The term "diastrophic" is Greek and means "crooked". Although diastrophic dysplasia occurs in most countries, the highest prevalence is found in Finland (1 in 33,000) where the carrier rate in the population is 1 – 2% (3). The incidence in non-Finnish populations is considerably lower, being 1 in 500,000 live births (6).
Diastrophic dysplasia is caused by a mutation in the gene coding for a sulfate transporter protein that is essential for normal cartilage function. This protein is called DTDST and was first identified by Hastabacka and colleagues in 1994 (1). The gene is located on chromosome 5 (5q31-q34). Mutations in the same gene are responsible for lethal chondrodysplasias.
Proteoglycans are complex molecules that absorb water and facilitate load bearing in articular cartilage. Reduction in sulfate transporter concentrations in chondrocytes causes under-sulfation of the proteoglycan matrix and predisposes individuals to early degenerative joint disease. Diastrophic dysplasia affects chondrocyte function in the growth plate, epiphyseal region and other areas such as the trachea.
The physical characteristics of diastrophic dysplasia include a short limbed form of disproportionate short stature. Both joint dislocations and joint contractures can be present. Intelligence is typically average.
Face & Skull
- Narrow nasal bridge and broad midportion of the nose
- Long and broad philtrum
- High, broad forehead
- Square jaw
- Cleft palate in approximately 50% of children
- Capillary hemangiomas called an "Angel's kiss" can be present in the midforehead region. They will disappear or fade with time.
- In the majority of patients in first 2 weeks of life, cystic swellings of the ear appear but resolve spontaneously, resulting in the characteristic “cauliflower ear” deformity.
Arms & Legs:
- Shortening of limbs
- "Hitchhiker’s thumb." Due to poor development of the bone supporting the thumb, the main thumb joint deviates outwards
- Limited movement of the fingers due to symphalangism
- Dislocations of the elbow and shoulder
- Dislocated kneecap
- Abnormal gait
- Weight bearing on balls of feet and toes with compensatory knee and hip flexion
What are the X-ray characteristics?
The radiographic features of Diastrophic Dysplasia include short and broad long bones of the limbs. The metaphyses are flared and crescent-shaped, and flattened epiphyses are typical. The epiphyses of the proximal tibias are triangular and larger than those of the distal femoral epiphyses. The metacarpals, metatarsals, and phalanges are deformed and shortened. Cervical kyphosis and thoraco-lumbar kyphoscholiosis are characteristic at different ages. There is a moderate narrowing of the interpediculate distances within the lower lumbar segments of spine. The hips are either partially or completely dislocated.
The condition is typically recognized at birth based on physical and radiographic evaluation. Milder variants or atypical cases may not be diagnosed until a later age. If suspicions arise during a prenatal ultrasound, molecular testing can be done from an aminocentesis sample.
In parents who already have children with diastrophic dysplasia, an ultrasound scan or molecular genetic testing (using DNA from amniocentesis or chorionic villus sampling) in the first trimester of pregnancy offers the possibility of prenatal diagnosis of this condition.
Cervical kyphosis is present in 30 – 50% of individuals. It is due to hypoplasia of the vertebral bodies and progressive degenerative changes in the intervertebral joints. Kyphosis can be sufficiently severe and will cause a predisposition to spinal cord compression and quadriplegia (weakness of all 4 extremities and incontinence). Short, sharply angulated curves are associated with severe kyphosis and increase the incidence of neurological abnormalities. Surgery may be necessary to alleviate the spinal cord compression in the neck. A halo and vest device is usually employed after surgery to support the neck until stable fusion is achieved. Occasionally, the kyphosis will resolve spontaneously.
Scoliosis, although not apparent at birth, will become severe as weight bearing increases. The curves usually develop around 5 years of age but can develop even before walking age. The spine curvature causes trunk deformity and barrel chest. Three distinct patterns of scoliosis occur: early progressive, idiopathic-type and mild non-progressive. Kyphoscoliosis occurs frequently (up to 90% of patients) in the lumbar region of the spine. Lumbar lordosis is increased due to exaggerated thoracic kyphosis and concomitant hip flexion contractures (hip joint is fixed with the thigh bent forwards).
Severe clubfoot is almost always present and typically requires surgical release. Surgery is usually undertaken around 1-year of age, to enable the child to start walking. In spite of early intervention, recurrence of the foot deformity is common and an osteotomy may become necessary. Special shoes are oftentimes required.
Progressive subluxation of the hips occurs because the soft articular cartilage is unable to perform its normal function of load bearing. Superimposed joint contractures around the hips and knees lead to restricted movement and deformity. If the deformity interferes with walking, an osteotomy is performed around the hips or knees. Due to the intrinsic cartilage abnormality, degenerative joint disease (arthritis) is common. Flexion deformities are pronounced. Knees are dislocated. Hip or knee replacement surgery is usually necessary in early to mid-adult life and typically has successful results.
