Lethal congenital contracture syndrome type 1

Lethal congenital contracture syndrome type 1 (LCCS1), also known as Multiple contracture syndrome, Finnish type, or Herva disease, is an extremely severe autosomal recessive disorder that is invariably fatal before birth. It is the most common lethal congenital contracture syndrome in Finland, where it was first described. LCCS1 is caused by mutations in the GLE1 gene, which encodes a protein essential for mRNA export from the nucleus, critically important for normal cellular function and development. The condition is characterized by total immobility of the fetus, detected as early as the second trimester of pregnancy. Key features include severe multiple joint contractures (arthrogryposis) affecting all limbs, marked fetal hydrops (abnormal fluid accumulation), micrognathia (small jaw), pulmonary hypoplasia (underdeveloped lungs), and pterygia (webbing of skin across joints). The anterior horn cells of the spinal cord show severe degeneration, indicating a profound motor neuron disease that underlies the lack of fetal movement. The brain may also show structural abnormalities. Affected pregnancies typically end in stillbirth or death immediately after birth, usually around 32 weeks of gestation. There are no treatments available for this condition. Genetic counseling is important for affected families, and carrier testing and prenatal diagnosis are possible in families where the causative mutations have been identified. The condition is enriched in the Finnish population due to a founder effect, though rare cases have been reported elsewhere.

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