Lethal congenital contracture syndrome (LCCS) is an extremely rare autosomal recessive neuromuscular disorder characterized by multiple joint contractures and complete absence of voluntary movements in the fetus. The pathology manifests itself already in the early stages of intrauterine development and leads to intrauterine death of the fetus or death of the newborn in the first hours of life. The clinical picture includes pronounced contractures of the joints of the upper and lower extremities, microcephaly, underdevelopment of the lungs and other severe developmental defects.
History of the disease and interesting historical facts
The first description of this syndrome was presented by Finnish researchers in 1985. It is important to note that the disease has a pronounced ethnic specificity - most cases are registered among the Finnish population. "This syndrome is an example of the so-called 'founder effect', when a mutation arose in a common ancestor and was passed on through generations," note specialists from the University of Helsinki. Of particular interest is the fact that the disease is almost never found outside the Scandinavian region.
Epidemiology
The incidence of the syndrome is estimated to be extremely low - less than 1 case per million newborns in the general population. However, among Finns, the frequency of the mutation carrier is approximately 1:70, which significantly increases the risk of developing the disease in consanguineous marriages. According to statistics, the disease ends in intrauterine fetal death in 98% cases. Between 1985 and 2020, only 36 confirmed cases of the disease were documented.
Genetic predisposition to this disease
The main gene responsible for the development of LCCS is GLE1, located on chromosome 9q34. Mutations in this gene lead to disruption of the GLE1 protein, which plays a key role in the process of nuclear export of mRNA. The main types of mutations include:
- Homozygous missense mutations
- Nonsense mutations
- Splicing mutations
Pentala et al. (2008) found that the Finnish variation c.1765C>T in the GLE1 gene is the cause of more than 90% cases of the disease.
Risk factors for the development of this disease
The main risk factors include:
- Consanguineous marriages among the Finnish diaspora
- Carrying a mutant allele of the GLE1 gene
- Living in isolated population groups
It is important to note that external environmental factors do not influence the development of this disease, since the pathogenesis is completely determined by genetic factors.
Diagnosis of this disease
Key diagnostic criteria include:
- Lack of fetal motor activity
- Multiple joint contractures
- Microcephaly
- Pulmonary hypoplasia
Laboratory diagnostics are based on molecular genetic analysis. Radiological examination shows a characteristic picture: "Ultrasound examination reveals fixed positions of the limbs and the absence of normal fetal movements starting from the 13th-14th week of pregnancy," experts point out.
Treatment
Due to the lethal outcome of the disease, therapeutic options are limited. Genetic counseling remains the main method of prevention. If the disease is suspected, it is recommended to:
- Prenatal diagnosis in families with known cases of the disease
- Medical and genetic counseling
- Early termination of pregnancy when diagnosis is confirmed
List of drugs used to treat this disease
Due to the lack of effective treatment, this disease has no specific drug therapy. Symptomatic treatment is not used due to the unfavorable prognosis.
Disease monitoring
Control stages include regular ultrasound examination of the fetus from the 12th week of pregnancy. The prognosis is extremely unfavorable - survival is less than 2%. Complications include:
- Intrauterine fetal death
- Pulmonary hypoplasia
- Multiple organ dysfunctions
Age-related features of the disease
The disease manifests itself exclusively in the perinatal period. The disease does not occur in adult patients. All registered cases were diagnosed during pregnancy or immediately after birth.
Questions and Answers
- What are the first signs of the disease? The first alarming signal is the absence of fetal motor activity, starting from the 12th-13th week of pregnancy.
- Can this disease be cured? Unfortunately, this disease is incurable and always ends in death.
- What is the likelihood of the disease recurring in a family? If one affected child is present, the risk of recurrence is 25% for each subsequent pregnancy.
Advice from Dr. Oleg Korzhikov
"Patients often ask me how this disease can be prevented. The answer is simple - timely genetic counseling and prenatal diagnostics. Here are the main recommendations:
- When planning a pregnancy, be sure to undergo genetic testing.
- If there have been cases of the disease in the family, undergo regular ultrasound examinations from the 12th week of pregnancy.
- If you have any doubts, please contact a medical geneticist.
Remember that early diagnosis can save future children from a difficult fate,” advises Dr. Korzhikov.
