Diastrophic dysplasia, which is also known as disastrophic dwarfism, is a rare disorder that is present at birth (congenital). The range and severity of associated symptoms and physical findings may vary greatly from case to case. However, the disorder is often characterized by short stature and unusually short arms and legs (short-limbed dwarfism); abnormal development of bones (skeletal dysplasia) and joints (joint dysplasia) in many areas of the body; progressive abnormal curvature of the spine (scoliosis and/or kyphosis); abnormal tissue changes of the outer, visible portions of the ears (pinnae); and/or, in some cases, malformations of the head and facial (craniofacial) area.
In most infants with diastrophic dysplasia, the first bone within the body of each hand (first metacarpals) may be unusually small and "oval shaped," causing the thumbs to deviate away (abduction) from the body ("hitchhiker thumbs"). Other fingers may also be abnormally short (brachydactyly) and joints between certain bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement of the finger joints. Affected infants also typically have severe foot deformities (talipes or "clubfeet") due to abnormal deviation and fusion of certain bones within the body of each foot (metatarsals). In addition, many children with the disorder experience limited extension, partial (subluxation) or complete dislocation, and/or permanent flexion and immobilization (contractures) of certain joints.
In most infants with diastrophic dysplasia, there is also incomplete closure of bones of the spinal column (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae). In addition, during the first year of life, some affected children may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). During adolescence, individuals with the disorder may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae within the neck area (cervical vertebrae). In severe cases, progressive kyphosis may lead to difficulties breathing (respiratory distress). Some individuals may also be prone to experiencing partial dislocation (subluxation) of joints between the central areas (bodies) of cervical vertebrae, potentially resulting in spinal cord injury. Such injury may cause muscle weakness (paresis) or paralysis and/or life-threatening complications.
In addition, most newborns with diastrophic dysplasia have or develop abnormal fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within the first weeks of life, the pinnae become swollen and inflamed and unusually firm, thick, and abnormal in shape. Over time, the abnormal areas of tissue (lesions) may accumulate deposits of calcium salts (calcification) and eventually develop into bone (ossification). Some affected infants may also have abnormalities of the head and facial (craniofacial) area including incomplete closure of the roof of the mouth (cleft palate) and/or abnormal smallness of the jaws (micrognathia). In addition, in some affected infants, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and certain air passages in the lungs (bronchi) may result in collapse of these airways, causing life-threatening complications such as respiratory obstruction and difficulties breathing. In some individuals with the disorder, additional symptoms and physical findings may also be present. Diastrophic dysplasia is inherited as an autosomal recessive trait.
The symptoms and physical findings associated with diastrophic dysplasia may be extremely variable, differing in range and severity even among affected family members (kindreds). However, in all individuals with the disorder, there is abnormal development of bones and joints of the body (skeletal and joint dysplasia).
During normal development before birth (embryonic and fetal development) as well as development during early childhood, cartilage in many areas of the body is gradually replaced by bone (ossification). In addition, a layer of cartilage (epiphyseal cartilage [growth plate]) separates the shafts (diaphyses) of long bones (e.g., bones of the arms and legs) from their ends (epiphyses), allowing long bones to grow until the cartilage is no longer present. In those affected by diastrophic dysplasia, however, there is delayed growth before and after birth (prenatal and postnatal growth retardation), the development of the ends of the long bones (epiphyses) is irregular, and the ossification of the epiphyses is delayed. Thus, affected newborns and children typically have markedly short, bowed arms and legs and short stature (short-limbed dwarfism). In addition, in such cases, growth failure is typically progressive, in part due to absence of the “growth spurt” that usually occurs during puberty. The severity of such growth failure may vary greatly from case to case, including among affected siblings.
Due to abnormalities of skeletal development, infants and children with diastrophic dysplasia also have additional distinctive malformations of bones of the hands, feet, and other areas of the body. For example, the first bone within the body of each hand (first metacarpals) may be unusually small, short, and “oval shaped.” As a result, the thumbs deviate away (abduction) from the body (“hitchhiker thumbs”). In addition, other fingers may be abnormally short (brachydactyly) and joints between particular bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement (reduced mobility) of the finger joints. In some cases, bones of the wrists may also be malformed due to premature ossification.
Infants with the disorder also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal fusion and deviation of bones within the body of each foot (metatarsals). In most cases, the heels turn outward (talipes valgus) while the fore part of each foot deviates inward (metatarsus adductus). In other infants, the soles of the feet may be flexed (talipes equinus) and, in some cases, the heels may also turn inward (talipes equinovarus). The great toes, like the thumbs, may also deviate away (abduction) from the body.
