Diastrophic dysplasia (DTD) is a rare genetic disorder of bone growth and formation that is evident at birth.
Diastrophic dysplasia is one of the genetic osteochondrodysplasias, a group of disorders characterized by abnormal growth and formation of bone and cartilage. The main features of DTD include: malformed ears, cleft palate, short limbs, short stature, spinal and joint deformities, and abnormalities of the bones of the hands and feet. Although children with DTD may experience delays in motor development (e.g. walking at a later age than expected), they are of normal intelligence. The syndrome derives its name from the Greek word, diastrophos, meaning twisted or crooked. Maroteaux and Lamy first used the term diastrophic dysplasia in 1960 to describe three of their patients and eleven other cases already reported in the literature. Since then, at least 300 cases of DTD have been described. Diastrophic dysplasia is also known as diastrophic nanism or diastrophic dwarfism and is abbreviated as DTD or DD.
The gene responsible for DTD, known as the diastrophic dysplasia sulfate transporter gene (DTDST gene), is located at the end of the long arm of chromosome 5, at position 5q32-33. The DTDST gene produces a protein that functions as a channel and transports sulfate across the cell membrane. DTD is inherited in an autosomal recessive manner. Affected individuals have a mutation in both copies of their DTDST gene; they inherit one mutation from each parent. Parents of affected individuals are carriers; they have a mutation in one copy of their DTDST gene and are without symptoms of the disorder.
Most bone in the body begins as cartilage and later hardens (ossifies) to form bone. In certain parts of the body such as the rib, auricle, and joints, cartilage does not ossify; it remains as cartilage and functions as load-bearing or shock-absorbing tissue. Cartilage contains sulfur-containing compounds, known as proteoglycans. It is thought that abnormal function of the DTD sulfate transporter leads to insufficient sulfate uptake by proteogycans in the cartilage. This undersulfation results in weakness and distortion of the cartilage. The exact mechanism by which this occurs is not fully understood.
Three other genetic skeletal dysplasias: recessively inherited multiple epiphyseal dysplasia (rMED), atelosteogenesis type 2 (AO-2), and achondrogenesis type IB (ACG-IB), are also due to mutations in the DTDST gene. When compared to DTD, both AO-2 and ACG-1B are more severe skeletal dysplasias, with the latter being a lethal disorder. Recessively inherited MED is a relatively mild condition. This broad range in severity, from mild to fatal, is attributed to the different types and combinations of genetic mutations within the DTDST gene that are responsible for these four related diseases.
Diastrophic dysplasia is a rare disorder in most parts of the world except in Finland where the incidence of the disease is estimated at one in every 32,600 live births. Approximately 1–2% of Finnish people are DTD carriers. Most Finnish DTD gene carriers possess the same ancestral mutation, known as DTDST (Fin). The high frequency of this single mutation in Finland is attributed to a founder effect.
Signs and symptoms
Diastrophic dysplasia is a variable condition that tends to become more severe with age. Many manifestations of the disorder are prenatal in onset and are therefore apparent at birth.
Diastrophic dysplasia is considered a short-limbed skeletal dysplasia because the limbs are disproportionately short for the overall height of the individual. The newborn with DTD tends to be short with an average birth length of 16.5 in (42 cm). This growth failure continues throughout childhood and is progressive in nature. The degree of deformity caused by orthopedic complications of this disorder can influence overall height. A wide range of final adult heights has been reported with lower limits at 2 ft 10 in (86 cm) and 3 ft 5 in (104 cm) and upper limits at 4 ft 5 in (135.7 cm) and 4 ft 3 in (129 cm) for males and females respectively. On x ray, the limb bones appear short and thick with broad metaphyses and flattened, irregular epiphyses.
One of the most distinct features of DTD is the socalled "cauliflower ear." In over 80% of infants with DTD, fluid-filled cysts appear on the outer ear (pinnae) during the first few weeks of life. These cysts later calcify and may eventually ossify to form bone. In as many as 75% of individuals with DTD, some form of cleft palate is present. Although individuals with DTD may have a small chin (micrognathia), the head is otherwise normal in size.
Occasionally there may be abnormalities of cartilage in the trachea, larynx, and bronchi, which may lead to a life-threatening complication—collapse of the airways—especially in early infancy.
Spina bifida occulta in the neck (cervical) and upper back (thoracic) region is the most common spinal abnormality found in DTD and is present in over 50% of cases. In spina bifida occulta there is incomplete closure of bones of the spinal column. Other common spinal abnormalities include progressive curvature of the spine, either from front to back (kyphosis) or from side to side (scoliosis ). Kyphosis in the neck region (cervical kyphosis) is present in at least 30% of affected individuals and is usually evident at birth. This type of spine curvature usually resolves over time without treatment. In severe cases however, cervical kyphosis can lead to respiratory problems. Scoliosis, which is generally not present at birth, may appear at an early age and become problematic in early adolescence. Nearly 50% of females and at least 20% of males will develop scoliosis.
