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Diastrophic dysplasia

Clinical signs

Diastrophic dysplasia is a hereditary disease that mainly affects bone growth. Patients with this condition have scoliosis, a form of bilateral clubfoot, malformed pinnae with calcification of the cartilage, premature calcification of the costal cartilages, and cleft palate in some cases. Particularly characteristic is the 'hitchhiker' thumb due to deformity of the first metacarpal. Median adult height is 136 cm for males and 129 cm for females. Growth failure is progressive, partly because of an absent or weak pubertal growth spurt. The severity of the growth failure varies greatly, even among siblings. The final height does not correlate with midparental height, but does correlate well with height at age 1 year and 5 years. The relative weight is normal in childhood but increases before puberty, and more than a quarter of the adults are overweight. Head circumference is normal.

Inheritance pattern

Autosomal recessive.

When both parents are carriers, the child will only be affected if he or she inherits two abnormal genes - one from the mother and one from the father.

Penetrance

Penetrance is complete, but the severity of the growth failure varies greatly, even among affected siblings.

The disease is relatively frequent in Finland, where at least 160 affected patients have been reported. The carrier rate among individuals of Finnish ancestry with no family history is 1 in 25.

Associated features that can be demonstrated in tests performed during pregnancy

In a significant number of cases of classical Diastrophic dysplasia, abnormally short limbs and lateral projection of the thumbs can be detected on ultrasound examination at 16 weeks of gestation.

These abnormalities should be checked for in subsequent pregnancies after the birth of an affected child. DNA tests can confirm the diagnosis.

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?

  • For a couple who has already had an affected child, the risk is 25% in every subsequent pregnancy. When only one parent carries the abnormal gene, there is no risk that any of their offspring will have the disease; however, in such families there is a 50% chance that the infant will be a carrier, but he himself will be healthy, like the carrier parent.

  • The risk for more distant relatives depends on the degree of relationship between the relatives and the affected individuals, the ethnic groups of their partners, affected relatives of partners, consanguinity between the parents, if present, etc., and is established within genetic counseling.

Molecular genetic information

The gene for the disease:

SLC26A2

Location

Chromosome 5q32-33.

Genetic testing

Diagnostic testing

In Finland, a direct test can be performed to identify the mutation in the gene by testing for the common mutations. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal recessive diseases.

Carrier testing

  • The mutation C26+2T→C in the gene causing Diastrophic dysplasia is the one that is common in the Finnish population. The carrier rate varies between 1:20 in the healthy population of Finland and 1:100 in people from other ethnic origins.

  • In view of this, it is very important to ascertain the ethnic origins of the couple, and it is advisable to examine (carrier DNA testing) those couples where both partners are fully or even partially of Finnish origin.

See also: "Introduction to population DNA screening for autosomal recessive diseases such as Cystic fibrosis and others".

Carrier status testing in relatives of Diastrophic dysplasia patients

It is important that relatives of Diastrophic dysplasia patients clarify which mutations are present in the patient or parents in their family in order to ascertain that they are included in the battery of mutations routinely tested for - otherwise it will be necessary to expand the list of mutations tested for and/or examine the partner. This will be discussed in genetic counseling.

Fetal testing

Same as the diagnostic test.

Prenatal diagnosis can also be offered to each couple who has had an affected child. The best way is after identifying the mutations in the parents, but if these are not found, indirect linkage analysis can be performed. See: Indirect testing for genetic markers in a family that has one or more patients - when there is only one gene that can cause the disease - autosomal recessive diseases.

Preimplantation diagnosis (before the embryonic cells implant in the uterine wall) can also be offered for this disease - this is performed in special centers, and in special cases this can be considered within genetic counseling.
 
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