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).

• 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.
• 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.

Suggestive Findings

NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Impaired perception of pain:
  • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt
  • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles.
  • A history of failure to recognize burns and other injuries
  • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively.
  • Impaired visceral pain perception
• Impaired temperature perception, confirmed when:
  • Consistent errors are made in distinguishing between hot and cold moist substances;
  • Extreme cold or heat fails to elicit the usual withdrawal response.
• Anhidrosis (absence of sweating), manifesting as recurrent febrile episodes beginning in early infancy
• Impairment of the autonomic nervous system, which may be evident by the presence of Horner syndrome and the cold pressor test
• Intellectual disability

Family history consistent with autosomal recessive inheritance, including affected sibs in a single generation, simplex cases (i.e., a single affected family member), and/or parental consanguinity

Establishing the Diagnosis

The diagnosis of NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) is established in a proband with biallelic pathogenic variants in NTRK1 identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic NTRK1 variants of uncertain significance (or identification of one known NTRK1 pathogenic variant and one NTRK1 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NTRK1-CIPA has not been considered – perhaps because they are too young to manifest the full spectrum of clinical findings – are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) is characterized by profound sensory loss affecting pain and temperature perception, absence of sweating (anhidrosis), and intellectual disability.

Anhidrosis. Because sweating plays an important role in maintaining normal body temperature, anhidrosis (the failure to sweat) disturbs thermoregulation in hot environmental conditions and increases susceptibility to recurrent febrile episodes [Indo 2002, Indo 2018].

Recurrent episodic fevers, usually the first clinical sign of NTRK1-CIPA, can begin in infancy or early childhood depending on environmental temperature. Recurrent febrile convulsions are also observed in some affected infants.

Occasionally, hypothermia is observed in cold environments.

Anhidrosis is present on the trunk and upper extremities in 100% of cases and more variable in other areas of the body [Ismail et al 1998, Axelrod 2002]. Although with warming the intertriginous areas of the neck, axillae, and groin can become slightly moist, no definite sweating is noted. This moisture is probably due to delayed insensible water loss.

Insensitivity to pain. While impaired pain perception may not be apparent in early infancy, parents may recall that their infant with NTRK1-CIPA did not cry during venipuncture or immunizations [Indo 2002, Indo 2018].

Tongue ulcers and fingertip biting, the characteristic self-mutilation signs observed in infants with NTRK1-CIPA, begin when the primary incisors erupt, and can result in a bifid or absent tongue. Although taste buds are normal, traumatic injuries of the tongue, such as a partial loss of papillae and scar formation, may cause secondary hypogeusia or decreased taste sensation [Amano et al 1998].

Biting of the fingers and ulcerated fingertips is common.

Bruises, cuts, and burns do not elicit normal reactions and are often unrecognized at the time that they occur. Accidental injuries such as falls or burns lead to multiple scars and can lead to cellulitis in the skin.

Orthopedic problems are one of the most characteristic and serious complications of NTRK1-CIPA [Bar-On et al 2002, Kim et al 2013].

Frequent orthopedic complications:

• Multiple fractures often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis
• Auto-amputation, self-mutilation (including self-inflicted soft tissue injuries)
• Leg length discrepancy
• Joint subluxation and dislocation resulting in Charcot neuroarthropathy of the feet, ankles, knees, and hips
• Septic arthritis
• Progressive scoliosis

Amputations of fingers or limbs are common as a result of these complications.

Decreased pain perception does not spare any area, affecting even cranial nerves and visceral sensation [Yagev et al 1999, Shorer et al 2001].

Neurotrophic keratitis (degenerative disease of the corneal epithelium resulting from impaired corneal sensation) manifests initially as superficial punctate keratopathy which later can result in corneal ulceration and even perforation [Yagev et al 1999, Amano et al 2006, Mimura et al 2008]. Of note, tearing (both overflow or emotional) is normal.

Intellectual disability. Most individuals with NTRK1-CIPA have varying degrees of intellectual disability and show characteristic behaviors [Indo 2002, Indo 2018]. Affected individuals show defects in conceptual thinking, abstract reasoning, and social behavior, as well as moderate to severe emotional disturbance. Some may exhibit rage. Assessments of cognitive and adaptive behavior suggest that many children with NTRK1-CIPA have intellectual disability (or learning disabilities) and severe attention-deficit/hyperactivity disorder [Levy Erez et al 2010].

Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age.

The prognosis for independent functioning varies.

