Hereditary sensory and autonomic neuropathy type 4

Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also known as congenital insensitivity to pain with anhidrosis (CIPA), is a rare autosomal recessive disorder caused by mutations in the NTRK1 gene (also called TRKA), which encodes the neurotrophic tyrosine kinase receptor type 1. This receptor is essential for the development and survival of sympathetic postganglionic neurons and nociceptive sensory neurons. The condition is characterized by the absence of pain sensation (insensitivity to pain), inability to sweat (anhidrosis), and intellectual disability of variable severity. Because the autonomic nervous system is affected, patients cannot regulate body temperature through sweating, leading to recurrent episodes of unexplained high fevers (hyperthermia), which can be life-threatening, particularly in infancy and early childhood. The insensitivity to pain results in repeated injuries, fractures, burns, and self-mutilating behaviors such as biting of the tongue, lips, and fingers. Patients frequently develop skin ulcers, joint deformities (Charcot joints), and osteomyelitis due to unrecognized trauma and infections. Corneal scarring from unnoticed eye injuries may also occur. The peripheral nervous system is primarily affected, with loss of small myelinated and unmyelinated nerve fibers. Thick skin and hyperkeratosis of the palms and soles are common findings. There is currently no cure or disease-modifying treatment for HSAN4. Management is supportive and multidisciplinary, focusing on prevention and early treatment of injuries, infections, and overheating. Temperature regulation through environmental control is critical. Dental care is important to prevent self-inflicted oral injuries. Orthopedic monitoring is necessary to manage fractures and joint complications. Families and caregivers must be educated about the risks associated with the inability to perceive pain and the importance of vigilant supervision, especially during childhood.

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