Congenital Insensitivity To Pain Causes, Symptoms, Diagnosis & T

CONDITIONS DRUGS & SUPPLEMENTS L I V I N G H E A LT H Y FO O D A D D I T I
Congenital insensitivity to
pain
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Congenital insensitivity to pain

Congenital insensitivity to pain causes
Congenital insensitivity to pain inheritance pattern
Congenital insensitivity to pain symptoms
Congenital insensitivity to pain diagnosis
Clinical examination
5 Supportive laboratory findings
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Genetic testing
Congenital insensitivity to pain treatment
Prevention of primary manifestations
Prevention of secondary complications
Surveillance
Congenital insensitivity to pain life expectancy
Congenital insensitivity to pain with anhidrosis
CIPA causes
CIPA inheritance pattern
CIPA signs and symptoms
Anhidrosis
Insensitivity to pain
Intellectual disability
Other
CIPA diagnosis
CIPA treatment
Surveillance
Congenital insensitivity to
pain
Congenital insensitivity to pain (CIP) is an extremely rare
inherited condition that inhibits the ability to perceive physical
pain. From birth, affected individuals never feel pain in any part
1)
of their body when injured . Individuals with congenital
insensitivity to pain do not feel pain from any noxious stimuli,
2)
including inflammation and heat . People with congenital
insensitivity to pain can feel the difference between sharp and
dull and hot and cold, but cannot sense pain, for example, that a
hot beverage is burning their tongue. This lack of pain
awareness often leads to repeated injuries, accumulation of
wounds,
5 bruises, broken bones, and prevents normal healing
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and other health issues that may go undetected. Young children
with congenital insensitivity to pain may have mouth or finger
wounds due to repeated self-biting and may also experience
multiple burn-related injuries. These repeated injuries often
lead to a reduced life expectancy in people with congenital
insensitivity to pain. Many people with congenital insensitivity to
pain also have a complete loss of the sense of smell (anosmia)
3)
.
Congenital insensitivity to pain is considered a form of

peripheral neuropathy because it affects the peripheral nervous
system, which connects the brain and spinal cord to muscles
and to cells that detect sensations such as touch, smell, and
pain.
Congenital insensitivity to pain is a rare condition; about 20

4)
cases have been reported in the scientific literature .
Figure 1. Congenital insensitivity to pain
5
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Footnote: (A) Typical loss of fingertips secondary to trauma,

poor wound healing, and chronic Staphylococcal aureus
infections in a child with congenital insensitivity to pain; (B)
Child with congenital insensitivity to pain showing loss of
portions of the lower lip as a result of self-biting; (C) Example of
a Charcot joint, or neuropathic joint, in an individual with
congenital insensitivity to pain. The affected individual had
chronic elbow dislocation, which is now permanent and results
in significantly reduced arm movement; (D) Method for applying
pressure to the proximal nail bed to test pain detection.
5)
[Source ]
Table 1. Genes Associated with Congenital Insensitivity to
Pain (CIP)
5
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Proportion
of Affected
Individuals
with
Mutation of Mode of
Gene This Gene inheritance Distinguishing Features
Severe non-progressive
learning disability
Delay in central nervous
system myelination
6)
One family reported
CLTCL1 Rare AR
Variable phenotype
Individuals with biallelic
null variants may have
anhidrosis, mild/moderate
intellectual disability,
prematurely aged
appearance, Staphylococcus
aureus infections, &
Charcot joints.
Individuals with a
homozygous missense
variant had impairment of
pain/temperature
sensation & Charcot joints,
normal intellect & normal
7)
sweating. 1
NGF Rare AR
5
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Proportion
of Affected
Individuals
with
Mutation of Mode of
Anhidrosis
Tendency to develop
corneal9)ulcers that heal
poorly
Intellectual disability in a
majority; always less
intellectually able than
unaffected family
members
Predisposition to
Staphylococcus aureus
infections
Charcot joints
Dry skin w/lichenification
8)
Also known as HSAN IV
NTRK1 Common AR
5
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Proportion
of Affected
Individuals
with
Mutation of Mode of
Non-global pain
insensitivity in some
Absent corneal reflex &
impaired tear production
Normal olfaction
Staphylococcus aureus
infections
No Charcot joints
Difficulties w/temperature
regulation in some
PRDM12
10)
Known as HSAN VIII
Intermediate AR
12)
Anosmia
Charcot joints
Normal corneal reflex &
11)
tear production
SCN9A Common AR
5
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Proportion
of Affected
Individuals
with
Mutation of Mode of
Delayed motor
development
Mild muscle weakness
Joint hypermobility
Gastrointestinal
dysfunction (intestinal
hypoperistalsis or diarrhea)
SCN11A Pruritis
3 Rare AD
Footnotes:
1. Three individuals from a large northern Swedish family who