Other

• Often the skin is dry with lichenification; the nails are dystrophic. Palmoplantar hyperkeratosis (thickening of the soles and the palms) appears in late infancy, often with scars and abrasions [Bonkowsky et al 2003]. Significant fissuring of the plantar skin is common. Some affected individuals develop deep heel ulcers that are slow to heal [Mardy et al 1999].
• Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [Axelrod 2002].
• Gastrointestinal dysmotility is mild or absent.
• Vomiting is not a feature, but can be observed in some affected individuals.
• Speech is usually clear.

Normal findings

• Touch, vibration, and position senses
• Motor functions (unless repeated trauma has caused secondary dysfunction of motor neurons or limbs)
• Deep tendon reflexes and superficial abdominal and cremasteric reflexes

Neurophysiology of NTRK1-CIPA

See Indo [2018] (full text) for information on the neurophysiology of NTRK1-CIPA.

Genotype-Phenotype Correlations

Clinical phenotype varies widely even among individuals with the same two NTRK1 pathogenic variants [Shatzky et al 2000].

Nomenclature

Terms previously used to describe NTRK1-CIPA include:

• Familial dysautonomia type II
• Congenital sensory neuropathy with anhidrosis

Prevalence

While NTRK1-CIPA (or HSAN IV) has been reported worldwide, it is extremely rare in most populations except the Japanese and Israeli Bedouins. Of note, the number of Japanese with NTRK1-CIPA was estimated between 130 and 210 [Haga et al 2015].

Relatively common founder pathogenic variants have been reported in the Japanese and Israeli Bedouin populations [Miura et al 2000b, Shatzky et al 2000, Indo 2001] (see Table 5):

• Three variants – c.851-33T>A, p.Arg554GlyfsTer104, and p.Asp674Tyr – account for roughly 70% of pathogenic NTRK1 variants among Japanese.
• One variant – p.Pro621SerfsTer21 – accounts for 89% of pathogenic NTRK1 variants among Israeli Bedouins [Shatzky et al 2000, Indo 2001].

Half of reported affected individuals are offspring of consanguineous parents [Axelrod 2002].

Specific carrier frequencies are not available.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology at a center that provides comprehensive care and communication between the various subspecialties that are needed for optimal care.

It is important to provide assistance and encourage therapies for behavioral, developmental, and motor delays that are appreciated during infancy and early childhood as well as to provide educational and social support for school-age children and adolescents.

For details see Table 3, Congenital Insensitivity to Pain Overview.

Prevention of Primary Manifestations

For details see Table 4, Congenital Insensitivity to Pain Overview.

Prevention of Secondary Complications

For details see Table 5, Congenital Insensitivity to Pain Overview.

Surveillance

In addition to daily evaluation by parents and caregivers for early signs of otherwise unrecognized injury, regular examinations by a pediatrician, orthopedist, dentist, dermatologist, and ophthalmologist are recommended to assess and advise on various physical, mental, and behavioral problems. For details, see Table 6, Congenital Insensitivity to Pain Overview.

Agents/Circumstances to Avoid

Avoid the following:

• 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 may be used to clarify the genetic status of at-risk infants so that those who are affected can be monitored to avoid:

• Hyperpyrexia and its potential complications, including febrile seizures;
• Injuries to the tongue, lips, and teeth when the primary teeth erupt.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with CIP are able to become pregnant and bear children normally; however, reports regarding pregnancy in women with NTRK1-CIPA are rare.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) is an autosomal recessive disorder caused by biallelic NTRK1 pathogenic variants. Typically, the proband has inherited one NTRK1 pathogenic variant from each parent. Alternatively, in some families, the proband has NTRK1-CIPA as the result of uniparental isodisomy for chromosome 1 (i.e., 2 copies of chromosome 1 with the NTRK1 pathogenic variant are inherited from one parent and no copy of chromosome 1 is inherited from the other parent).

Risk to Family Members

Parents of a proband

• In most families, both parents of an affected child are carriers (i.e., heterozygotes) for an NTRK1 pathogenic variant.
• Less commonly, only one parent is heterozygous for an NTRK1 pathogenic variant and the child has NTRK1-CIPA as the result of uniparental isodisomy for chromosome 1 and consequent homozygosity for the NTRK1 pathogenic variant from the carrier parent [Miura et al 2000a, Indo et al 2001, Kurth et al 2016].
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an NTRK1 variant. If carrier testing detects the variant in only one parent:
  • And the child appears to have homozygous NTRK1 pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 1.
  • And the child has compound heterozygous NTRK1 pathogenic variants, the child may theoretically have one inherited variant and one de novo pathogenic variant (de novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If each parent is known to be heterozygous for an NTRK1 pathogenic variant, each sib of an affected individual has at conception 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.
• If the proband has NTRK1-CIPA as the result of uniparental isodisomy for chromosome 1 and only one parent is heterozygous for an NTRK1 pathogenic variant, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier (the risk to the sibs of being affected with NTRK1-CIPA is not increased over that of the general population).

