Hypochondroplasia is an autosomal dominant mutation that results in short stature with disproportionately short arms and legs, but normal head size.
Description
Hypochondroplasia is a genetic form of short stature (dwarfism) due to a problem of bone growth and development. There are many causes for short stature including hormone imbalances, metabolic problems, and problems with bone growth. Hypochondroplasia is a common form of short stature and belongs to a class of dwarfism referred to as a chrondrodystrophy or skeletal dysplasia. All skeletal dysplasias are the result of a problem with bone formation or growth. There are over 100 different types of skeletal dysplasia.
Because the features of hypochondroplasia are so mild, the disorder may go undiagnosed. Although infants with hypochondroplasia may have low birth weight, hypochondroplasia is often not evident until between two and six years of age. In general, individuals with hypochondroplasia have disproportionate short stature with an average height of 51-57 in (130-145 cm). The degree of disproportion of the limbs to the body is variable.
Most individuals with hypochondroplasia have a normal IQ although some studies suggest that up to 10% of individuals with hypochondroplasia may have mild mental retardation or learning disabilities. This finding is controversial and more studies are currently underway to verify it. The motor development of infants with hypochondroplasia is normal. In rare cases, individuals with hypochondroplasia may experience neurologic problems due to spinal cord compression. The spinal
canal (which holds the spinal cord) can be smaller than normal in patients with hypochondroplasia.
Genetic profile
Hypochondroplasia is caused by a mutation, or change, in the fibroblast growth factor receptor 3 gene (FGFR3) located on the short arm of chromosome 4.
FGFR (fibroblast growth factor receptor) genes provide the instruction for the formation of a cell receptor. Every cell in the body has an outer layer called a cell membrane that serves as a filter. Substances are transported into and out of the cells by receptors located on the surface of the cell membrane. Every cell has hundreds of different types of receptors. The fibroblast growth factor receptors transport fibroblast growth factor into a cell. Fibroblast growth factors play a role in the normal growth and development of bones. When the receptors for fibroblast growth factor do not work properly, the cells do not receive enough fibroblast growth factor and the result is abnormal growth and development of bones.
Approximately 70% of hypochondroplasia is caused by mutations in the FGFR3 gene. The genes (or gene) responsible for the other 30% of cases are not known. The FGFR3 gene is comprised of 2,520 bases. In a normal (non-mutated) gene, base number 1620 codes for the amino acid asparagine. In most individuals with hypochondroplasia, a mutation changes the asparagine to the amino acid lysine. Two specific mutations account for approximately 70% of hypochondroplasia. These small substitutions change the amino acid that affects the protein structure. Both of these small substitutions cause a change in the fibroblast growth factor receptor (FGFR) that affects the function of this receptor.
The remaining 30% of patients diagnosed with hypochondroplasia do not show FGFR3 gene mutations. It has not yet been made clear if these patients have a different gene abnormality, an unrecognized FGFR3 gene mutation, or are normal variants. Another possibility is that these individuals actually have another disorder in which short stature results.
Mutations in the FGFR3 gene are inherited in an autosomal dominant manner. All people have two FGFR3 genes—one from their father and one from their mother. In an autosomal dominant disorder, only one gene has to have a mutation for a person to have the disorder. An individual with hypochondroplasia has a 50% chance of passing the changed (mutated) gene to his or her offspring. An individual can inherit a mutated gene from one parent or the mutation can occur for the first time in that person. Mutations that arise for the first time in affected individuals are called de novo mutations. The causes of mutations are not known.
Demographics
Because hypochondroplasia has such a wide range of variability, many people mildly affected with hypochondroplasia may never be diagnosed. Thus, the true incidence of hypochondroplasia is unknown. No studies have been done to determine the incidence of hypochondroplasia but it is assumed to be a relatively common disorder with an incidence equal to achondroplasia—one in 15,000 to one in 40,000.
Signs and symptoms
Individuals with hypochondroplasia have disproportionate short stature, limb abnormalities, and rhizomelic shortening of the limbs. Rhizomelic shortening of the limbs means that those segments of a limb closest to the body (the root of the limb) are more severely affected. In individuals with hypochondroplasia, the upper arms are shorter than the forearms and the upper leg (thigh) is shorter than the lower leg. In general, the upper limbs are more affected than the lower limbs in individuals with hypochondroplasia.
In addition to shortened limbs, individuals with hypochondroplasia have other characteristic limb differences such as a limited ability to rotate and extend their elbows. They can develop bowed legs, a finding that usually improves as they get older. Their hands and feet are short and broad, as are their fingers and toes. Their final adult height is usually 51-57 inches (130-145 cm). Their body habitus or shape is described as thick and stocky with a relatively long trunk. They may have lumbar lordosis (or curved back) giving them a swayed back appearance.
Diagnosis
The diagnosis of hypochondroplasia can be extremely difficult to make for a number of reasons. There is no one physical feature or x ray finding specific to hypochondroplasia and there is a great deal of overlap between individuals with hypochondroplasia and individuals
in the general population. Many of the physical findings of hypochondroplasia (short stature, bowed legs and a stocky build) are seen in individuals without hypochondroplasia. The same is true for the "typical" x ray findings. All of the possible x ray findings associated with hypochondroplasia can also be seen in unaffected individuals. There is no consensus on specific criteria necessary for diagnosis; however, it is usually made based on a combination of physical and x ray findings and is rarely made in infants.