were homozygous for the NM_002506.2:c.661C>T, (p.Arg211Trp)
13)
pathogenic variant . A proportion of adults who were
heterozygous for the NM_002506.2:c.661C>T, (p.Arg211Trp)
pathogenic variant in this family had mild or moderate
problems with joint deformities but were not believed to
actually be affected by congenital insensitivity to pain.
2. Pathogenic variants are typically truncating, although one
missense variant and one in-frame deletion have been
14)
described
3. The pathogenic NM_014139.2:c.2432T>C (p.Leu811Pro)
variant was found in three affected individuals and was de novo
in each case. The pathogenic NM_014139.2:c.3904C>T,
(p.Leu1302Phe) variant was found in an affected mother and
15)
two children. All six of these individuals had hyperhidrosis .
5
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Abbreviations: AD = autosomal dominant; AR = autosomal
recessive; HSAN = hereditary sensory and autonomic
neuropathy; MOI = mode of inheritance
16)
[Source ]
Congenital insensitivity to pain causes

Mutations in the SCN9A gene cause congenital insensitivity to
pain. The SCN9A gene provides instructions for making one part
(the alpha subunit) of a sodium channel called NaV1.7. Sodium
channels transport positively charged sodium atoms (sodium
ions) into cells and play a key role in a cell’s ability to generate
and transmit electrical signals. NaV1.7 sodium channels are
found in nerve cells called nociceptors that transmit pain signals
to the spinal cord and brain. The NaV1.7 channel is also found in
olfactory sensory neurons, which are nerve cells in the nasal
cavity that transmit smell-related signals to the brain.
The SCN9A gene mutations that cause congenital insensitivity to

pain result in the production of nonfunctional alpha subunits
that cannot be incorporated into NaV1.7 channels. As a result,
the channels cannot be formed. The absence of NaV1.7
channels impairs the transmission of pain signals from the site
of injury to the brain, causing those affected to be insensitive to
pain. Loss of this channel in olfactory sensory neurons likely
impairs the transmission of smell-related signals to the brain,
leading to anosmia.

inheritance pattern
Congenital insensitivity to pain is inherited in an autosomal
recessive pattern, which means both copies of the gene in each
cell
5 have mutations. The parents of an individual with an
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autosomal recessive condition each carry one copy of the
mutated gene, but they typically do not show signs and
symptoms of the condition.
It is rare to see any history of autosomal recessive conditions

within a family because if someone is a carrier for one of these
conditions, they would have to have a child with someone who
is also a carrier for the same condition. Autosomal recessive
conditions are individually pretty rare, so the chance that you
and your partner are carriers for the same recessive genetic
condition are likely low. Even if both partners are a carrier for
the same condition, there is only a 25% chance that they will
both pass down the non-working copy of the gene to the baby,
thus causing a genetic condition. This chance is the same with
each pregnancy, no matter how many children they have with or
without the condition.
If both partners are carriers of the same abnormal gene, they

may pass on either their normal gene or their abnormal gene to
their child. This occurs randomly.
Each child of parents who both carry the same abnormal gene
therefore has a 25% (1 in 4) chance of inheriting a abnormal
gene from both parents and being affected by the condition.
This also means that there is a 75% ( 3 in 4) chance that a child
will not be affected by the condition. This chance remains the
same in every pregnancy and is the same for boys or girls.
There is also a 50% (2 in 4) chance that the child will inherit just
one copy of the abnormal gene from a parent. If this happens,
then they will be healthy carriers like their parents.
Lastly, there is a 25% (1 in 4) chance that the child will inherit
both normal copies of the gene. In this case the child will not
have the condition, and will not be a carrier.
5
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These possible outcomes occur randomly. The chance remains
the same in every pregnancy and is the same for boys and girls.

