October 16, 2017
Years published: 1989, 1992, 1997, 2005, 2017
NORD gratefully acknowledges Robert M. Campbell Jr., MD, Division of Orthopaedics, Director, The Center for Thoracic Insufficiency Syndrome, The Children’s Hospital of Philadelphia, for assistance in the preparation of this report.
Spondylocostal dysplasia is a rare genetic disorder characterized by defects of the bones of the spine (vertebrae) and abnormalities of the ribs. Ribs can be fused or missing in chaotic patterns. These malformations are present at birth (congenital). The severity and specific symptoms can vary among affected individuals, even among members of the same family. Some infants may have difficulty breathing because of a reduced size of the thorax. The thorax is the middle portion of the body extending from the neck to the abdomen and including the chest cavity. Sometimes, breathing difficulties can be severe and life-threatening. Most times, spondylocostal dysplasia is inherited in an autosomal recessive manner and is caused by a change (mutation) in one of four genes, DLL3, MESP2, LFNG, HES7. Rarely, spondylocostal dysplasia can be inherited in an autosomal dominant manner. One gene, TBX6, is known to cause autosomal dominant spondylocostal dysplasia. Many individuals do not have a mutation in any of these genes. With treatment, most individuals survive well into adulthood.
There is significant confusion in the medical literature regarding names for spondylocostal dysplasia. For years, this disorder and a similar disorder, spondylothoracic dysplasia, were considered the same disorder and referred to as Jarcho-Levin syndrome. Researchers now know that these disorders are separate entities with different causes and associated malformations. The term Jarcho-Levin syndrome is still used for both disorders, and sometimes it is used as an “umbrella” term to describe a broad range of conditions associated with spinal and rib defects. This has led to confusion for individuals and families who receive a diagnosis of Jarcho-Levin syndrome. Some researchers have advocated that Jarcho-Levin syndrome be reserved for people with spondylocostal dysplasia. Other researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. Jarcho and Levin were two doctors who first described what is now known as spondylothoracic dysplasia in the medical literature in 1938.
The signs and symptoms of spondylocostal dysplasia can vary greatly from one person to another, even among members of the same family. Affected individuals have abnormalities in the development of the spine and ribs.
The bones of the spine (vertebrae) may be fused together or misshapen. Sometimes, they are underdeveloped and wedge-shaped (hemivertebrae). Multiple vertebrae are always affected, usually at least 10 segments in a row (contiguously). The ribs may be fused together, misaligned, broadened, split or forked (bifid), and sometimes some of the ribs are missing. Boys have an increased risk of developing inguinal hernia, a condition characterized by protrusion of parts of the large intestine through an opening in the abdominal wall near the groin.
The trunk, which is the part of the body that extends from the neck to the abdomen, may be disproportionately smaller in comparison to their height. In addition, affected individuals may be shorter than would otherwise be expected for their age and gender (short stature). Affected individuals may have a short neck with limited mobility. Some individuals have abnormal sideways curvature of the spine, a condition called scoliosis. Scoliosis is usually mild, but, in rare instances, can be severe. Scoliosis usually does not get worse, but should be carefully followed with spine x-rays
Because of the malformation of the spine and ribs, the lungs of affected individuals may not be able to grow and develop properly. This is known as thoracic insufficiency syndrome. Affected infants and children cannot expand their chests sufficiently with causes reduced lung capacity, which means the lungs can hold less air than they normally would. Consequently, they can have difficulties breathing and experience repeated respiratory infections. Breathing problems are usually mild or moderate, but sometimes can become life-threatening and be fatal. Some children may develop high blood pressure of the pulmonary artery, which is the main artery that delivers blood to the lungs (pulmonary hypertension). Pulmonary hypertension is a chronic and, if not treated, life-threatening complication. Reduced lung capacity also increases the risk of heart failure another life-threatening complication.
