What is the disease?

Spondylocostal Dysostosis (also called Jarcho-Levin Syndrome) is a group of conditions characterized by abnormal development of bones in the spine and ribs. The bones of the spine are misshapen and abnormally joined together.

There are multiple genes that cause the disease, but the DLL3(delta like canonical Notch ligand 3) gene and other genes involved in spondylocostal dysostosis play roles in the Notch signaling pathway, which is important in embryonic development. One of the functions of Notch signaling is directing the separation of future vertebrae and ribs from one another during early development, a process called somite segmentation. When the Notch signaling pathway is disrupted, somite segmentation does not occur properly, resulting in the malformation and fusion of the bones of the spine and ribs seen in spondylocostal dysostosis.

The protein produced from the gene, the DLL3 protein, regulates the activity of the NOTCH1 protein. The DLL3 protein attaches to the inactive NOTCH1 protein and isolates it or marks it to be broken down so that it cannot be activated.

How was the disease discovered?

The syndrome was first described by Saul Jarcho and Paul M. Levin at Johns Hopkins University in 1938.

How does it affect the world?

The incidence rate of the disease, is that each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. **(While this is true, additional information about the incidence rate in the US and the world are not discovered.)

Specific populations of people that are affected more than others, include males with SCDO appear to be at increased risk for inguinal hernia, and infants with STD are at the highest risk for respiratory insufficiency and have a nearly 50% mortality rate by the end of infancy. Also, approximately 75% of cases of AR SCDO have occurred in consanguineous families, usually from communities in which cousin partnerships are normal.

symptoms

Many people with this condition have abnormal side-to-side curvature of the spine due to malformation of the vertebrae. In addition to spinal abnormalities, some of the rib bones may be fused together or missing. Affected individuals have short, rigid necks and short torsos because of the bone malformations. As a result, people with spondylocostal dysostosis have short bodies but normal-length arms and legs, called short-trunk dwarfism.

The disease SCDO is diagnosed based on radiologic findings. Subtypes are defined by identification of two mutated alleles in any one of the four genes in which pathogenic variants are known to cause autosomal recessive (AR) SCDO: DLL3, MESP2, LFNG, and HES7.

The prognosis for a patient diagnosed with the disease, is that ARSD may cause respiratory insufficiency that may lead to life-threatening complications in the first year of life.

The disease can be treated by respiratory support, including intensive care, which is provided as needed for acute respiratory distress and chronic respiratory failure. Inguinal herniae are treated as per routine. Surgical intervention may be necessary when scoliosis is significant; external bracing, for example by use of an expandable prosthetic titanium rib, may be attempted but experience is limited.