Figure 2 illustrates autosomal recessive inheritance. The
example below shows what happens when both dad and mum
is a carrier of the abnormal gene, there is only a 25% chance
that they will both pass down the abnormal gene to the baby,
thus causing a genetic condition.
Figure 2. Congenital insensitivity to pain autosomal

recessive inheritance pattern
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People with specific questions about genetic risks or genetic
testing for themselves or family members should speak with a
genetics professional.
Resources for locating a genetics professional in your

community are available online:
The National Society of Genetic Counselors

(https://www.findageneticcounselor.com/) offers a searchable
directory of genetic counselors in the United States and Canada.
You can search by location, name, area of
practice/specialization, and/or ZIP Code.
The American Board of Genetic Counseling
(https://www.abgc.net/about-genetic-counseling/find-a-certified-
counselor/) provides a searchable directory of certified genetic
counselors worldwide. You can search by practice area, name,
organization, or location.
The Canadian Association of Genetic Counselors
(https://www.cagc-accg.ca/index.php?page=225) has a
searchable directory of genetic counselors in Canada. You can
search by name, distance from an address, province, or
services.
The American College of Medical Genetics and Genomics
(http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx)
has a searchable database of medical genetics clinic services in
the United States.

symptoms
Characteristic findings
Age-Related
5
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Infants and young children:
Self-mutilating injuries of the fingers (biting off fingertips) and
oral cavity such as loss of the tongue tip, injuries to the inside of
the teeth/gums, and avulsion of teeth are common (see Figure
1A and 1B).
Cuts and bruises may be present.
17)
Burns due to impaired temperature sensation can occur .
Recurrent otitis media may be due to selectively reduced
18)
immunity to Staphylococcus aureus (see Infections) .
Older individuals:
Painless fractures and joint damage frequently occur and can
lead to permanent damage.
Bony deformities due to past fractures can occur.
Charcot joints (neuropathic arthropathy), most commonly of the
ankles, hips, and lumbar spine, are almost universal (Figure 1C).
Charcot spine may present with progressive deformity or new
19)
motor and/or sensory deficits .
Eyes
All affected individuals are at risk for corneal injuries due to

absent corneal reflexes.
Permanent corneal scarring can develop and is best assessed
through a slit-lamp examination.
Emotional tearing, as opposed to pain induced tearing, is likely
20)
to be present .
Infections
Apparent selectively reduced immunity to Staphylococcus

aureus has been observed in some affected individuals, leading
5
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to recurrent soft tissue infections, abscesses, and osteomyelitis.
Temperature Regulation, Anhidrosis, and Hyperhidrosis

Some individuals have anhidrosis (lack of sweating), which

disturbs thermoregulation and can lead to recurrent episodes of
21)
unexplained fever (see Table 1 above) .
Marked hyperhidrosis may be seen in those affected individuals

who have a heterozygous pathogenic c.2432T>C (p.Leu811Pro)
22)
variant in SCN11A .
23)
Hyperpyrexia can be fatal if untreated .
Hypothermia can occur in cold conditions.
Development and Intellect
Development and intellect may be normal or delayed/disabled

(see Table 1).
Individuals with congenital insensitivity to pain caused by

biallelic pathogenic variants in SCN9A and PRDM12 typically
have normal intellect.
Individuals with congenital insensitivity to pain caused by
biallelic pathogenic variants in NTRK1 may have a variable
degree of intellectual disability (see Table 1).
Hyperactivity, impulsivity, and attention deficit are common in
24)
children with biallelic pathogenic variants in NTRK1 .
Other
Chronic anemia of unknown cause was observed in 22/28 Israeli

5
affected individuals with congenital insensitivity to pain and
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25)
25)
anhidrosis .
A few individuals have neuropathic pain, although this does not

C O N D I T I O N S 26)D R U G S & S U P P L E M E N T S
L I V I N G H E A LT H Y FO O D A D D I T I
limit activities .

diagnosis
There are no consensus clinical diagnostic criteria for congenital
insensitivity to pain. However, a diagnosis requires visible proof
of lack of nociception in a conscious individual of normal
intellectual ability. In those with intellectual disability congenital
insensitivity to pain may be more difficult to diagnose clinically.
Clinical examination
Nociception is assessed by applying painful stimuli, which in
people with normal nociception would be so difficult to bear
that they would move the part of the body away from the
stimulus and/or express discomfort. The authors have
experience of children being incorrectly judged to have
insensitivity to pain after an inadequately painful stimulus.
The technique should not damage/scar prior to significant pain