Offspring of a proband. The offspring of an individual with NTRK1-CIPA are obligate heterozygotes (carriers) for an NTRK1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for an NTRK1 pathogenic variant, his or her family members are at risk of being a carrier.

Carrier Detection

Carrier testing for parents, sibs, and other at-risk relatives requires prior identification of the NTRK1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk infants for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the NTRK1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NTRK1 encodes TrkA, a receptor tyrosine kinase for nerve growth factor (NGF) [Indo et al 1996, Mardy et al 1999, Indo 2001, Mardy et al 2001]. Defects in NGF-TrkA signal transduction cause the loss of various NGF-dependent neurons during developmental apoptosis, resulting in the selective loss of NGF-dependent neurons in otherwise intact systems.

NGF-dependent neurons in the peripheral nervous system (PNS) include sympathetic postganglionic neurons and NGF-dependent primary afferents that depend on the NGF-TrkA system during development [Indo 2012]. NGF-dependent primary afferents are defined as primary afferent (sensory) neurons with small-diameter, thinly myelinated Aδ (delta) fibers, or unmyelinated C-fibers. NGF-dependent neurons also exist in the central nervous system (CNS) [Indo 2014].

NGF-dependent neurons in the PNS also contribute to inflammatory processes; therefore, control of various neuronal or inflammatory processes via these neurons in pain, itch, and inflammation response is likely abnormal in the absence of TrkA [Indo 2010].

These NGF-dependent neurons play pivotal roles in interoception to represent the physiologic status of all tissues of the body, as well as in stress response [Indo 2018]. It is also likely that these neurons are required for neurobiologic processes of "emotions and feelings" in our species. (For more information about the neuroscience of NGF-dependent neurons, click here.)

Mechanism of disease causation. NTRK1-CIPA is caused by loss-of-function variants in NTRK1 resulting in loss of TrkA function.

Lack of all NGF-dependent neurons in the PNS causes:

• Absence of pain due to absence of primary afferents (sensory neurons) in the dorsal root ganglion, which carry nerve impulses from painful and temperature stimuli;
• Anhidrosis due to absence of sympathetic postganglionic neurons, which innervate sweat glands.

Intellectual disability and characteristic behaviors are probably neuron-deficient within the CNS (brain).

NTRK1-specific laboratory technical considerations. Several individuals with NTRK1-CIPA have been reported with homozygosity for an NTRK1 pathogenic variant resulting from uniparental isodisomy for chromosome 1 [Miura et al 2000a, Indo et al 2001, Kurth et al 2016]. In these instances, two copies of chromosome 1 with the NTRK1 pathogenic variant were inherited from one parent and no copy of chromosome 1 was inherited from the other parent. If parental testing for an apparently homozygous NTRK1 pathogenic variant detects the variant in only one parent, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 1.

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Author Notes

Dr Indo’s work is in the fields of Pediatrics, Clinical and Molecular Genetics, and Clinical Neuroscience.

Kumamoto University Repository – An interview with the researcher (in Japanese)

Acknowledgments

This work was supported in part by the Japan Society for the Promotion of Science (JSPS) (KAKENHI) Grant-in-Aid for Scientific Research and by the Ministry of Health, Labor and Welfare: Health and Labor Science Research Grants (Research on Intractable Diseases).

Author History

Felicia B Axelrod, MD; New York University Medical Center (2008-2014)
Gabrielle Gold-von Simson, MD, MSc; New York University Medical Center (2008-2014)
Yasuhiro Indo, MD, PhD (2014-present)
Carole Oddoux, PhD; New York University Medical Center (2008-2014)

Revision History

• 30 April 2020 (bp) Comprehensive update posted live
• 17 April 2014 (me) Comprehensive update posted live
• 24 November 2009 (cd) Revision: deletion/duplication analysis available clinically
• 5 August 2008 (me) Review posted live
• 5 May 2008 (fba) Original submission