Disease summary: Congenital insensitivity to pain (CIP) presents a spectrum of phenotypic variations. The genes related to the disease are CLTCL1 (rare), NGF (rare), NTRK1 (common), PRDM12 (intermediate), SCN9A (common), SCN11A (rare), ZFHX2 (rare, one family reported). Development and intellect may be normal or delayed/impaired. Individuals with disease caused by the SCN9A and PRDM12 variants generally possess normal intellectual capacities. Individuals with CIP with anhydrosis caused by biallelic pathogenic variants in NTRK1 have variable degrees of intellectual disability, hyperactivity, impulsivity, and attention deficit.1 

Congenital insensitivity to pain and anhidrosis (CIPA), is a rare autosomal recessive neuropathy characterised by insensitivity to painful stimuli, changes in temperature control, and varying degrees of cognitive impairment.2 Mutations in the NTRK1 gene inhibit the development of NGF-dependent sensory and autonomic neurons during the embryonic period.3 The expression of NGF is increased in traumatised and inflamed tissues, and activation of tyrosine kinase receptor type A in nociceptive neurons potentiates pain through several mechanisms.3,4 

Insensitivity to pain and cognitive impairment predisposes patients with CIP to self-mutilation (especially fingers, lips, and tongue), corneal lacerations, non-painful fractures, Charcot arthropathies, and joint deformities leading to chronic osteomyelitis and septic arthritis.5,6 Thermal sensitivity varies, but most patients have some degree of cold and heat sensitivity. The reduction in the central and peripheral activities of noradrenaline and anhidrosis can lead to the development of perioperative hypotension, bradycardia and hyperthermia.6 

The diagnosis of CIP is based on the clinical presentation (particularly self-mutilation in early life) and genomic sequencing. When the known genes are sequenced and no disease-causing variant is identified, it is exceptional to have absence of pain sensation as opposed to a raised pain threshold. Many people have a high pain threshold, particularly those with an autistic spectrum disorder. Pharmacological testing (intradermic reaction to 1:10,000 histamine), and neuropathological exam can be considered in patients with a remarkable genomic sequencing after expert review. 

Specific treatment is not available.