(e.g., sternal rub, which bruises before significant pain).
Application of 5-10 kg pressure with a pen pressed onto the nail
bed (the nail bed blanches for a few seconds afterward) is
reliable (see Figure 1D).
Assessment of the remainder of the peripheral and central

nervous system is typically normal (touch, vibration and position
sense, motor functions, and deep tendon reflexes).
5
Supportive
SHARES laboratory findings
Routine nerve conduction studies and electromyogram are
27)
typically normal .

Nerve biopsy is not routinely performed in clinical practice. Skin
biopsy to determine intra-epidermal nerve fiber density and
autonomic innervation is performed in adults in some centers.
For more information about autonomic function testing for

congenital insensitivity to pain with anhidrosis please go here
(https://www.ncbi.nlm.nih.gov/books/NBK481553/bin/hsan4-
special-studies.pdf).
Genetic testing
Molecular genetic testing approaches can include a combination
of targeted gene testing (multigene panel or single-gene testing)
and genomic testing (comprehensive genomic sequencing).
Targeted gene testing requires the clinician to develop a

hypothesis as to which specific gene(s) are likely to be involved,
whereas genomic testing does not. Targeted testing is feasible
based on phenotype in anyone older than approximately age
five years (because of the difficulties of assessing subtle
problems of intellectual developmental, sweating, temperature
sensing, and autonomic features in infants and young children),
with the exception of SCN11A.
Serial single-gene testing
The phenotype may guide the choice of which gene(s) to analyze

first. Consider performing sequence analysis of:
SCN11A first in a newborn with severe intestinal hypomotility.
5
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SCN9A first in an individual with normal intelligence who has
anosmia.
C O N DPRDM12
I T I O N S firstDin
R UanG Sindividual
& S U P P with
L E M Enormal
N T S intelligence,
staphylococcal infections, and hypohidrosis. Because some
individuals with NTRK1-CIP and NGF-CIP have minimal learning
problems, sequence analysis of these two genes should be
considered next if molecular genetic testing of SCN9A and
PRDM12 yield no pathogenic variants.
NTRK1 and NGF first in an individual with evidence of learning
problems or late development, staphylococcal infections, and
hypohidrosis. Unexplained fever due to anhidrosis (the inability
to sweat) is a characteristic and often initial feature (more so in
hot climates).
If no pathogenic variant in SCN11A is found through sequence

analysis OR if no or only one pathogenic variant is found
through sequence analysis of the remainder of the genes listed
in Table 1, gene-targeted deletion/duplication analysis should
be considered.
Note: Whole-gene deletions have been reported in individuals

28)
with NGF-CIP and SCN9A-CIP.
A multigene panel that includes genes for congenital

insensitivity to pain and other genes of interest may be
considered.
Note: 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; thus,
clinicians need to determine which multigene panel is most
likely to identify the genetic cause of the condition at the most
5
reasonable cost while limiting identification of variants of
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uncertain significance and pathogenic variants in genes that do
not explain the underlying phenotype. (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.
Comprehensive genomic testing (when available) including

exome and genome sequencing may be considered. Such
testing may provide or suggest a diagnosis not previously
considered (e.g., mutation of a different gene or genes that
results in a similar clinical presentation).

treatment
No consensus treatment or surveillance guidelines have been
developed. Treatment is supportive and is best provided by
specialists in pediatrics, orthopedics, dentistry, ophthalmology,
and dermatology.
Individuals with congenital insensitivity to pain typically learn

that others have pain and tend to respond to others’ pain
normally. They often learn to simulate having pain in
appropriate situations; e.g., being tackled during football.
The possibility that naloxone may temporarily relieve congenital

