Hypochondrogenesis

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Hypochondrogenesis

Definition

Hypochondrogenesis is a lethal genetic skeletal dysplasia caused by a mutation in the COL2A1 gene . This condition is characterized by a severe limb and trunk shortening with a disproportionately large head. Infants with this disorder usually die soon after birth of respiratory failure.

Description

Hypochondrogenesis is a rare form of skeletal dysplasia (or dwarfing syndrome) caused by mutations in the COL2A1 gene. The COL2A1 gene provides the instruction for the formation of collagen II, which is a major building block of cartilage, a major component of bone. Because of these mutations, infants with hypochondrogenesis have defects in their bone formation that cause them to have severely shortened limbs (arms and legs) and a small chest with short ribs. As infants with hypochondrogenesis have small chests and abnormal ribs, their lungs are underdeveloped, which leads to respiratory (breathing) difficulties at birth. In addition, the vertebrae or spinal bones in the neck and part of the sacrum (pelvis) do not harden, or ossify, properly. The face of an infant with hypochondrogenesis is flat and ovalshaped, with widely spaced eyes, a small chin, and, in some cases, an opening in the roof of the mouth called a cleft palate. Rarely, fetuses with hypochondrogenesis can develop a condition called hydrops fetalis in which excess fluid builds up in the abdomen and body before birth. One report has suggested that some infants with hypochondrogenesis may also have heart defects.

There are many causes for impaired growth or dwarfism, including hormone imbalances, metabolic problems, and problems with bone growth. Hypochondrogenesis belongs to a class of dwarfism referred to as a chrondrodystrophy or skeletal dysplasia and results from a problem with bone growth. All skeletal dysplasias are the result of a problem with bone formation or growth. There are more than 100 different types of skeletal dysplasias. Hypochondrogenesis is also sometimes referred to as a collagenopathy because the specific abnormality in hypochondrogenesis is a problem in the formation of collagen.

The collagenopathies are a group of disorders that affect connective tissue, the tissue that supports the body's joints and organs. Collagenopathies, as a group, are caused by defects in either type II or type IX collagen. Hypochondrogenesis is caused by a defect in the formation of type II collagen. Collagen is a complex molecule that provides structure, strength, and elasticity to connective tissue.

There are other skeletal dysplasias that have features very similar to hypochondrogenesis. Consequently, hypochondrogenesis is considered to belong to a spectrum, or continuum, of skeletal dysplasias that vary in severity. This spectrum includes anchondrogenesis type II at the severe end and spondyloepiphyseal dysplasia congenita (SEDc) at the milder end. Infants withachondrogenesis type II also have the same spinal changes as seen in hypochondrogenesis, but the condition is generally more severe and is invariably lethal. Infants with spondyloepiphyseal dysplasia congenita have the same findings as an infant with hypochondrogenesis, but their condition tends to be milder. Infants with SEDc can survive, but generally have many complications due to their severe skeletal problems.

Genetic profile

Hypochondrogenesis is caused by a mutation, or change, in the COL2A1 gene located on the long arm of chromosome 12 (12q13.11-q13.2). Hypochondrogenesis has autosomal dominant inheritance ; however, there is usually no prior history of the condition in the family. In an autosomal dominant disorder, only one gene has to have a mutation for the person to have the disorder. Every individual has two COL2A1 genes: one from their father and one from their mother. However, all infants with hypochondrogenesis are born to average-stature parents. The infant's hypochondrogenesis is the result of a de novo, or new, mutation. The occurrence of hypochondrogenesis is almost always due to a de novo mutation. This de novo mutation typically occurs in one of the type II collagen gene from an average-sized parent. No one knows the cause of de novo mutations. Because infants with hypochondrogenesis do not survive to reproductive age, there is no risk of their passing on this mutated gene. Because most de novo mutations occur sporadically, the recurrence risk is small.

