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Achondroplasia and hypochondroplasia


Types

Achondroplasia - a relatively common type of very short stature due to a defect in growth of the long bones. Hypochondroplasia - in general this is a milder type of achondroplasia with relatively mild signs.

Clinical signs

Achondroplasia is well known to the public - affected individuals have marked shortening of the limbs, while the trunk is almost completely normal. Because of this, when they are sitting down they do not appear to be so short - only when they are standing can the extreme shortening of their height be seen (approximately 120 cm). There is a less severe variation of this disease known as hypochondroplasia. Patients with hypochondroplasia have a larger than normal head circumference due to disproportionate growth of the cranial bones, but have no mental problems.

The diagnosis can be confirmed by performing a skeletal X-ray.

In childhood the limbs are more flexible than usual - this is the reason why some affected children used to act as "rubber children" in circuses. They have a tendency to have recurrent ear infections. In adult life, back pain, mainly during walking, may occur. Sometimes the legs are bowed; they can be surgically straightened. Nowadays there are also limb-extending operations, with relatively good results.

A precise diagnosis is important, and a diagnosis made in the past may not always have been made according to today's standards and methods and is not always accurate by today's standards.

Because of this, the diagnosis must always be confirmed in a genetic institute by examining the patient, or at least by looking at the clinical picture, photographs, X-rays and other data.

Even though we know a lot about the inheritance patterns, the risk of recurrence, the mechanism of the manifestations of the disease, etc., most of these diseases have exceptions, and each case/family must be examined individually in a genetic institute.

Inheritance pattern

Autosomal dominant. 80% of cases are born to healthy parents and represent a new mutation.

Penetrance

Full.

Associated features that can be demonstrated in tests performed during pregnancy

It is difficult to diagnose this type of bone disease during pregnancy as the stunted growth, assessed by measuring the length of the fetus's femur or the increased head circumference, becomes significant only after weeks 30 - 32.

If in week 24 of pregnancy, when the ultrasound system scan is performed, the head circumference is found to be greater and the length of the femur less than the number of the weeks of gestation, and the difference between them is one and a half weeks or more, then this requires further investigation to ensure that the difference does not increase, as if it does, this could indicate a problem of bone development. The vast majority of the cases where a difference has been found are not associated with significant medical problems in the fetus, although such a combination may indicate that the fetus has achondroplasia. In this disorder, the shortening of the femur and the enlargement of the head circumference become obvious only in the late stages of pregnancy (week 34 and later), which is relatively late to undertake investigations and to act in accordance with the results.

What is the risk of recurrence in a subsequent pregnancy?

Achondroplasia: if only one of the parents has achondroplasia, the risk of recurrence is 50% in every subsequent pregnancy. However, if both parents have achondroplasia, the risk for the offspring in future pregnancies is as follows:

50% will have achondroplasia like the parents.

25% will be normal

25% will suffer from a lethal type of severe skeletal disease that is a result of the combination of two abnormal genes, one from each parent.

Healthy parents who have had a child with achondroplasia have a risk of recurrence in future pregnancies of less than 1:1000. The same applies for more distant relatives.

The risk for more distant relatives depends on the number of affected individuals in the family, the degree of relationship between the relatives and the affected individuals, consanguinity between the parents, if present, etc. This risk is established within genetic counseling.

Molecular genetic information

The gene for the disease

FGFR3. This gene apparently has a characteristic mutation in 97% of cases of achondroplasia. There is another mutation that is responsible for approximately 70% of the cases of hypochondroplasia. Because most patients represent a new mutation, i.e. their parents are healthy, the conclusion is that these mutations occur at "hotspots" in the gene that are predisposed to mutate. It can further be deduced that a mutation causing achondroplasia affects the gene at a point more critical for the protein. There are also other recognized mutations in the gene that cause a more severe, lethal disease known as thanatophoric dysplasia.

Location

The short arm of chromosome 4 (4p16.3).

Genetic testing

Diagnostic testing

A direct test for finding the common mutation that is characteristic in 97% of cases of achondroplasia. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal dominant diseases.

Rare cases of achondroplasia or hypochondroplasia have been found in which mutations in other regions of the FGFR3 gene are present, but these are more difficult to test for and therefore such tests are usually not carried out.

Carrier testing

re is no carrier status - carriers are affected.

Fetal testing

As for diagnostic testing. Achondroplasia can be identified in the early weeks of pregnancy only by testing for the gene mutation in amniotic fluid cells. This test can be considered as soon as the combination of short femur and increased head circumference has been found, although in approximately 99% of cases the result is normal. Alternatively, the test can be deferred and the fetus monitored by ultrasound - only if the differences in the growth index and the deviations from the norm increase is amniocentesis performed for molecular-genetic testing.
 
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