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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 institute.

Inheritance pattern

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 transmitted by autosomal recessive inheritance.

Penetrance

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 during pregnancy.

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 by 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 family.

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.

Genetic testing

Diagnostic testing

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.

Carrier testing

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.

Fetal testing

As for diagnostic testing.
 
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