DNA testing for hypochondroplasia is also complicated because testing will only detect 70% of the mutations that cause hypochondroplasia. DNA testing can be performed on blood samples from children or adults. If an individual is suspected of having hypochondroplasia and a mutation is detected, then the diagnosis is confirmed. If a mutation is not detected, then the diagnosis of hypochondroplasia has neither been confirmed nor ruled out. This individual could be one of the 30% of individuals with hypochondroplasia due to unknown mutations or he or she could have short stature due to another disorder.
Prenatal testing for hypochondroplasia can be performed using DNA technology. A sample of tissue from a fetus is obtained by either chorionic villus sampling (CVS) or by amniocentesis. Chorionic villus sampling is generally done between 10 and 12 weeks of pregnancy and amniocentesis is done between 16 and 18 weeks of pregnancy. Chorionic villus 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. DNA can be isolated from these skin cells. The fetal DNA is then tested to determine if it contains either of the two mutations responsible for achondroplasia.
Prenatal DNA testing for hypochondroplasia is not routinely performed in low-risk pregnancies. This type of testing is generally limited to high-risk pregnancies, such as when one parent has hypochondroplasia. This testing can also only be performed if the mutation causing hypochondroplasia in the parent has been identified.
Treatment and management
There is no cure for hypochondroplasia. Because of the wide range of variability of this condition there is no consensus on the medical management of individuals with hypochondroplasia either. Individuals with more severe cases are the only individuals likely to need medical management. The recommendations for the medical management of individuals with achondroplasia have been outlined by the American Academy of Pediatrics' Committee on Genetics and should be used as a guide for the management of individuals with severe hypochondroplasia. The potential medical complications of hypochondroplasia range from mild to moderate. Early intervention may avert some of the long-term consequences of these complications.
As children with hypochondroplasia develop, certain conditions and behaviors should be monitored. Their height, weight, and head circumference should be measured regularly and plotted on growth curves developed for children with achondroplasia as a guide. Neurologic problems such as lethargy, abnormal reflexes, or loss of muscle control should be seen by a neurologist to make sure that they are not experiencing compression of their spinal cord. Compression of the spinal cord is rare in individuals with hypochondroplasia but can occur because of the abnormal size of their spinal canal.
Children with hypochondroplasia should also be monitored for sleep apnea. Sleep apnea occurs when an individual stops breathing during sleep. This can occur for several reasons including obstruction of the throat by the tonsils and adenoids, spinal cord compression, and obesity. Individuals with hypochondroplasia are more prone to sleep apnea due to the changes in their spinal canal and foramen magnum. Treatment for sleep apnea depends on the cause of the sleep apnea. Obstructive sleep apnea is treated by surgically removing the tonsils and adenoids. Weight management may also play a role in the treatment of sleep apnea.
The bowed legs of children with hypochondroplasia usually improve as they get older and rarely require surgical intervention. Children with hypochondroplasia can often have an increased risk for middle ear infections which can be treated with oral antibiotics and the surgical placement of ear tubes.
Children with visible physical differences can have difficulties in school and socially. Support groups such as Little People of America can be a source of guidance on how to deal with these issues. It is important that children with hypochondroplasia not be limited in activities that pose no danger.
Two treatments have been used to try to increase the final adult height of individuals with hypochondroplasia–limb-lengthening and growth hormone therapy. There are risks and benefits to both treatments and as of 2001, they are still considered experimental.
Limb-lengthening involves surgically attaching external rods to the long bones in the arms and legs. These rods run parallel to the bone on the outside of the body. Over a period of 18-24 months, the tension on these rods is increased which results in the lengthening of the underlying bone. This procedure is long, costly, and
has potential complications such as pain, infections, and nerve problems. Limb-lengthening can increase overall height by 12-14 in (30.5-35.6 cm). This is an elective surgery and individuals must decide for themselves if it would be of benefit to them. The optimal age to perform this surgery is not known.
Growth hormone therapy has been used to treat some children with hypochondroplasia. Originally there was doubt about the effectiveness of this treatment because children with hypochondroplasia are not growth hormone deficient. Studies have shown mixed results. Some children with hypochondroplasia show improvement in their growth rate and others do not. It is too early to say how effective this treatment is because the children involved in this study are still growing and have not reached their final adult height.
Prognosis
The prognosis for most people with hypochondroplasia is very good. In general, they have minimal medical problems, normal IQ, and most achieve success and have a long life regardless of their stature. The most serious medical barriers to an excellent prognosis are the neurologic complications that very rarely arise in hypochondroplasia, including mild mental retardation and spinal cord compression.
Successful social adaptation plays an important role in the ultimate success and happiness of an individual with hypochondroplasia. It is very important that the career and life choices of individuals with achondroplasia not be limited by preconceived ideas about their abilities.
ORGANIZATIONS
Human Growth Foundation. 997 Glen Cove Ave., Glen Head, NY 11545. (800) 451-6434. Fax: (516) 671-4055. <http://www.hgf1@hgfound.org>.
Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. (806) 737-8186 or (888) LPA-2001. lpadatabase@juno.com. <http://www.lpaonline.org>.
MAGIC Foundation for Children's Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 362-4423. Fax: (708) 383-0899. mary@magicfoundation.org. <http://www.magicfoundation.org/ghd.html>.