In addition to having limited flexion of finger joints, many affected infants and children also experience partial dislocation (subluxation) and/or complete dislocation of particular joints of the body. For example, in many cases, dislocations of the knees and hips occur upon weightbearing. Affected individuals may also have abnormally loose and/or stiff joints; experience limited extension of joints at the elbows and/or knees; and/or develop permanent flexion and immobilization (contracture) of certain joints (e.g., knees). Due to joint and bone abnormalities such as those affecting the feet, many individuals with diastrophic dysplasia have a tendency to walk on tiptoe. In addition, affected individuals may be predisposed to degenerative changes (osteoarthrosis) of particular joints (e.g. of the hips), resulting in pain with use of the joint, tenderness, stiffness, and, in some cases, deformity.
Many infants with diastrophic dysplasia also have abnormalities of bones within the spinal column (vertebrae). For example, in most affected infants, there may be incomplete closure of vertebrae (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae) and/or abnormal narrowing of portions of the vertebrae of the lower back (interpedicular narrowing in lumbar vertebrae). During the first year of life, some infants may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). In addition, during adolescence, individuals with diastrophic dysplasia may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae of the neck region (cervical vertebrae). In severe cases, progressive kyphosis may result in difficulties breathing (respiratory distress). Some individuals with the disorder may also be prone to experiencing partial dislocation of joints between the central areas (bodies) of cervical vertebrae (cervical subluxation), potentially resulting in compression of the spinal cord. (This cylindrical structure of nerve tissue extends from the lower portion of the brain and is located inside the central canal within the spinal column [spinal cavity].) Such spinal cord injury may result in muscle weakness (paresis) or paralysis and/or life-threatening complications.
Most newborns with diastrophic dysplasia also have or develop fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within approximately two to five weeks after birth, the pinnae become swollen and inflamed. When such swelling and inflammation subside, the pinnae remain unusually thick, hard, and abnormal in shape. The abnormal areas of tissue (lesions) may gradually accumulate deposits of calcium salts (calcification) and eventually be replaced by bone (ossification). Although affected infants may experience associated abnormal narrowing (stenosis) of the external ear canal (external auditory canal), hearing is usually normal. However, according to reports in the literature, other affected infants and children may experience hearing impairment due to such auditory canal stenosis or abnormal fusion or absence of the three tiny bones (auditory ossicles) in the middle ear that conduct sound to the inner ear.
Some infants with diastrophic dysplasia also have characteristic malformations of the head and facial (craniofacial) area, such as an unusually high, prominent forehead; abnormal smallness of the jaws (micrognathia); and/or a broad, highly arched roof of the mouth (palate) or incomplete closure of the palate (cleft palate). Cleft palate has been reported to occur in anywhere from 25 to 60% of affected infants, and may cause difficulties with feeding and/or breathing. In addition, in some infants with diastrophic dysplasia, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and air passages in the lungs (bronchi) may cause abnormal narrowing (e.g., laryngotracheal stenosis) and collapse of such airways. In such cases, life-threatening complications such as respiratory obstruction and difficulties breathing (respiratory distress) may result. However, in many cases nasal speech (hyponasality) occurs as a result of the abnormally shaped vocal tract.
Approximately one third of infants and children with diastrophic dysplasia also have dental abnormalities, such as abnormally small teeth and dental crowding. In addition, in some cases, affected infants may have benign, reddish purple growths in the midportion of the face (midline frontal hemangioma) due to an abnormal distribution of tiny blood vessels (capillaries). Some individuals with the disorder may also have additional symptoms and physical findings.
Diastrophic dysplasia is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutated copy of the gene, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Parents of some individuals with diastrophic dysplasia have been closely related by blood (consanguineous). If both parents carry an altered gene for the disorder, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.
A gene responsible for diastrophic dysplasia, known as DTDST (for “diastrophic dysplasia sulfate transporter” gene), has been located on the long arm (q) of chromosome 5 (5q32-q33.1). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 5q32 refers to band 32 on the long arm of chromosome 5.
The symptoms and findings associated with diastrophic dysplasia are thought to result due to abnormalities in the formation of cartilage, thus affecting skeletal development. Early during normal embryonic development, the skeleton mainly consists of cartilage that is gradually replaced by bone (ossification). After birth, many bones of the skeleton still consist primarily of cartilage that will eventually ossify. However, researchers suspect that certain changes (mutations) of the DTDST gene result in abnormalities of cartilage cells (chondrocytes) and the substance (matrix) that lies between such cells, ultimately causing the symptoms and findings associated with the disorder. For example, in individuals with diastrophic dysplasia, the growth plate of long bones may contain an abnormal distribution of cartilage cells (chondrocytes) and abnormal fibrous and cystic areas within its matrix.
