NORD gratefully acknowledges Santina A. Zanelli, MD, Associate Professor of Pediatrics, Division of Neonatology, University of Virginia Health System, for assistance in the preparation of this report.
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.
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.
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TEXTBOOKS
Campbell RM Jr. Asphyxiating Thoracic Dystrophy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:155-56.
Jones KL. Ed. Smith’s Recognizable Patters of Human Malformation. 5th ed. W.B. Saunders CO., Philadelphia, PA; 1997:292-95.
JOURNAL ARTICLES
Faudi E, Brischoux-Boucher E, Huber C, Dabudyk T, Lenoir M, Baujat G, Michot C, Van Maldergem L, Cormier-Daire V, Piard. A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy. J.Eur J Med Genet. 2020 Apr;63(4):103823.
Keppler-Noreuil KM, Adam MP, Welch J, Muilenburg A, Willing MC. Clinical insights gained from eight new cases and review of reported cases with Jeune syndrome (asphyxiating thoracic dystrophy. Am J Med Genet A. 2011 May;155A(5):1021-32. doi: 10.1002/ajmg.a.33892. Epub 2011 Apr 4.
Campbell RM Jr., Smith MD, Mayes TC, et al. The characteristics of thoracic insufficiency syndrome associated with fused ribs and congenital scoliosis. J Bone Joint Surg. 2003;85:399-408.
Campbell RM Jr., Hell-Vocke AK. Growth of the thoracic spine in congenital scoliosis after expansion thoracoplasty. J Bone Joint Surg. 2003;85:409-420.
Das BB, Nagaraj A, Fayemi A, et al. Fetal thoracic measurements in prenatal diagnosis of Jeune Syndrome, Indian J. Pediatr. 2002;69:101-03.
Kaddoura IL, Obeid MY, Mrouch SM, et al. Dynamic thoracoplasty for asphyxiating thoracic dystrophy. Ann Thorac Surg. 2001;71-1755-58.
Ho NC, Francomano CA, van Allen M. Jeune asphyxiating thoracic dystrophy and short-rib polydactyly type III (Verma-Naumoff) are variants of the same disorder. Am J Med Genet. 2000;90:310-14.
Aronson DC, Van Nierop JC, Taminlau A, et al. homologous bone graft for expansion thoracoplasty in Jeune’s asphyxiating dystrophy. J. Pediatr Surg. 1999:34:500-03.
Labrune P, Fabre M, Trioche P, et al. Jeune syndrome and liver disease: report of three cases treated with ursodeoxycholic acid. Am J Med Genet. 1999;87:324-28.
Sarimurat N, Elcioglu N, Tekant GC, et al. Jeune’s asphyxiating thoracic dystrophy of the newborn. Eur J Pediart Surg. 1998;8:100-01.
Chen CP, Lin SP, Liu FF, et al. Prenatal diagnosis of asphyxiating thoracic dysplasia (jeune syndrome). Am J Perinatol. 1996;13;495-95.
Davis JT. Lateral thoracic expansion for Jeune’s asphyxiating thoracic dysplasia. Ann thorax Surg. 1995:60:694-96.
Yang SS, Heidelberger KP, Brough AJ, et al. Three Conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib polydactyly syndrome spectrum: a clinicopathologic study. AM J Med Genet. 1987;3 (Suppl):191-207.
Oberklaid F, Danks FM, Mayne V, et al. Asphyxiating thoracic dysplasia. Clinical radiological, and pathological information on 10 patients. Arch Dis Child. 1977;52:756-65.
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.
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