29)
insensitivity to pain analgesia has been suggested . While this
medication could be of use in detecting the source of
injury/illness in an affected individual, it may also expose the
affected person to widespread pain from accumulated injuries.
Agents
5 and circumstances to avoid
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Avoid the following:
Jumping, high-impact/contact sports, pastimes and jobs that

involve the potential for blunt injury or severe bone and joint
trauma
The paucity of males with congenital insensitivity to pain who
are older than age 20 years correlates with behaviors fueled by
inability to feel pain (e.g., greater risk taking, deliberately picking
fights, participation in extreme sporting events).
Hot or cold environments; hot or cold foods, hot showers or
baths; heating blankets, particularly in the perioperative period
Pregnancy management
Women with congenital insensitivity to pain are able to become

pregnant and bear children normally. Obstetric staff must be
made aware of the diagnosis of congenital insensitivity to pain.
Labor progresses normally, but will be painless, while other
senses (stretch and touch) are intact. A delay in detecting pelvic
fractures in an affected woman in the postnatal period has been
30)
reported .
Table 2. Treatment of manifestations in individuals with

congenital insensitivity to pain
Manifestation/Concern Treatment Considerations/Other
Tooth extraction
&/or filing
(smoothing) of
sharp incisal edges
31)
; use of a mouth
32)
Dental & oral lesions guard
5
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Treatment w/an external

CONDITIONS DRUGS & SUPPLEMENTS L I V I N Gfixator
H E A LT H Y → potentially
may FO O D A D D I T I
serious infectious
Bone fractures Standard treatment complications.
Prolonged & intensive

monitoring is necessary
Corrective to avoid deformity or
Bone & joint deformity osteotomy incomplete healing.
The value of surgical

intervention needs to be
weighed against
Shoe lift or nonsurgical approaches
33) 34)
Leg length discrepancy epiphysiodesis incl close monitoring .
Surgical treatment of
neurotrophic keratitis
Lubricating eye has not been successful
35)
Dry eyes drops or ointments .
Longstanding Wide surgical

infections debridement
Appropriate footwear &

periods of non-weight
bearing may be
Ulcerating foot lesions Standard treatment appropriate.
Direct cooling in a Control of environmental

bath or w/cooling temperatures is
Hyperthermia blanket essential.
Warming by a
Hypothermia blanket
5
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Untreated dry skin can →

CONDITIONS DRUGS & SUPPLEMENTS L I V I N Gskin
H E infections,
A LT H Y FO O D↑A D D I T I
which
the risk for serious
Skin dryness & Topical moisturizer infections (cellulitis or
cracking (lotion or cream) osteomyelitis).
Developmental delay and intellectual disability

management issues
The following information represents typical management

recommendations for individuals with developmental delay /
intellectual disability in the United States; standard
recommendations may vary from country to country.
Developmental delay and intellectual disability educational

issues may be seen in those with CTCL1-CIP, NGF-CIP, or NTRK-
CIP.
Ages 0-3 years. Referral to an early intervention program is

recommended for access to occupational, physical, speech, and
feeding therapy. In the US, early intervention is a federally
funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the
local public school district is recommended. Before placement,
an evaluation is made to determine needed services and
therapies and an individualized education plan (IEP) is
developed.
Ages 5-21 years
In the US, an individualized education plan (IEP) based on the
individual’s level of function should be developed by the local
public school district. Affected children are permitted to remain
5 in the public school district until age 21.
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Discussion of transition plans including financial,
vocation/employment, and medical arrangements should begin
at age 12 years. Developmental pediatricians can provide
assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is
recommended to ensure the involvement of appropriate
community, state, and educational agencies and to support
parents in maximizing quality of life. Consideration of private
supportive therapies based on the affected individual’s needs is
recommended. Specific recommendations regarding type of
therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is

recommended. DDA is a public agency that provides services
and support to qualified individuals. Eligibility differs by state
but is typically determined by diagnosis and/or associated
cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for
supplemental security income for their child with a disability.
Social and behavioral concerns
Consultation with a developmental pediatrician may be helpful

in guiding parents through appropriate behavior management
strategies or providing prescription medications when
necessary.
Irritability, hyperactivity, impulsivity, and acting-out behaviors

typically improve with age.
Prevention
5 of primary manifestations
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Table 3. Prevention of primary manifestations in individuals
with congenital insensitivity to pain

Manifestation/
Concern Prevention Considerations/Other
Stair gates; soft-round edging

on tables & protruding
Injuries objects; guard all heating
occurring devices; close supervision of
around the younger children in the
home kitchen
Inform personnel at school of

