Asphyxiating Thoracic Dystrophy

Summary

Asphyxiating thoracic dystrophy (ATD) is a very rare form of skeletal dysplasia that primarily affects 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.

Introduction

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.

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), 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.

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 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 for 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.

The incidence of ATD is about 1 in 100,000 to 150,000 live births. Males and females appear to be affected in equal numbers, as do persons of various ethnic or racial backgrounds.

The following disorders have presentations that can be similar to those of ATD and should be considered for a differential diagnosis.

Ellis-Van Creveld syndrome (also known as chondroectodermal dysplasia) is characterized by short stature with striking shortening of the proximal limbs (mesomelia) extremities. Extra fingers and toes, fused wrists, dystrophy of the fingernails, lip abnormalities, and heart defects also occur in this disorder. The disorder is inherited as autosomal recessive condition. (For more information on this condition, choose “Ellis Van Creveld syndrome” as your search term in the Rare Disease Database.)

Metatrophic dysplasia is noticed in infancy, and is characterized by the development of a long narrow thorax, flattening of the vertebral bones and relatively short limbs. Progressive deformity (kyphoscoliosis) of the bones of the thorax and spine results in a short trunk as the child gets older. (For more information on this condition, choose “metatropic dysplasia” as your search term in the Rare Disease Database.)

Diastrophic dysplasia is a relatively common form of short stature recognized art birth by the presence of short limbs, clubfeet, short hand with a hitchhiker thumb, cleft palate and cauliflower ear deformity. Although breathing problems may be present at birth and continue thereafter, life expectancy is normal. (For more information on this condition, choose “diastrophic dysplasia” as your search term in the Rare Disease Database.)

Short rib-polydactyly syndromes (SRPs) are a heterogenous group of skeletal ciliopathies inherited as autosomal recessive disorders. SRPs I-IV are lethal SRPs characterized by an undersized (hypoplastic) thorax, short ribs, severe pulmonary hypoplasia, short limbs, multiple fingers and toes (polydactyly), and abdominal (visceral) abnormalities. All of the variants are thought to be inherited in an autosomal recessive pattern. SRPs belong to the short rib dysplasia with or without polydactyly family which also includes ATD, Ellis-Van Creveld syndrome, Sensenbrenner syndrome, and Weyer acrofacial dyostosis. Of note, the narrowing of the chest is much less severe in ATD than it is in SRPs I-IV.

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 varies considerably specifically with regard to 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.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://nord1dev.wpengine.com/for-patients-and-families/information-resources/news-patient-recruitment/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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INTERNET
Zanelli SA. Asphyxiating Thoracic Dystrophy. (Jeune Syndrome) Medscape. Updated: May 01, 2019. http://emedicine.medscape.com/article/945537-overview. Accessed Dec 3, 2020.

Jeune syndrome.Genetic and Rare Diseases Information Center (GARD). Last Update 4/29/2015. https://rarediseases.info.nih.gov/gard/3049/asphyxiating-thoracic-dystrophy/Resources/1 Accessed Dec 3, 2020.

Baujat, Genevieve.Jeune Syndrome. Orphanet. Last Update December 2011. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=474. Accessed Dec 3, 2020.

Asphyxiating thoracic dystrophy. Genetics Home Reference. Reviewed May 2015. https://ghr.nlm.nih.gov/condition/asphyxiating-thoracic-dystrophy Accessed Dec 3, 2020.