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Last updated: 4/23/2025
Years published: 2025
NORD gratefully acknowledges Ella Gaul, Editorial Intern from the University of Notre Dame, and Alasdair Parker, MBBS, MRCPCH, MD, MA, PG Cert. Ed. Consultant Pediatric Neurologist Associate Lecturer, University of Cambridge, for assistance in the preparation of this report.
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Summary
Congenital insensitivity to pain type 8 (HSAN 8) is a hereditary sensory neuropathy characterized by congenital insensitivity to pain (CIP).1
All forms of congenital insensitivity to pain (CIP) affect nociceptors which are the special nerve cells that sense pain. In people with CIP, these nerve cells either don’t work properly or don’t develop the way they should. As a result, pain signals don’t reach the brain and the person doesn’t feel pain even when injured.1,2 Cognitive development is normal.3,4 Symptoms appear in infancy due to impaired sensory nerve development in the first trimester of the mother’s pregnancy and persist throughout a person’s lifetime.5
Some people with this condition seem to have a weaker immune response specifically to Staphylococcus aureus (a common type of bacteria). Because of this, they may get repeated skin infections, abscesses (pockets of pus), or infections in the bones (osteomyelitis).1,2
HSAN 8 is caused by changes (variants) in two copies of the PRDM12 gene which typically plays a role in the development of nociceptors.6 HSAN 8 is inherited in an autosomal recessive pattern.5
Symptom management and multidisciplinary treatment are very important as there is no curative therapy for this condition.2 However, individuals can learn to manage their condition as they age, developing the ability to properly monitor their bodies for injury.2 Life expectancy is reported to be normal if the symptoms are properly managed. Individuals may need care from a wide range of medical professionals including ophthalmologists, orthopedic surgeons, dentists, geneticists and primary care physicians.
NORD also has an overview report on Congenital Insensitivity to Pain (CIP).
Symptoms typically begin in infancy. The following signs and symptoms have been reported in people with this syndrome.1-5,7-9
HSAN 8 is caused by changes (variants) in the PRDM12 gene.10,11 When the PRDM12 gene does not work properly, there are problems with the development of nociceptors beginning during fetal development.
Nociceptors are special nerve endings that sense pain. They’re part of the peripheral nervous system which connects the brain and spinal cord to the rest of the body. These nerve endings are found throughout the body in the skin, muscles, joints and even internal organs. Their function is to detect harmful stimuli like extreme heat or cold, pressure, or certain chemicals.
When nociceptors sense something potentially dangerous, they send signals through the nerves to the brain. The brain then interprets those signals as pain. Pain is the body’s way of warning the body that something might be wrong, so the body can respond. In people who can’t feel pain properly, these warning signals don’t reach the brain the way they should. As a result, they may not notice injuries right away which makes them more likely to get hurt without realizing it, either by accident or without knowing how serious the injury is.2
Inheritance
HSAN 8 is inherited in an autosomal recessive pattern.11 Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
HSAN 8 is an extremely rare condition described in 5-20 families 3,5 and the incidence and prevalence are not known. It is estimated to occur in less than 1 in 1,000,000 people in the general population.
HSAN 8 should be considered in any child with a history of diminished or absent responses to painful stimuli.2 People with HSAN 8 often have unexplained oral injuries as well as unexplained burns, bruises and fractures. On physical examination, an excessive number of injuries may be observed which can initially raise concerns for neglect or abuse.2
To evaluate for absent pain perception, a physician applies a painful stimulus that would typically provoke an immediate withdrawal response or expression of discomfort in individuals with normal nociception.2 A common method is the pressure test, in which a pen is pressed onto the nail bed with 5–10 kg of force.1 People with congenital insensitivity to pain will not have a withdrawal response, indicating a lack of pain sensation.1 Beyond pain perception, the assessment of the peripheral and central nervous system is typically unremarkable with preserved touch, vibration and position sense, as well as normal motor function and deep tendon reflexes.7
Definitive diagnosis can be supported by a skin biopsy which may reveal a loss of bare nerve endings in the epidermis, or a nerve biopsy which can show a deficiency of small myelinated nerve fibers characteristic of this condition.1 However, these procedures are rarely performed in current clinical practice.1 As with most genetic conditions, confirmation of this specific HSAN subtype requires DNA testing, such as targeted gene sequencing, multigene panel testing, or comprehensive genomic sequencing.1,9
Clinical Testing and Work-Up
Individuals with HSAN 8 typically have routine nerve conduction studies and electromyograms (both should be normal).12 Affected persons should be evaluated by an ophthalmologist to assess the eye-related symptoms and have X-ray imaging of their ankles, knees, hips and lower spine, followed by evaluation by an orthopedist.1
There is no cure yet for HSAN 8. Treatment is focused on managing and treating specific symptoms and supporting educational needs to help the affected person reach their maximum potential.
Multidisciplinary surveillance from diagnosis throughout childhood by a pediatrician, orthopedic surgeon, ophthalmologist and other specialists depending on injuries, is required. X-ray imaging of leg bones/joints is required every one to two years through the age of six after which frequency can be reduced in the absence of injury.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/No patient organizations found related to this disease state.