Ntrk1 Congenital Insensitivity To Pain With Anhidrosis
Summary
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 pregnancies 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.
Diagnosis
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).
Option 1
Single-gene testing. Sequence analysis of NTRK1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Note: Targeted analysis for pathogenic variants can be performed first in individuals of the following ancestry (see Table 5):
- Israeli Bedouins. Variant p.Pro621SerfsTer12 accounts for 89% of pathogenic variants [Shatzky et al 2000].
- Japanese. Variant p.Arg554GlyfsTer104 accounts for more than 50% of pathogenic variants, c.851-33T>A for 13%, and p.Asp674Tyr for 10% [Indo 2001].
Note: Homozygosity for an NTRK1 pathogenic variant in an individual with NTRK1-CIPA may be the result of uniparental isodisomy for chromosome 1 (i.e., two copies of the chromosome 1 with the NTRK1 pathogenic variant are inherited from one parent and no copy of chromosome 1 is inherited from the other parent). Therefore, accurate recurrence risk counseling relies on testing both parents to determine if each is heterozygous for that NTRK1 variant (see Genetic Counseling).
A multigene panel that includes NTRK1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in NTRK1 Congenital Insensitivity to Pain with Anhidrosis
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| NTRK1 | Sequence analysis 3 | >97% 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | <3% 7, 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Miura et al [2000b], Indo [2001], Geng et al [2018], Li et al [2019], and data derived from the subscription-based professional view of Human Gene Mutation Databas [Stenson et al 2017]
- 5.
While two variants common in Asian populations, c.851-33T>A and c.[851_798C>T;851_794C>G], are detectable by sequence analysis, they are outside the range normally analyzed [Indo 2001, Geng et al 2018, Li et al 2019].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Huehne et al [2008], Geng et al [2018], Xue et al [2018], Li et al [2019]
- 8.
Detection rate varies by population. An intragenic deletion was observed in multiple Chinese families [Geng et al 2018].
Clinical Characteristics
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.
Differential Diagnosis
The differential diagnosis of NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) includes other genes associated with congenital insensitivity to pain (see Congenital Insensitivity to Pain Overview) as well as other hereditary disorders (see Table 2) and acquired conditions (see Table 3) with clinical manifestations similar to those of NTRK1-CIPA.
Table 2.
Hereditary Disorders in the Differential Diagnosis of NTRK1-CIPA
| Gene(s) | Disorder | MOI | Clinical Features of Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/NTRK1-CIPA | Distinguishing from NTRK1-CIPA | |||
| COL1A1 COL1A2 | COL1A1/2-related osteogenesis imperfecta | AD | Multiple fractures |
|
| EDA EDAR EDARADD | Hypohidrotic ectodermal dysplasia | XL AR AD |
| Insensitivity to pain not a feature |
| ELP1 (IKBKAP) | Familial dysautonomia (HSAN III) | AR | ↓ pain from birth | GI dysfunction, vomiting crises, recurrent pneumonia, cardiovascular & temperature instability |
| HPRT1 | Lesch-Nyhan syndrome | XL | Progressive self-injurious behavior (biting fingers, hands, lips, cheeks; banging the head or limbs) |
|
| MPV17 | MPV17-related hepatocerebral mitochondrial DNA depletion syndrome | AR |
|
|
| NGF | NGF-CIPA 1 (HSAN V) | AR | Insensitivity to pain, anhidrosis, & ID 1, 2 | NGF-CIPA & NTRK1-CIPA cannot reliably be differentiated on a clinical basis. 2 |
AD = autosomal dominant; AR = autosomal recessive; CIPA = congenital insensitivity to pain with anhidrosis; DD = developmental delay; GI = gastrointestinal; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Carvalho et al [2011]
- 2.
Indo [2012]
Table 3.
Acquired Conditions in the Differential Diagnosis of NTRK1-CIPA
| Disorder | Overlapping Clinical Features | Clinical Features of the Disorder Distinguishing from NTRK1-CIPA |
| Leprosy 1 |
|
|
| Non-accidental /abusive injury | Multiple unexplained injuries |
|
- 1.
Daneshjou et al [2012], Iftikhar & Javed [2013]
Management
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.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with NTRK1 Congenital Insensitivity to Pain Disorders
| System/Concern | Evaluation | Comment | |
|---|---|---|---|
| Anhidrosis | Physical exam of the skin | Assess for dry skin & palmoplantar hyperkeratosis (often assoc w/cracking); determine if individual is using skin moisturizer daily. | |
| Regulation of body temperature | Inquire about history of hyperthermia or hypothermia. | ||
| Insensitivity to pain | Multiple unintentional injuries | Physical exam of whole body | Assess for bruises, cuts, & burns, as well as fingertip biting. |
| Orthopedic injuries | Exam of bones & joints by an orthopedist | Assess for fractures, avascular necrosis, septic arthritis/osteomyelitis, self-mutilation, joint subluxation, Charcot neuroarthropathy, leg length discrepancy, & scoliosis. | |
| Dental risks for injury | Exam for oral lesions | Assess for traumatic lingual injuries, burns, self-biting, auto-extraction of teeth, & overall dental health. | |
| Neuropathic keratitis | Ophthalmologic exam | Assess for superficial punctate keratopathy & corneal ulceration/perforation/infection. | |
| Developmental delay | Neurologic exam & standardized tests for developmental milestones | Assess for DD & ID, incl defects in conceptual thinking & abstract reasoning. | |
| Behavioral problems | Formal eval of cognitive & adaptive functions | Assess for social behaviors & emotional disturbances; ADHD. | |
| Genetic counseling | By genetics professionals 1 | To inform affected persons & families re nature, MOI, & implications of NTRK1-CIPA in order to facilitate medical & personal decision making | |
| Family support/Resources | Assess:
| ||
ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
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.