Several different tyes of mutations in the COL2A1 gene are responsible for hypochondrogenesis. These mutations may include small deletions, or missing pieces, of the COL2A1 gene, missense mutations that lead to the substitution of one amino acid for another, and other changes that leave out important parts of the protein. All of these changes interfere with the formation of mature triple-stranded type II collagen molecules, which results in hypochondrogenesis by affecting tissues that are rich in type II collagen.

Demographics

Hypochondrogenesis occurs equally in males and females. There is no exact prevalence data for hypochondrogenesis, but collectively, collagenopathies are found in about one in 10,000 people. Because achondrogenesis and hypochondrogenesis can be difficult to tell apart, the incidence data reflect the incidence of both disorders. Hypochondrogenesis and achondrogenesis type II together occur in approximately one in 40,000–60,000 births. With the advent of DNA testing and the ability to make a more definitive diagnosis, it should soon be possible to have an incidence figure for hypochondrogenesis alone.

Signs and symptoms

Physical findings

Type II collagen is a major building block of the spine, cartilage, and the vitreous protein in the eye. Defects in this collagen and the cartilage that it forms cause infants with hypochondrogenesis to have micro-melia (extremely short limbs), a short trunk (or body) with shortened ribs, and a head that appears large. Their faces have a characteristic appearance with a flat ovalshaped face, wide-set eyes (hypertelorism), small chin, and, occasionally, an infant with hypochondrogenesis will also have a cleft palate or opening on the roof of the mouth. They may also have heart defects.

X-ray findings

Infants with hypochondrogenesis also have very characteristic or unique x-ray findings. In order to understand what these findings are, it is important to know a little bit about how x rays work. X rays are a form of energy that is able to pass through some objects and not others. When x rays pass through a body, more x rays are absorbed by the denser parts (such as teeth and bone) than by softer tissues (such as muscles and digestive organs). X rays create a negative image on the x-ray film. Soft tissues, such as blood, muscles, and digestive organs, appear darker or do not appear at all because the x rays pass directly through the tissues onto the film. Bones and teeth appear brighter because fewer x rays penetrate these structures and reach the film during exposure.

When looking at the x ray of an infant with hypochondrogenesis, it is easy to see abnormalities with their bones. Because their vertebra are underdeveloped and have not hardened, they are quite difficult to see on an x ray; they should be easy to see. Those vertebrae that can be seen are usually abnormally shaped. The ribs appear very thin. In addition to vertebral and rib abnormalities, the bones of the pelvis and in particular the hip socket are abnormally shaped. Hip sockets are usually curved, but in hypochondrogenesis these bones are flattened and smaller than usual.

While the findings in hypochondrogenesis are distinctly abnormal, it is important to distinguish these findings from those seen in achondrogenesis type II and those seen in spondyloepiphyseal dysplasia congenita. The x-ray findings of achondrogenesis type II are more severe than those of hypochondrogenesis, and the findings of SEDc are generally milder than those seen in hypochondrogenesis.

Diagnosis

The diagnosis of hypochondrogenesis can be made prenatally by ultrasound, or shortly after birth. A number of different tests, including x rays, biopsies, and DNA testing, is used to confirm the diagnosis. Consultation with experts in the field of skeletal dysplasias may also be helpful.

The diagnosis of hypochondrogenesis can also be made prenatally (during pregnancy), either by ultrasound (sonogram) or by prenatal DNA testing. Sonograms use sound waves to provide an image of a fetus. The structural abnormalities of hypochondrogenesis, including severely shortened limbs, shortened truck with abnormal ribs, and unossified vertebral bones, can be observed during the second trimester of pregnancy. Because of overlapping features with other skeletal dysplasias, it can be very difficult to definitively diagnose hypochondrogenesis by sonogram. DNA testing can have a role in clarifying ambiguous ultrasound findings.

The neonatal diagnosis in infants is made by physical examination shortly after birth. Severe shortening of the limbs, a small trunk, abnormal facial features, and a cleft palate are often seen and raise the suspicion of the diagnosis of hypochondrogenesis. The diagnosis cannot be made by physical examination alone as hypochondrogenesis and numerous other skeletal dysplasias look very similar.

