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Congenital Insensitivity/Indifference to Pain

Also known as: Hereditary and Sensory Autonomic Neuropathy Types I-IV, HSAN Types I-IV, Congenital Insensitivity to Pain, Congenital Analgesia, Channelopathy Insensitivity to Pain

Background

In our bodies all the nerves and nerve cells outside the central nervous system (brain and spinal cord) make up the peripheral nervous system. With the help of peripheral nerves, people are able to carry out voluntary actions (such as picking up a pen) and involuntary (or autonomic) actions (such as breathing). The autonomic nervous system has two parts: the sympathetic and the parasympathetic. Both supply essentially the same organs but cause opposite effects. This is because the chemicals that send messages (called neurotransmitters) are different.

Pain is a sense, like vision, like smell. Specific receptors on our body detect pain, or something that is about to be painful. These receptors are in specialised sensory neurons (nerve cells). Once the receptors are triggered the signal from these sensory neurons gets relayed to the brain, where we react to and 'feel' pain. The relay to the brain can involve two pathways, by the spinal cord or by the sympathetic nervous system. This entry covers the commoner genetic disorders where the pain sensing system either doesn't work properly, or did not develop.

Credits

Medical text written December 2012 by Professor Geoff Woods, Honorary Consultant Clinical Geneticist, Addenbrooke's Hospital, Cambridge, UK.

Congenital insensitivity to pain

There are only two features of this condition: a totally inability to feel any pain ever; and no sense of smell. Otherwise, the affected individuals are healthy, of normal intelligence and have no other problems with their nervous system. The condition is inherited in an autosomal recessive manner and is caused by having a change (mutation) in each SCN9A gene. SCN9A seems to be an 'amplifier' for all the specific pain receptors, and if not present, means a pain nerve can't be fired. The only way to make a diagnosis is by analysing the SCN9A gene to look for the mutation. The management of children with this condition can be challenging and involves stopping them injuring themselves, teaching them what is dangerous, and when to get medical attention. An informed and involved GP, paediatrician and orthopaedic surgeon are an absolute necessity, especially in the first ten years of life.

Inheritance pattern
Autosomal recessive.

Prenatal diagnosis
This is available in affected families.

Congenital insensitivity to pain and the hereditary sensory and autonomic neuropathies

This is the name of a group of disorders which have in common a failure of development of the pain sensing nerves. They are best called the hereditary and sensory autonomic neuropathies (HSANs), and there are five separate conditions. The various categories are distinguished according to features, including age of onset, progressive (becoming worse over time) or non-progressive, presence or absence of abnormalities of the autonomic nervous system if the system is sympathetic or parasympathetic and also according to the nature of structural abnormalities in peripheral nerves.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1)

HSAN type I occurs in late childhood or more commonly adolescence. The nerve fibres involved in pain sensation and their connections to the spinal cord decline in function. Impaired pain sensation starts furthest away from the spinal cord in the legs and later the arms. Nerve biopsy (removal of a small piece of nerve tissue for examination) shows that the nerves involved in sensing and movement are degenerated. A mutation in the SPTLC1 gene on chromosome 9 is responsible for HSAN type I. Often there is a dull continuous pain initially which gradually disappears as all pain sensing is lost. Due to the unawareness of pain, damage to skin, nails, and joints occurs without the affected person being aware until they see the bruise, skin infection, or see the deformity at a site of fracture. The condition is usually diagnosed and managed by adult neurologists (specialist doctor in neurology).

Inheritance pattern
autosomal dominant.

Prenatal diagnosis
This is potentially possible.

Hereditary sensory and autonomic neuropathy type 2 (HSAN2)

HSAN2 is congenital (present at birth) or occurs very early on in life. There is universal absence of pain in most, and reduced ability to feel anything from touch (tactile sensation) in many, resulting in burns, mutilation of finger tips, painless fractures and painless arthritis with joint destruction. Usually there are areas of normal sensation on the body. There may be impaired bladder sensation with overdistention (enlargement of the bladder). There is deafness in some affected individuals. In most, the condition does not progress, or progresses very slowly. Rarely there is rapid progression. Despite the name, affects on the autonomic nervous system are absent or minimal. A sensory nerve biopsy shows a marked reduction in the number of myelinated nerves and degeneration of those myelinated nerves, and a lesser loss of non-myelinated nerves. Myelin is a special covering around nerves which insulates them and allows nerve impulses to be effectively passed through the nerve. A mutation in the WNK1 gene causes the condition and analysis of this gene may confirm the diagnosis.

Inheritance pattern
Autosomal dominant

Prenatal diagnosis
This is potentially possible.

Hereditary sensory and autonomic neuropathy type 3 (HSAN3)

This genetic condition is more commonly known as Riley-Day syndrome or Familial Dysautonomia. It occurs almost exclusively in Ashkenazi Jews. It is present at birth and symptoms include floppiness, severe feeding difficulties (vomiting, constipation), pneumonia (that occurs because of an inability to swallow and cough), lack of taste, inability to produce tears, unstable temperature and blood pressure control. The condition is cause by a progressive degeneration of sensory, sympathetic, and parasympathetic neurons throughout life. There is indifference to pain, but this is usually far less of a problem than the autonomic dysfunction. Intelligence is usually normal, but emotions can be unstable. Sadly, life expectancy is severely reduced with pneumonia is a common cause of death in childhood. In adulthood there may be renal (kidney) failure. Treatment is complex, will involve a specialist and life-long. Testing for the condition can be carried out by looking for the mutation in the IKBKAP gene.

Inheritance pattern
The condition is inherited in an autosomal recessive

Prenatal diagnosis
This is possible if the genetic mutation in a family is known.

Hereditary sensory and autonomic neuropathy type 4 and 5 (HSAN4/5)

HSAN4 and HSAN5 are the same condition with different severities (which had originally suggested that they may be different conditions). HSAN4 was known as congenital insensitivity to pain and anhidrosis (inability to sweat), but this can lead to confusion with CIP. HSAN4/5 is present at birth with a lack of pain sensing, inability to feel and regulate temperature. In the first few years, the lack of sweating and dry skin lead to intense itching, and inability to sense temperature means that hyperthermia (leading to fits and exhaustion) is a risk. Nearly all affected individuals have mild-moderate learning difficulties, and many self-injure, which can be distressing. Children affected are at risk of Staphylococcal infections such as osteomyelitis and septic arthritis, as well other skin infections. An immunologist should be involved in providing care to the child. Nerve biopsy shows a lack of unmyelinated sensory nerves. Diagnosis is possible by looking for mutation in NTRK1 and NGF genes, which cause the condition.

Inheritance pattern
The condition is inherited in autosomal recessive manner.

Prenatal diagnosis
This is possible if the genetic mutation in a family is known.

Is there support?

There is no support group for congenital insensitivity/indifference to pain. Families can use Contact a Family's freephone helpline for advice, information and, where possible, links to other families. Contact a Family's web-based linking service MakingContact.org can be accessed at www.makingcontact.org

Information and support in the UK for familial dysautonomia (HSAN Type III) is provided by the Dysautonomia Society of Great Britain (see entry Familial Dysautonomia).

Information and support in the UK for Riley-Day syndrome (HSAN Type III) is provided by Climb (see entry Inherited Metabolic Diseases).