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Achondroplasia and hypochondroplasia
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Types
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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.
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Clinical signs
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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.
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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.
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Inheritance pattern
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Autosomal dominant.
80% of cases are born to healthy parents and represent a new mutation.
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Penetrance
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Full.
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Associated features that can be demonstrated in tests performed during pregnancy
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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.
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What is the risk of recurrence in a subsequent pregnancy?
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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.
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Molecular genetic information
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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).
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Genetic testing
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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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