As discussed below (see “Affected Population”), diastrophic dysplasia is particularly frequent in Finland. Genetic analysis has revealed that a specific mutation, designated as “DTDST(Fin),” is present in affected members of many Finnish families (kindreds) and suggests that a single mutation event may have occurred in a common ancestor (i.e., founder mutation) in the past. However, in some Finnish kindreds, the disorder has been shown to result from different DTDST gene mutations (DTD-causing alleles) that do not descend from the common ancestral (founder) mutation. In addition, different mutations of the DTDST gene have been identified in some non-Finnish individuals with the disorder.
Diastrophic dysplasia affects males and females in equal numbers.
Although the disorder is extremely rare, the percentage of carriers in certain groups is high. In Finland, 1-2% of the general population are carriers and a total of 183 cases have been diagnosed, with a prevalence ratio of 1 in 30,000. Diastrophic dysplasia has been observed in most white populations
In some families with a previous history of diastrophic dysplasia, it is possible that the disorder may be detected before birth (prenatally) during early pregnancy (e.g., first trimester) based upon the results of specialized genetic (i.e., DNA marker) testing. In addition, in some cases, the disorder may be detected during mid pregnancy (e.g., second trimester) through fetal ultrasonography, a specialized imaging technique in which sound waves are used to create an image of the developing fetus. In such cases, diagnosis is most easily established when a clear family history is present. During fetal ultrasonography, a diagnosis of diastrophic dysplasia may be considered due to detection of certain characteristic findings, such as marked shortening of bones of the fingers (phalanges), arms, and legs; abnormal deviation (abduction) of the thumbs ("hitchhiker thumbs") and great toes; severe deformities of both feet (talipes or "clubfeet"); and/or other findings.
In most cases, diastrophic dysplasia is diagnosed and/or confirmed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specializing tests, such as advanced imaging techniques. For example, specialized x-ray studies such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to detect, confirm, and/or characterize certain skeletal abnormalities that may be associated with diastrophic dysplasia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body.
Specialized diagnostic testing (i.e., audiological tests) may also be performed to help detect hearing deficits that may occur in some children with diastrophic dysplasia.
The treatment of diastrophic dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; dental specialists (orthodontists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.
Specific therapies for the treatment of diastrophic dysplasia are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate preventive or corrective treatment of respiratory obstruction and distress that may result due to certain abnormalities potentially associated with the disorder (e.g., laryngotracheal stenosis). In addition, special supportive measures may be used to help ensure an appropriate intake of nutrients in infants who experience feeding difficulties due to cleft palate. In some cases, surgical procedures may be performed to correct malformations resulting in breathing and/or feeding difficulties. The specific procedures performed will depend upon the location, severity, and combination of such anatomical abnormalities.
In addition, various orthopedic techniques, including surgery, may also be used to help prevent, treat, and/or correct certain skeletal deformities associated with diastrophic dysplasia. In some cases, physical therapy in combination with surgical and supportive measures may be helpful in improving an affected individual's ability to walk and perform other movements (mobility). According to the medical literature, although the foot deformities (i.e., talipes or clubfeet) associated with the disorder may be resistant to treatment, early, persistent therapy may be helpful in achieving beneficial results. In addition, because particular skeletal changes associated with diastrophic dysplasia are progressive (e.g., kyphosis) and, in some cases, may lead to severe complications (e.g., respiratory distress, compression of the spine, potential paresis or paralysis), physicians may perform ongoing monitoring to ensure prompt detection of and appropriate preventive and/or corrective measures for such abnormalities.
In affected children with dental abnormalities, braces (orthodontics), dental surgery, and/or other corrective procedures may be undertaken to correct such malformations. Steroid injections and/or other measures may also be used to help decrease the ear deformity that often affects infants with the disorder.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
The Chorionic Villus Sampling Birth Defects Registry has been established to collect information about individuals exposed to chorionic villus sampling who developed hemangiomas. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). For more information, contact:
Caroline McGuirk, MPH, Coordinator
Chorionic Villus Sampling Birth Defects Registry
Tel: (888) 287-0738
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eMedicine – Diastrophic Dysplasia : Article by Shital Parikh, MBBS, MS