X rays are often helpful in establishing the diagnosis of hypochondrogenesis. X-ray findings include underossified vertebra, abnormally thin ribs, and abnormally shaped hip bones. The x-ray findings of achondrogenesis type II are generally more severe, and the findings of SEDc are less severe.

Biopsies are the collection of tissue that can then be examined under a microscope. In hypochondrogenesis, a skin biopsy may be done to obtain skin cells for DNA analysis. Biopsies of the connective tissue may also be collected so that the collagen and other connective tissues can be examined microscopically.

DNA testing can also be performed on a blood or skin sample. The presence of a mutation in the COL2A1 gene would confirm the diagnosis of hypochondrogenesis. As of 2005, it is estimated that DNA testing will detect greater that 90% of mutations in the COL2A1 gene. Because scientists have not yet found all of the mutations in this gene, the absence of a detectable mutation does not completely rule out the diagnosis. The COL2A1 gene is a large gene with many possible mutations. Because of this, the results of DNA testing may take 4–6 weeks.

Prenatal testing can also be done using DNA technology. A sample of tissue from a fetus is obtained by either chorionic villi sampling (CVS) or by amniocentesis . Chorionic villi sampling is generally done between 10 and 12 weeks of pregnancy, and amniocentesis is done between 14 and 18 weeks of pregnancy. Chorionic villi sampling involves removing a small amount of tissue from the developing placenta. The tissue in the placenta contains the same DNA as the fetus. Amniocentesis involves removing a small amount of fluid from around the fetus. This fluid contains some fetal skin cells from which DNA can be isolated. The fetal DNA is then tested to determine whether there are any mutations in the COL2A1 gene. This test is not done in low-risk couples and may only be available if a specific mutation has already been characterized in a family.

Because hypochondrogenesis is such a rare disorder and has a great deal of overlap with other skeletal dysplasia, it can be very difficult to diagnose definitively. It can be helpful to consult with skeletal dysplasia experts who may suggest further specialized testing to help clarify the diagnosis.

Treatment and management

There is no cure or treatment for hypochondrogenesis. If the diagnosis is made prior to birth, the parents may wish to meet with a neonatalogist to discuss management of the birth.

If hypochondrogenesis is detected during a pregnancy, patients have the option to terminate the pregnancy based upon the lethality of this condition. This is a very personal decision and should be made following serious counseling about the nature and outcome of this diagnosis.

Once the diagnosis has been firmly established, there is no need for resuscitation and ventilatory support for the infant given the established lethality of the conditions. Infants should be provided with basic supportive care, including warmth, nourishment and comfort.

If the diagnosis has not been confirmed prior to birth, resuscitation and ventilatory (breathing) support are appropriate to allow time for a thorough diagnostic evaluation. X rays should be performed, and skin and connective and blood tissue should be collected.

The diagnosis of hypochondrogenesis is shocking for families. The bleak prognosis and lack of treatment can be devastating. Families should be reassured that there is nothing that they did or did not do that could have prevented the outcome. The family needs time to process the information about the diagnosis. The family should also be provided emotional support. The neonatal staff can aid in collecting reminders of the baby, including footprints, photographs, and locks of hair, that can help the family as they deal with the crisis. In addition to providing emotional support, it is equally important to make sure that the parents understand the genetic diagnosis and its implications for future pregnancies. They need to understand the sporadic nature of this diagnosis and that it is unlikely to recur in a future pregnancy. Because the interpretation of some of the test results are complicated, it is best that the family be referred to a genetics center for counseling following the diagnosis of hypochondrogenesis.

Prognosis

The prognosis for an infant with hypochondrogenesis is bleak. Some infants are stillborn, and those that are live born die shortly after birth due to respiratory failure. Survival can range from a few days to a few weeks. If an infant with suspected hypochondrogenesis does survive the newborn period, it is assumed that they actually have spondyloepiphyseal dysplasia congenita. In cases where the diagnosis is ambiguous, DNA testing can help to confirm the diagnosis and may allow for a more accurate prognosis.