NTRK1 Congenital Insensitivity to Pain with Anhidrosis

Excerpt

Clinical characteristics: NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of NTRK1-CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.

Diagnosis/testing: The diagnosis of NTRK1-CIPA is established in a proband with suggestive clinical findings and biallelic pathogenic variants in NTRK1 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. For anhidrosis: Monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. For insensitivity to pain: Modify as much as reasonable a child’s activities to prevent injuries. Inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. Methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of a mouth guard. Skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for eyes, prevention of corneal infection, and daily observation of the ocular surface. Interventions for behavioral, developmental, and motor delays as well as educational and social support for school-age children and adolescents are recommended.

Surveillance: Daily evaluation by parents and caregivers for early signs of otherwise unrecognized injury. Regular examinations by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology to help prevent serious injuries and initiate early treatment. Annual follow up at a center that provides comprehensive care and communication between the various subspecialties that are needed for optimal care.

Agents/circumstances to avoid: Hot or cold environments; hot or cold foods; hot showers or baths; jumping or high-impact activities and sports.

Evaluation of relatives at risk: If the NTRK1 pathogenic variants in a family are known, molecular genetic testing can clarify the genetic status of at-risk infants, so that those who are affected can be monitored to avoid hyperpyrexia and its potential complications and oral injuries when the primary teeth erupt.

Genetic counseling: NTRK1-CIPA results from the presence of two NTRK1 pathogenic variants. Typically one pathogenic variant is inherited from each parent (autosomal recessive inheritance); however, in some instances both pathogenic variants are from one parent (uniparental isodisomy).

1. Autosomal recessive (AR) inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

2. Uniparental isodisomy. The risk to sibs of an affected individual is not increased over that of the general population.

For AR inheritance, once the NTRK1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

For uniparental isodisomy, once the NTRK1 pathogenic variant has been identified in an affected family member, carrier testing for at-risk family members is possible.