Respiratory obstruction, including laryngeal stenosis, may occur in newborns. The mortality rate due to respiratory distress can approach 25% in early infancy.
Hypoplastic cartilage in the trachea and larynx causes voice abnormalities and breathing difficulty.
Small Auditory Canals
Small auditory canals are characteristic, but this does not usually impair hearing. However, deformity of the middle ear ossicles can result in
In infancy, it is important to be regularly monitored by a pediatric orthopedic surgeon so that future problems of the feet and spine can be managed and possibly evaded. Surgery is usually performed before walking age to correct foot deformities.
Later in life, patients must look out for worsening foot deformities, progressive curvature of the spine, and hip pain in early adult life (due to arthritis). Common surgical procedures intended to correct these problems include an osteotomy of the foot or lower leg (to achieve a plantigrade foot) or hip replacement surgery (for progressive degenerative arthritis).
Occasionally, spinal cord compression in the neck can lead to quadriparesis, resulting in a loss of limb function. Symptoms to watch for include a loss of walking or reduced endurance, altered sensations in the arms and legs, or incontinence. Oftentimes patients undergo spinal fusion surgery in the neck or lower back, along with decompression of the spinal cord.
Generally all skeletal dysplasias warrant multidisciplinary attention. Regular assessment by an orthopedist, geneticist, pediatrician, dentist, neurologist, and physical therapist will provide the most comprehensive treatment.
- Hastbacka, J.; Sistonen, P.; Kaitila, I.; Weiffenbach, B.; Kidd, K. K.; de la Chapelle, A. : A linkage map spanning the locus for diastrophic dysplasia (DTD). Genomics 11: 968-973, 1991.
- Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
- Poussa, Mikko. Merikanto, Juhani. Ryoppy, Soini. Marttinen, Eino. Kaitila, Ilkka. The Spine in Diastrophic Dysplasia. Spine; 16(8):881-887. 1991.
- Scott, Charles I. Dwarfism. Clinical Symposium, 1988; 40(1):9-10.
- Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.
- Diastrophic Dysplasia Booklet http://pixelscapes.com/ddhelp/DD-booklet/
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All About Genetics
What do you know about your family tree? Have any of your relatives had health problems that tend to run in families? Which of these problems affected your parents or grandparents? Which ones affect you or your brothers or sisters now? Which problems might you pass on to your children?
Thanks to advances in medical research, doctors now have the tools to understand much about how certain illnesses, or increased risks for certain illnesses, pass from generation to generation. Here are some basics about genetics.
Genes and Chromosomes
Each of us has a unique set of chemical blueprints affecting how our body looks and functions. These blueprints are contained in our DNA (deoxyribonucleic acid), long, spiral-shaped molecules found inside every cell. DNA carries the codes for genetic information and is made of linked subunits called nucleotides. Each nucleotide contains a phosphate molecule, a sugar molecule (deoxyribose), and one of four coding molecules called bases (adenine, guanine, cytosine, or thymine). The sequence of these four bases determines the genetic code.
The specific segments of DNA that contain the instructions for making specific body proteins are called genes. Right now, scientists believe that human DNA carries from 25,000 to 35,000 genes. Some genes direct the formation of proteins that eventually determine physical features such as brown eyes or curly hair. Others provide instructions for the body to produce important chemicals called enzymes (which help control the chemical reactions in the body).
Sometimes, depending on the codes of a specific gene, even a small error within the DNA structure can mean serious problems for the entire body. Sometimes, an error in just one gene can result in a life that's shortened or physically difficult.
Genes are found in specific segments along the length of human DNA, neatly packaged within structures called chromosomes. Every human cell contains 46 chromosomes, arranged as 23 pairs (called autosomes), with one member of each pair inherited from each parent at the time of conception. After conception, the chromosomes duplicate again and again to pass on the same genetic information to each new cell in the developing child. Twenty two autosomes are the same in males and females. In addition, females have two X chromosomes and males have one X and one Y chromosome. The X and the Y are known as sex chromosomes.
Human chromosomes are large enough to be seen with a high-powered microscope, and the 23 pairs can be identified according to differences in their size, shape, and the way they pick up special laboratory dyes.
Abnormal Numbers of Chromosomes (Trisomies and Monosomies)
Genetic problems can happen for many reasons. Sometimes, a mistake occurs during cell division, causing an error in the chromosome number either before or shortly after conception. The developing embryo then grows from cells that have either too many chromosomes or too few.
In trisomy, for example, there are three copies of one particular chromosome instead of the normal two (one from each parent). Down syndrome, trisomy 18 (Edwards) syndrome, and trisomy 13 (Patau) syndrome are examples of this type of genetic problem.
Trisomy 18 syndrome affects 1 out of every 3,000 newborns. Children with this syndrome have a low birth weight and a small head, mouth, and jaw. Their hands typically form closed fists with abnormal finger positioning. They also might have malformations involving the hips and feet, heart and kidney problems, and intellectual disability (also called mental retardation). Only about 5% of these children live longer than 1 year.