Despite the potential for serious complications, most individuals with spondylocostal dysplasia live until adulthood. They may experience chronic back pain. Intelligence is usually unaffected, and neurological complications are rare.
Researchers are studying spondylocostal dysplasia to determine whether there are any genotype-phenotype correlations. Genotype is the distinct set of genes a person carries. Phenotype refers to the observable characteristics of a person. People with an altered LFNG gene usually have the most severe shortening of the spine. People with an altered HES7 gene have improper separation (malsegmentation) of the bones of the entire spine. People with an altered DLL3 gene usually (but not always) have mild scoliosis that does not require surgical intervention.
Spondylocostal dysplasia is caused by a change (mutation) in one of at least five different genes, specifically the DLL3, MESP2, LFNG, HES7, and TBX6 genes. An altered DLL3 gene is the most common cause. Many people do not have a mutation in any of these genes, suggesting that as-yet-unidentified genes also cause spondylocostal dysplasia. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.
The DLL3, MESP2, LFNG, and HES7 genes are inherited in an autosomal recessive manner. There are reports of the TBX6 gene being inherited in an autosomal dominant as well as in a recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one 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 altered gene and 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 normal genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, an autosomal dominant disorder is due to spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
The altered genes that cause spondylocostal dysplasia produce proteins that are involved in the NOTCH signaling pathway. This pathway is a series of chemical reactions that are vital to the health and function of the body, particularly with the development of the spine and ribs. The protein produced by the altered gene is inefficient or defective, or the gene does not produce enough of the protein. Without the protein in question, the normal chemical reactions that occur in the NOTCH signaling pathway are impaired, leading to the signs and symptoms of spondylocostal dysplasia.
Spondylocostal dysplasia is a rare disorder. The exact prevalence or incidence of the disorder is unknown. Because it is a rare disorder, some people may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Spondylocostal dysplasia affects both men and women, and is seen in all ethnic groups (panethnic).
A diagnosis of spondylocostal dysplasia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Workup
X-rays (radiographs) of the spine can show characteristic changes to the spine and ribs that characterized spondylocostal dysplasia.
A diagnosis of spondylocostal dysplasia can be confirmed through molecular genetic testing in some individuals. Molecular genetic testing can detect alterations in the specific genes known to cause spondylocostal dysplasia, but is available only as a diagnostic service at specialized laboratories. Also, many people do not have a mutation in any of the genes known to cause this disorder and their diagnosis cannot be confirmed through molecular genetic testing.
Prenatal diagnosis of spondylocostal dysplasia is possible by fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can reveal some of the defects associated with spondylocostal dysplasia.
The treatment of spondylocostal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, specialists who diagnose and assess heart disorders (cardiologists), specialists who diagnose and treat lung disorders (pulmonologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Infants who experience breathing difficulties can require some form of respiratory support. This can include the use of a machine or device to help an infant breath. Some infants may require intensive care, which involves constant monitoring in a hospital. Surgery is used to repair an inguinal hernia. If scoliosis is severe enough, surgery may be required to straighten the spine. Antibiotics may be necessary to treat recurrent respiratory infections.
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 spondylocostal dysplasia, ribs are separated and VEPTRs are placed on the concave side of the chest. It is manufactured by DePuy Synthes Spine Co. in Raynham Mass.
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 web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
For more information about spondylocostal dysplasia please contact:
The Center for Thoracic Insufficiency Syndrome
The Children’s Hospital of Philadelphia
Campbell RM. VEPTR Expansion Thoracoplasty. In: The Growing Spine. Management of Spinal Disorders in Children, Akbarnia BA, Yazici M, Thompson GH, editors. 2016 Springer-Verlag, Berlin. Pp. 669-690.
Jones KL, Jones MC, del Campo Casanelles. Eds. Jarcho-Levin syndrome. In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:782-783.
Campbell RM. Jarcho-Levin syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:207-208.
