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Pseudoachondroplasia

“Pseudo” means “false.” Thereby, this disorder is one that resembles, but is clinically distinct from, achondroplasia.The incidence of pseudoachondroplasia is estimated at 1 in 30,000, however the birth prevalence is not yet known (2).

 
How Pseudoachondroplasia Is Inherited

Pseudoachondroplasia can either be inherited in an autosomal dominant inheritance pattern (1). Parental germinal mosaicism is often found, which explains why many affected children have unaffected parents. Mosaicism causes the condition to behave in an autosomal recessive fashion.

 
Causes of Pseudoachondroplasia

Pseudoachondroplasia results from a mutation in the gene coding for cartilage oligomeric matrix protein (COMP) (1). COMP is a normal constituent of the extra-cellular matrix in cartilage, ligaments, and tendons. Defective COMP results in the accumulation of proteoglycans within cartilage cells.

 
Physical Characteristics

Both the epiphyses and metaphyses are affected in pseudoachondroplasia. Clinically, it is recognized as a form of short-limbed dwarfism, with body proportions similar to those of achondroplasia, yet with normal-sized heads and facial features.

The postnatal onset of short-limbed growth deficiency will not become apparent until between 18 and 24 months of age. Pseudoachondroplasia manifests itself over time. Ultimately, adult stature is between
82 and 130 cm.

Face & Skull
  • Normal head size and facial features
Trunk, Chest, & Spine:
Arms & Legs:
What are the X-ray characteristics?

The radiographic features of pseudoachondroplastic patients include short and broad long bones with flaring of the metaphyses. Epiphyseal ossification is delayed. The epiphyses appear irregular and fragmented. The hips and knees are primarily affected. Due to their dysplastic nature, the carpals ossify late.

In the pelvis, the acetabulum (hip socket) is shallow and accentuates hip dysplasia. The triradiate cartilage is also late to mature and ossify. Arthrograms are helpful in identifying joint surfaces and planning surgery for angular deformities. The capital femoral epiphyses are small and irregular in children; in adults, there is marked dysplasia of the femoral head. The femoral head is flattened and fragmented. This leads to hip joint incongruity and exacerbates the effects of hip subluxation.

X-rays of the spine show platyspondyly and flame-shaped anterior projections. The interpedicular distance does not progressively decrease in the lumbar spine. In the neck, lateral X-rays of the cervical spine may reveal odontoid hypoplasia. The vertebrae will at first seem deformed, but the irregularities generally disappear by adolescence. Flexion-extension radiographs should be obtained to rule out atlantoaxial instability. MRI scans of the cervical spine (static, flexion/extension views and CSF flow studies) are helpful in identifying any compression of the spinal cord.

 
Making the Diagnosis

The average length at birth is 49 cm, which is within the normal range. Pseudoachondroplasia is therefore not readily recognized at birth. But, lack of longitudinal growth manifests itself in the first 2 years of life (below 5th percentile on standard growth charts). By this point the abnormal gait is present and measurements suggest pseudoachondroplasia. Diagnosis is typically made between 1 and 4 years of age and is based on clinical examination and characteristic X-ray appearances. Prenatal testing is now available by direct DNA analysis. The test detects the abnormal COMP gene by mutation scanning. Prenatal diagnosis may be appropriate during pregnancy in women with pseudoachondroplasia. It must be stressed that the majority of cases are spontaneous mutations.

 
Musculoskeletal Problems
Spine

The cervical spine should be monitored for the presence of atlantoaxial instability. Lateral flexion-extension x-rays of the cervical spine is recommended, if a pre-existing abnormality such as hypoplastic odontoid is present. Posterior cervical decompression and fusion should be performed if the instability exceeds 8 mm or neurological symptoms (cervical myelopathy) occur. Scoliosis should be looked for and is managed similar to idiopathic curves. Lateral c-spine x-rays should be routinely obtained in all children with pseudoachondroplasia undergoing surgery for any reason.

Lower Limbs

Angular deformities around the knee are corrected using osteotomies. Careful pre-operative planning is essential to restore normal mechanical axes in sagittal and coronal planes (down the middle of the body). Since the epiphyses are distorted, intraoperative arthrography may be necessary to properly visualize the joint surfaces. The effect of ligamentous laxity on alignment should be ascertained as part of the pre-operative planning. Recurrence of deformity is common and several procedures may be necessary to achieve lower extremity skeletal alignment at maturity. Up to 50% of adults will require joint replacement surgery for early onset degenerative arthritis. Hip/ knee replacement surgery in patients with skeletal dysplasia is a technically demanding exercise due to abnormal skeletal size and shape. Subluxation of the hips is a combination of femoral deformity, failure of epiphyseal ossification, acetabular dysplasia (failure of hip socket development), and joint contractures (flexion and adduction). A combination of femoral and pelvic osteotomies may be necessary. Since the femoral head is flattened, a valgus proximal femoral osteotomy is preferred to a varus procedure. If the hip joint is not congruous, acetabular augmentation procedures (Chiari osteotomy or Shelf procedure) are used to salvage the hip.

 
Problems Elsewhere in Body

Few problems, if any, occur and good general health can be expected.

 
What to Watch For

Pseudoachondroplastic patients should look out for neurological symptoms such as weakness of the lower limbs, incontinence, pain in the legs, reduced endurance, and tingling/ numbness of the legs. These symptoms may indicate compression of the spinal cord in the neck.

Lower extremity pain of gradual onset or changes in walking (waddling/ limping) may also result from altered alignment of the legs. In later life, pain in the hips and knees is usually the result of degenerative arthritis.

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.

 
References
  1. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
  2. Posey, Karen L. Hayes, Elizabeth. Haynes, Richard. Hecht, Jacqueline T. 2004. Role of TSP-5/COMP in Pseudoachondroplasia. The International Journal of Biochemistry and Cell Biology. 36: 1005-1012.
  3. Scott, Charles I. Dwarfism. Clinical Symposium, 1988; 40(1);11-14.
  4. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.

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.

Genetic Problems

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.)

Sex Chromosomes

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.

Gene Mutations

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.

Reviewed by: Louis E. Bartoshesky, MD, MPH
Date reviewed: June 2010
Originally reviewed by: Linda Nicholson, MS, MC