Trisomy 13 syndrome affects 1 out of every 5,000 newborns. This syndrome causes cleft lip, flexed fingers with extra digits, hemangiomas (blood vessel malformations) of the face and neck, and many different structural abnormalities of the skull and face. It can also cause malformations of the ribs, heart, abdominal organs, and sex organs. Long-term survival is unlikely but possible.
In monosomy, another form of number error, one member of a chromosome pair is missing. There are too few chromosomes rather than too many.
Deletions, Translocations, and Inversions
Sometimes it's not the number of chromosomes that's the problem, but that chromosomes are incomplete or abnormally shaped. In both deletions and microdeletions, for example, some small part of a chromosome is missing. In a microdeletion, the missing part of a chromosome is usually so small that it amounts to a single gene or only a few genes.
Important genetic disorders caused by deletions and microdeletions include Wolf-Hirschhorn syndrome (affects chromosome 4), Cri-du-chat syndrome (chromosome 5), DiGeorge syndrome (chromosome 22), and Williams syndrome (chromosome 7).
In translocations (which affect 1 out of every 500 newborns), bits of chromosomes shift from one chromosome to another. Most translocations are "balanced," which means there is no net gain or loss of genetic material; some are "unbalanced," which means some genetic material is extra or missing.With inversions (which affect about 1 out of every 100 newborns), small parts of the DNA code seem to be snipped out and reinserted flipped over. Translocations may be either inherited from a parent or arise spontaneously in a child's own chromosomes.
Both balanced translocations and inversions typically cause no malformations or developmental problems in the kids who have them. However, adults with either translocations or inversions who wish to become parents may have an increased risk of miscarriage or chromosome abnormalities in their own children. Unbalanced translocations or inversions are associated with developmental and/or physical abnormalities.
Genetic Problems (cont.)
Genetic problems also occur when abnormalities affect the sex chromosomes. Normally, a child will be a male if he inherits one X chromosome from his mother and one Y chromosome from his father. A child will be a female if she inherits a double dose of X (one from each parent) and no Y.
Sometimes, however, children are born with only one sex chromosome (usually a single X) or with an extra X or Y. Turner syndrome is the name of the disorder affecting girls born with only one X chromosome, whereas boys with Klinefelter syndrome are born with XXY or XXXY.
Sometimes, too, a genetic problem is X-linked, meaning that it's associated with change in a gene carried by the X chromosome. Fragile X syndrome, which causes intellectual disability in boys, is one such disorder. Other diseases that are carried by genes on the X chromosome include hemophilia and Duchenne muscular dystrophy.
Females may be carriers of these diseases, but because they also inherit a normal X chromosome, the effects of the gene change on the affected X will be reduced. Males, on the other hand, only have one X chromosome and are almost always the ones who have the substantial effects of the X-linked disorder.
Some genetic problems are caused by a single gene that's present but altered in some way. Such changes in genes are called mutations. When there is a mutation in a gene, the number and appearance of the chromosomes is usually still entirely normal. To pinpoint the defective gene, scientists use sophisticated DNA screening techniques. Some examples of genetic illnesses caused by a single problem gene include: phenylketonuria (PKU), cystic fibrosis, sickle cell anemia, Tay-Sachs disease, and achondroplasia (a type of dwarfism).
Although experts originally believed that no more than 3% of all human diseases were caused by errors in a single gene, new research suggests that this may be an underestimate. Within the last few years, scientists have discovered genetic links to many different diseases that weren't originally thought of as genetic, including several different types of cancer.
Oncogenes (Cancer-Causing Genes)
Researchers have identified 20 to 30 cancer-susceptibility genes that greatly increase a person's odds of getting some form of malignancy. For example, a gene on chromosome number 9 may be linked to basal cell carcinoma, a common skin cancer. This gene, labeled PTC or patched, someday might be important in screening for this type of cancer. Another gene (HNPCC) that is carried by 1 out of every 300 Americans might greatly increase someone's risk for colon cancer. And the doubly dangerous gene BRCA-1 seems to give women an 85% chance of developing breast cancer as well as a 50% chance of ovarian tumors.
Other Genetically Linked Diseases
Altered genes may play a role in the development of many other devastating illnesses. Parkinson's disease, for example, may be linked to a gene on chromosome number 4, and multiple sclerosis may be linked to alterations in a gene on chromosome number 6. Alzheimer's disease, linked to a gene on chromosome 19, can already be diagnosed (in some cases) by screening for that altered gene, although such screening is viewed by many as controversial.
Although heart disease and diabetes appear to be related to simultaneous changes in many different genes, the first of these may already have been identified. According to the American Heart Association, this gene may be an artery-clogging gene that almost doubles the risk of fatty deposits blocking the coronary arteries. Having the gene may also triple someone's chances of getting adult-onset diabetes.
It's important to note that much of the newest information from genetic research has not yet been translated into useful screening tests. However, experts predict that this will soon change, and they estimate that the number of available genetic tests will increase dramatically in the years to come.