What is diastrophic dysplasia?

Risk Factors

Those whose biological parents both carry a mutant copy of the SLC26A2 gene are at risk of inheriting diastrophic dysplasia. This disease is found in all populations and occurs equally in men and women. It is particularly prevalent in Finland.

Etiology and Genetics

Diastrophic dysplasia is an autosomal recessive genetic disease and is caused by mutations in the SLC26A2 gene. Someone must possess two copies of the mutant form of this gene to have this disorder. The SLC26A2 gene is located on the long arm of chromosome 5, in band regions 32–33. If both parents carry one mutant copy of SLC26A2, then each sibling has a 25 percent chance of receiving two mutant copies and contracting diastrophic dysplasia.

The SLC26A2 gene encodes the information for the synthesis of a protein called solute carrier family 26, member 2. This protein is embedded in the cell membrane. The cell membrane is composed of phosphate-containing lipids that border the cell and delimit the cell interior from the exterior. The structure of the cell membrane prevents charged and large polar molecules from entering or exiting the cell. If the cell needs such molecules, then specific transport proteins inserted into the membrane facilitate the import or export of particular molecules. Solute carrier family 26, member 2 is a transport protein that allows the entrance of sulfate ions into cells.

Sulfate ions are essential for the production of normal cartilage. A major component of cartilage is a group of proteins called proteoglycans. Proteoglycans are proteins with long sugar chains attached to them, but these sugar molecules also have sulfate ions linked to them. The cells that produce cartilage are called chondrocytes, and if these cells do not possess a normal solute carrier family 26, member 2, then they cannot properly import sulfate ions for the synthesis of proteoglycans and they will make abnormal cartilage.

Cartilage also establishes the pattern for bone development. The long bones of the arms, legs, and other structures initially develop as long cartilage rods that are replaced later by bone (endochondral ossification). Because the cartilage precursors act as templates for the bones, if the original cartilage rods are abnormal, then the bones that replace them will also be abnormal. Chondrocytes in individuals with diastrophic dysplasia lack the ability to import sulfate ions and make normal proteoglycans, and therefore, they make structurally abnormal cartilage that is replaced by abnormal bone. The ends of the cartilage rod make the joint-specific cartilage, which is also abnormal in diastrophic dysplasia.

In developing humans, not all cartilage is used to make bone. Many structures, like joints, the voice box (larynx), external ears, and the windpipe (trachea) are made, largely, from cartilage. These structures are also abnormal in individuals with diastrophic dysplasia and often do not function properly.

Symptoms

The main characteristics of this disease include short stature and short arms and legs. The joints show permanent shortening (contractures). The feet tend to turn downward and inward (club feet). The thumbs are placed farther back on the hand (hitchhiker thumbs). The spine is abnormally curved (kyphosis). About one-third of babies with diastrophic dysplasia are born with a hole in the roof of the mouth (cleft palate). Two-thirds of newborn children also show swollen ears.

Screening and Diagnosis

Ultrasound can detect clinical features such as shortened limbs with a normal-sized skull, a small chest, hitchhiker thumbs, and joint contractures as early as twelve weeks of gestation. X-ray analysis reveals poorly developed and malformed bones. Tissue (histopathological) analysis reveals abnormal cartilage that contains too few sulfate-containing proteoglycans. Molecular genetic testing can confirm the diagnosis.

Treatment and Therapy

In children, physical therapy and casting can help joint problems, and surgery can correct club feet. In young adults, a surgical technique called arthroplasty, which replaces abnormal joints with synthetic articulations made from cobalt chromoly and high molecular weight polyethylene, relieves pain and increases hip and knee joint mobility. Spinal surgery can fix excessive curvature of the spine. One caveat with surgical therapies is that deformities tend to reoccur after orthopedic surgery.

Prevention and Outcomes

Rib and windpipe abnormalities can prevent proper breathing, which causes increased death rates in newly born babies with diastrophic dysplasia. If the baby survives, then surgical corrections probably will be required to allow the child to walk and to reduce the abnormal curvature of the spine. Spinal curvature and the health of the joints should be checked annually.

Obesity tends to place too great a load on the joints and should be avoided. If they survive early childhood, then children with diastrophic dysplasia have normal intelligence and can excel in academic, social, and artistic endeavors.

Bibliography

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