology
AO I and AO III result from mutations in the gene that encodes FLNB. Because these disorders are highly lethal, these mutations are sporadic in occurrence, although germ cell mosaicism has been seen. AO II is caused by either homozygosity or a compound heterozygosity for mutations in the diastrophic dysplasia sulfate transporter (DTDST, SLC26A2) .
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