Lefebvre M, Duffourd Y, Jouan T, et al. Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis. Clin Genet. 2016; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/27861764
Karlin JG, Roth MK, Patil V, et al. Management of thoracic insufficiency syndrome in patients with Jarcho-Levin syndrome using VEPTRs (vertical expandable prosthetic titanium ribs). J Bone Joint Surg Am. 2014;96:e181. https://www.ncbi.nlm.nih.gov/pubmed/25378514
Sparrow DB, McInerney-Leo A, Gucev ZS, et al. Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum Mol Genet. 2013;22:1625-1631. https://www.ncbi.nlm.nih.gov/pubmed/23335591
Berndon WE, Lampl BS, Cornier AS, et al. Clinical and radiological distinction between spondylothoracic dysostosis (Lavy-Moseley syndrome) and spondylocostal dysostosis (Jarcho-Levin syndrome). Pediatr Radiol. 2011;41-384-388. https://www.ncbi.nlm.nih.gov/pubmed/21174082
Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20:905-916. https://www.ncbi.nlm.nih.gov/pubmed/21147753
Ramirez N, Flynn JM, Emans JB, et al. Vertical expandable prosthetic titanium rib as treatment of thoracic insufficiency syndrome in spondylocostal dysplasia. J Pediatr Orthop. 2010;30:521-526. https://www.ncbi.nlm.nih.gov/pubmed/20733413
Gucev ZS, Tasic V, Pop-Jordanova N, et al. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet A. 2010;152A:1378-1382. https://www.ncbi.nlm.nih.gov/pubmed/20503311
Offiah A, Alman B, Cornier AS, et al. Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. Am J Med Genet A. 2010;152A:1357-1371. https://www.ncbi.nlm.nih.gov/pubmed/20503308
Sparrow DB, Sillence D, Wouters MA, Turnpenny PD, Dunwoodie SL. Two novel missense mutations in Hairy-and-Enhancer-of-Spilt-7 in a family with spondylocostal dysostosis. Eur J Hum Genet. 2010;18:674-679. https://www.ncbi.nlm.nih.gov/pubmed/20087400
Campbell RM Jr. Spine deformities in rare congenital syndromes: clinical issues. Spine (Phil Pa 1976). 2009;134:1815-1827. https://www.ncbi.nlm.nih.gov/pubmed/19644333
Giampietro PF, Dunwoodie SL, Kusumi K, et al. Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans. Ann NY Acad Sci. 2009;1151:38-67. https://www.ncbi.nlm.nih.gov/pubmed/19154516
Kulkarni ML, Navaz SR, Vani NH, Manjunath KS, Matani D. Jarcho-Levin syndrome. Indian J Pediatr. 2006;73:245-247. https://www.ncbi.nlm.nih.gov/pubmed/16567923
Beine O, Bolland J, Verloes A, et al. Spondylocostal dysostosis: a rare genetic disease. Rev Med Liege. 2004;59:13-16. https://www.ncbi.nlm.nih.gov/pubmed/15562550
Bulman MP, Kusumi K, Frayling TM, et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000;24:3438-441. https://www.ncbi.nlm.nih.gov/pubmed/10742114
Karnes PS, Day D, Berry SA, Pierpont ME. Jarcho-Levin syndrome: four new cases and classification of subtypes. Am J Med Genet. 1991;40:264-270. https://www.ncbi.nlm.nih.gov/pubmed/1951427
Le Merrer M. Autosomal Recessive Spondylocostal Dysostosis. Orphanet Encyclopedia, January 2009. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2311 Accessed: September 28, 2017.
Turnpenny PD, Young E; ICVS (International Consortium for Vertebral Anomalies and Scoliosis). Spondylocostal Dysostosis, Autosomal Recessive. 2009 Aug 25 [Updated 2013 Jan 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK8828/ Accessed September 28, 2017.
Genetics Home Reference. Spondylocostal Dysostosis.Reviewed June 2016. Available at: https://ghr.nlm.nih.gov/condition/spondylocostal-dysostosis Accessed: September 28, 2017.
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