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Severe skeletal disorders resulting in intrauterine death or death up to the age of a few weeks - lethal types of skeletal disease


Types and clinical signs

These are severe diseases that result in intrauterine death or death up to the age of a few weeks. There are a number of types:

One is osteogenesis imperfecta type 2 (see: Osteogenesis imperfecta (defective mineralization of bone)) in which a defect in the collagen 1 molecule can be demonstrated in skin cells.

The second is thanatophoric dysplasia, a lethal form of skeletal disease featuring changes mainly in the structure of the long bones. The defect here is in the gene causing achondroplasia, which is FGFR3. This condition can be identified by its characteristic intrauterine X-ray and ultrasound signs.

The third is achondrogenesis, a lethal type of skeletal disease that manifests as a major disorder in the formation of the vertebrae with characteristic signs in the long bones. The gene is the one for the collagen 2 molecule, the same as in spondylo-epiphyseal dysplasia.

Other disorders - there are a number of other rare diseases in which the chest does not develop normally and there are marked breathing difficulties - the signs depend on the specific type and distribution of cases in the family.

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

Thanatophoric dysplasia - autosomal dominant. All cases are born to healthy parents and usually represent a new mutation.

Achondrogenesis - autosomal dominant. There are also cases with autosomal recessive inheritance.

Other disorders - the inheritance pattern depends on the specific type and the distribution of cases in the family.

Penetrance

Always full.

Associated features that can be demonstrated in tests performed during pregnancy

Thanatophoric dysplasia - the changes in the skeleton are prominent on ultrasound examination.

Achondrogenesis - the changes in the skeleton are prominent on ultrasound examination.

Other disorders - depends on the type.

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?

Thanatophoric dysplasia - a couple who has had an affected child in a previous pregnancy has a low risk of recurrence, as long as the diagnosis was correct. For more distant relatives or siblings of an affected individual, the risk of having a child with the same condition is less than 1%.

Achondrogenesis - a couple who has had an affected child in a previous pregnancy usually has a low risk of recurrence, but this risk can be up to 25% in some families. For more distant relatives or siblings of an affected individual, the risk of having a child with the same condition is less than 1%.

Other disorders - the risk of recurrence depends on the specific type of disease, the inheritance pattern, and the relationship to the patient, in accordance with the laws of inheritance.

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

Thanatophoric dysplasia - this is caused by a mutation in the same gene that causes achondroplasia. This gene is called FGFR3, and it is situated on the short arm of chromosome 4 (4p16.3). The mutation in thanatophoric dysplasia is different from the one responsible for achondroplasia - it is in a different base and it apparently causes more severe damage to the gene.

Achondrogenesis - genes for proteins forming type 2 collagen.

Other disorders - depends on the exact type.

Genetic testing

Thanatophoric dysplasia - the common mutations in the gene can be tested for directly. This test is practical but usually unnecessary. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal dominant diseases.

Achondrogenesis - this is a complex test that requires the testing of a number of genes. As noted, collagen 2 can be examined in skin cells (or 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.

Other disorders - depends on the specific type.

Carrier testing

Thanatophoric dysplasia - there is no carrier status. Carriers are affected.

Achondrogenesis - 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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