Asphyxiating thoracic dystrophy (ATD) is a very rare form of skeletal dysplasia that primarily affects the development of the bone structure of the chest (thorax) resulting in a very narrow and bell-shaped chest. Other major characteristics include kidney problems (due to renal cyst development), shortened bones of the arms and legs, extra fingers and toes, and a shortened stature.
ATD is inherited as an autosomal recessive genetic disorder. It is caused by changes (mutations) in at least 24 different genes that encode for ciliary transport protein: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753.
ATD is classified as a ciliopathy with major skeletal involvement or ciliary chondrodysplasia. Ciliopathies are conditions caused by mutations in genes involved in making proteins in the finger-like projections on the surface of cells (cilia). Abnormal cilia can lead to problems in the development of cartilage and bone.
Symptoms
ATD is characterized by abnormal development of the rib cage (thorax) resulting in a small thoracic cavity. The characteristic “bell-shaped” chest cavity restricts the growth of the lungs and results in a variable degree of lung hypoplasia and breathing problems (respiratory distress) in the newborn period.
Other clinical features that can be apparent at birth include too many fingers and/or toes (polydactyly), mild to moderate shortening of the long bones of the arms and legs (micromelia), and insufficient growth of the pelvic bones, and cardiac defects.
Patients typically present in the newborn period with variable degrees of respiratory distress and recurrent respiratory infections. These breathing problems are the most serious complications of ATD and are the main cause of mortality in these patients. Some reports indicate that 50-60% of children with ATD die in infancy or during the first few years after birth. For those patients that live into early childhood, the breathing problems tend to improve with age such that a subset of patients may live into adolescence or adulthood.
Other complications of ATD can occur as the child grows including high blood pressure, renal cysts, pancreatic cysts, and, less commonly liver diseases, dental abnormalities, and reduced or deteriorating vision (retinal dystrophy).
Affected individuals may develop chronic nephritis (a kidney condition) that may lead to kidney failure or malfunctions. Heart abnormalities and narrowing of the airway may also occur.
Causes
Mutations in 24 genes have been found to cause ATD to date. The genes are IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753.
It is estimated that 70 percent of affected individuals have mutations in one of these genes. Mutations in these genes result in abnormal cilia proteins that affect bone development.
ATD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Diagnosis
ATD is diagnosed based on clinical presentation as well as radiologic findings of short ribs and abnormalities of the pelvis and limbs. A combination of breathing difficulties in the presence of a small, narrow chest, along with obvious shortened limb development is usually sufficient for a diagnosis. Molecular genetic testing is available to confirm the diagnosis.
The presentation and severity of asphyxiating thoracic dystrophy vary considerably specifically about the degree of breathing difficulties which may vary from life-threatening to the apparent absence of any distress.
Prenatal diagnosis may be possible with ultrasound imaging.
Treatment
Treatment is based on managing respiratory infections and monitoring renal and hepatic function regularly. The risk of severe respiratory infections diminishes after age two.
The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylothoracic dysplasia, ribs are separated on each side of the chest, and VEPTRs are placed on each side of the chest.
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