Joint changes in diastrophic dysplasia are progressive in nature and can be a painful complication of this disorder. Individuals with DTD may experience limited mobility and/or permanent immobility (contractures), especially in the knees and shoulders. The joints in an individual with DTD are also prone to partial or complete dislocations in the shoulders, hips, kneecaps, and elbows.
Hands and feet
The hands of a child with diastrophic dysplasia are distinct. The fingers are short (brachydactyly ) and there may be fusion of the joints between the bones of the fingers (symphalangism). The metacarpal bone of the thumb is short and oval-shaped; these bony deformations cause the thumb to deviate away from the hand and assume the appearance of the so-called "hitchhiker thumb," a classic feature of DTD. The bony changes in the feet are similar to those found in the hands. The great toes may deviate outward, much like the thumbs. Clubfoot deformity (talipes), due to abnormal formation and limited mobility of the bones of the feet, is a common birth defect found in newborns with DTD.
At birth the diagnosis of diastrophic dysplasia is based on the presence of the characteristic physical and radiologic (x ray) findings. DNA mutation analysis may be helpful in confirmation of a suspected diagnosis. In those rarer cases where DNA mutation analysis does not detect changes, a laboratory test that measures the uptake of sulfate by fibroblasts or chondrocytes may be useful in making a diagnosis.
If there is a family history of diastrophic dysplasia and DNA is available from the affected individual, then prenatal diagnosis using DNA methods, either mutation analysis or linkage analysis, may be possible. DNA mutation analysis detects approximately 90% of DTDST mutations in suspected patients. In patients where the mutations are unknown or undetectable, another DNA method known as linkage analysis may be possible and, if so, it can usually distinguish an affected from an unaffected pregnancy with at least 95% certainty. In linkage analysis, DNA from multiple family members, including the person with DTD, is required. DNA-based testing can be performed through chorionic villus sampling or through amniocentesis .
If DNA-based testing is not possible, prenatal diagnosis of diastrophic dysplasia in an at-risk pregnancy may be made during the second and third trimesters through ultrasound. The ultrasound findings in an affected fetus may include: a small chin (micrognathia), abnormally short limbs, inward (ulnar) deviation of the hands, the "hitchhiker" thumb, clubfeet, joint contractures, and spinal curvature.
General population carrier screening is not available except in Finland where the frequency of a single ancestral mutation is high.
Treatment and management
There is currently no treatment that normalizes the skeletal growth and development in a child with diastrophic dysplasia. The medical management and treatment of individuals with DTD generally requires a multidisciplinary team of specialists that should include experts in orthopedics. At birth it is recommended that a neonatologist be present because of the potential for respiratory problems. Surgery may be indicated in infancy if congenital abnormalities such as open cleft palate and/or clubfoot deformity are present. Throughout childhood and adulthood, bracing, surgery, and physical therapy are measures often used to treat the spinal and joint deformities of DTD. Such measures, however, may not fully correct these deformities.
Due to the significant short-limbed short stature associated with diastrophic dysplasia, certain modifications to home, school, and work environments are necessary in order for a person with DTD to perform daily tasks. Occupational therapy may help affected individuals, especially children, learn how to use assistive devices and to adapt to various situations.
In infancy there is an increased mortality rate, as high as 25%, due to respiratory complications caused by weakness and collapse of the cartilage of the wind pipe (trachea) and/or the voice box (larynx), conditions which may require surgical intervention. Some forms of cleft palate and micrognathia may be life threatening in early life as they can result in respiratory obstruction. Severe spinal abnormalities such as cervical kyphosis may also cause respiratory problems. After the newborn period, the life span of an individual with DTD is usually normal with the exception of those cases where spinal cord compression occurs as a result of severe cervical kyphosis with vertebrae subluxation. Spinal cord compression is a significant medical problem that can lead to muscle weakness, paralysis, or death. In a susceptible individual, spinal cord compression may occur for the first time during surgery due to the hyperextended neck position used during intubation. Other anesthetic techniques may be indicated for such cases.
People with diastrophic dysplasia are of normal intelligence and are able to have children. Since many of the abnormalities associated with DTD are relatively resistant to surgery, many individuals with DTD will have some degree of physical handicap as they get older. They may continue to require medical management of their spinal and joint complications throughout adult life.
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National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923 (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
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Dawn Cardeiro, MS, CGC