Osteogenesis imperfecta (defective mineralization of bone)
Types and clinical signs
In this group of diseases the bones are relatively translucent. They are deficient
in calcium and also lack other minerals. There are 4 main types:
Type 1 and type 4 are similar
- in both of these types, there is a tendency for fractures in the long bones. Usually
in childhood at any one time there can be 2 - 4 fractures on average, and it is
typical for the fractures to be caused by relatively light blows or traumas. There
are cases where there can be a very large number of fractures at the same time.
The fractures heal, usually without resulting disability. These children may have
slightly short stature, on average 10 cm below their genetic height or below the
average. In some cases there may also be involvement of the teeth, where the enamel
can be deficient. In some cases there is some loss of hearing over the years in
adult life. Type 1 differs from type 4 only in that the sclerae of the eyes are
blue. In these types, the bones strengthen over the years so that fractures do not
occur in adults. Treatment is by drugs known as bisphosphonates, which are administered
to patients with a tendency for multiple fractures. Diagnosis can be confirmed by
X-ray, which shows low mineralization of the vertebrae in a lateral view, and typical
signs of blood vessel footprints over the cranium in a lateral view.
Type 2 is a very severe type of OI.
Affected infants have multiple fractures in all bones from a young age in utero.
These infants usually die after birth.
Type 3 is a severe type with multiple
fractures in utero and after birth, although the infants do survive.
Because of the multiple fractures, deformities develop in the structure of the bone
because of distorted healing of the fractures, and the final stature is very short.
These children must be protected from even minor blows in order to allow them to
have periods without fractures. The bones strengthen over the years. Here too there
is involvement of the enamel of the teeth. Treatment with bisphosphonates is ineffective
in this type of osteogenesis imperfecta.
In all types of OI biochemical diagnosis can be undertaken by carrying out a skin
biopsy. Skin cells, known as fibroblasts, are cultured from the skin and these are
examined for the presence of different types of collagen. There are many types of
collagen, each of which is composed of a number of components. In the various types
of OI there is a defect or deficiency in one of the two components of collagen 1.
The test for this is currently performed abroad - skin cell cultures are sent for
testing. To diagnose the different types of OI, in most cases it is not necessary
to perform a biochemical collagen test unless there is a situation where a clinical
diagnosis must be made urgently to identify a child affected by OI, etc., or to
perform prenatal diagnosis if there is a question of type 3 inheritance. Concerning
all the sections below, the following must be remembered:
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
Types 1 and 4 - autosomal dominant.
Type 2 - usually autosomal dominant. All these patients are born
to healthy parents and usually represent a new mutation. However, a large percentage
of cases are a result of mosaicism
in one of the parents - i.e. one of the parents has a mutation in the gene for collagen
1 in only some cells of the body, mainly in the reproductive system, so that the
disease is not expressed in the parent but may be transmitted to offspring.
Type 3 - usually autosomal dominant, in which case it is the result
of a new mutation. In a significant percentage of cases, however, the disease is
autosomal recessive inheritance.
Types 1 and 4 are similar
- the expression is not always full.
Type 2 - full penetrance.
Type 3 - full penetrance.
Associated features that can be demonstrated in tests performed during pregnancy
Types 1 and 4 - these cannot
be detected by ultrasound examination in pregnancy. They can be diagnosed by a biochemical
test on amniotic fluid
or chorionic villi,
but because of the mild expression of this disease, the test is not usually performed
Type 2 - on Ultrasound examination a number of clear
signs can be seen, such as multiple fractures, hypomineralization of the cranium,
which appears almost completely transparent, a concertinaed femur due to multiple
fractures, rib fractures, etc.
Type 3 - on Ultrasound examination clear evidence of
fractures in utero can be seen. The cranial signs are similar to those in type 2.
It is possible to perform biochemical testing of collagen 1 in chorionic villus testing.
In all these cases it is important to refer the couple for genetic counseling, to which they should bring
all data, including the results of other tests performed during the pregnancy such
as alpha-fetoprotein, nuchal translucency, etc.
What is the risk of recurrence in a subsequent pregnancy?
Types 1 and 4 - if, as is
usually the case, one of the parents has either the severe or the mild type of OI,
the risk of recurrence is 50% in every pregnancy.
Type 2 - a couple that has
had an affected child in a previous pregnancy has a 6% risk of recurrence. For more
distant relatives or siblings of patients, the risk of having an affected child
is less than 1%.
Type 3 - this depends on
whether the inheritance is
autosomal dominant or autosomal recessive. The cases that are transmitted
autosomal dominant inheritance represent new mutations and the risk of recurrence
for a couple with an affected child in a previous pregnancy is usually low. In the
cases transmitted by autosomal recessive inheritance, a couple that has had an affected
child has a 25% risk of recurrence in each subsequent pregnancy. For more distant
relatives who are unaffected, or siblings of patients, the risk of having an affected
child is less than 1% for both inheritance patterns. For affected individuals, the
risk of having an affected child is usually about 50% for the type transmitted by
autosomal dominant inheritance. In the less common cases of autosomal recessive
inheritance, the risk for a patient to have an affected child is less than 1%, as
long as his/her partner is not a relative and has no affected individuals in his/her
For all types of OI, 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
Genes for proteins constituting the collagen 1 molecule.
This is a complex test that requires the testing of a number of genes. As noted,
collagen 1 can be examined in skin cells, or in chorionic villus or amniotic fluid
cells, directly using biochemical methods. See: Indirect testing for genetic markers
in a family with a number of patients in the family - when there are a number of
different genes that can each cause the disease - all of the genes having been located
/ identified / mapped - autosomal dominant disease. See also: Screening test for identifying defects (mutations) using various
methods such as SSCP - autosomal dominant diseases.
In families in whom the mutation in the gene responsible for the disease has been
found, other relatives may be tested both for signs of the disease itself and for
carrier status. There are no carrier tests for the healthy population.
As for diagnostic testing.