Arthrogryposis-hyperkeratosis syndrome, lethal form

Arthrogryposis-hyperkeratosis syndrome, lethal form (also known as lethal arthrogryposis with anterior horn cell disease, or lethal congenital contracture syndrome with hyperkeratosis) is an extremely rare and fatal genetic disorder characterized by the combination of severe multiple joint contractures (arthrogryposis) and widespread thickening of the skin (hyperkeratosis). The condition is apparent at birth and affects the musculoskeletal system, skin, and nervous system. Affected neonates present with fixed flexion or extension contractures of multiple joints, markedly thickened and hardened skin, and evidence of anterior horn cell degeneration in the spinal cord, which contributes to the profound lack of fetal movement that leads to the joint contractures. Key clinical features include multiple congenital joint contractures involving both upper and lower limbs, diffuse ichthyosis-like hyperkeratosis of the skin, pulmonary hypoplasia (underdeveloped lungs), and facial dysmorphism. The condition is uniformly lethal, with affected infants typically dying in the neonatal period or being stillborn, primarily due to respiratory failure related to pulmonary hypoplasia and restricted chest wall movement. The underlying pathology involves degeneration of motor neurons in the anterior horns of the spinal cord, leading to severe fetal akinesia (lack of movement) during development. Given the lethal nature of this condition, there are no curative treatments available. Management is limited to supportive and palliative care. Genetic counseling is important for affected families, particularly regarding recurrence risk in future pregnancies. Prenatal diagnosis may be possible through ultrasound detection of decreased fetal movements and joint contractures, as well as through molecular genetic testing when the familial mutation is known.

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