Injuries the diagnosis; seek help when
occurring at an accident occurs but the
school child does not seem hurt.
Communicating with
other families of
individuals with
Education of affected congenital insensitivity
Self-inflicted individuals about their to pain (especially
injuries condition. affected adults)
Artificial tears are

particularly helpful
to those with
PRDM12-CIP
All individuals
w/congenital
corneal anesthesia
At least annual have had SCN9A-
Corneal ophthalmologic evaluation; CIP.
abrasion artificial tears
5
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Manifestation/
Concern Prevention Considerations/Other
CONDITIONS D R U G S &Good
SUPPhand
L E Mhygiene
E N T S & L I V I N G H E A LT H Y FO O D A D D I T I
care; use of antiseptic
soaps; early use of topical
antibiotics
Investigation of swollen
joints, limping and limb Affects those w/NTRK1-,
underuse for infection by NGF-, CLTCL1-, &
Staphylococcus x-ray and C-reactive PRDM12-CIP; infections
aureus protein are specific for S aureus
infections only.

Table 4. Prevention of secondary manifestations in
individuals with congenital insensitivity to pain
Manifestation/Concern Prevention Considerations/Other
Consider providing a
laminated letter confirming
Inability to use pain as Laminated the diagnosis, stating the
an indicator in information pathogenic variant(s), &
diagnosing or assessing letters/MediAlert giving advice on diagnosis &
injury severity bracelets treatment
Early treatment
of dental caries Regular dental
Osteomyelitis of the & periodontal examinations & restriction
mandible disease of sweets
5
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Manifestation/Concern Prevention Considerations/Other
Activities that
C O NBone
D I T I O&Njoint
S injury
D R U Gdue
S & S U Plead
PLEMtoE N T S L I V I N G H E A LT H Y FO O D A D D I T I
to strenuous activity increased Dancing (particularly ballet),
when an individual has strength, swimming, cycling, & non-
poor baseline balance, & body traumatic martial arts may
conditioning awareness be considered.
Inadequate sedation in
postoperative period Tachycardia & hypertension
may trigger in postoperative period
unexpected Adequate should raise consideration
movement, causing sedation during of the possibility of
secondary injury. procedures inadequate sedation.
Careful
monitoring of
temperature
during
perioperative
Hyper- or hypothermia period
Surveillance
In addition to regular evaluations by a pediatrician and
dermatologist (to assess and advise on skin infections/injuries)
the measures in Table 5 are recommended.
Table 5. Recommended surveillance for individuals

congenital insensitivity to pain
Manifestation/Concern Evaluation Frequency/Comment
Dental caries / Tooth Regular examinations

damage Dental care (at least every 6 mos)
5
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Manifestation/Concern Evaluation Frequency/Comment
Evaluation by parents
CONDITIONS D R U G S & S U P&Pcaregivers
L E M E N T S for signs
Early injuries of unrecognized injury Daily
Prompt investigation
& treatment of
orthopedic
consequences of
congenital At least yearly, or
insensitivity to pain by more frequently
a named orthopedic depending on bony
Bone health surgeon injuries
At least annually, or
Ophthalmology more frequently as
Corneal damage evaluation indicated
Monitoring of body
temperature may
allow timely treatment
of hyper- or
Hyper- or hypothermia hypothermia. As needed
Congenital insensitivity to pain life

expectancy
Congenital insensitivity to pain is a rare disease with a short life
expectancy, proper management could be administered in
order to extend the patient’s life expectancy.

with anhidrosis
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare
inherited
5 disorder whose core clinical features consist of the
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inability to feel pain and temperature, and decreased or absent
36)
sweating (anhidrosis) . CIPA or congenital insensitivity to pain
with anhidrosis is also known as hereditary sensory and
CONDITIONS D R U G S & S U P P L E M E N 37)
TS L I V I N G H E A LT H Y FO O D A D D I T I
autonomic neuropathy type IV (HSAN IV) . CIPA is a rare
autosomal recessive genetic disorder that is caused by the
38)
failure of nociceptive and sympathetic neuron development .
39)
In 1996, Indo et al first identified neurotrophic tyrosine
kinase receptor type 1 (NTRK1) mutations in three unrelated
CIPA patients. The gene NTRK1 located on chromosome 1q21-
q22 includes 17 exons and yields a 796-residue protein
(tropomyosin-related kinase A [TrkA]). TrkA protein specifically
binds to extracellular nerve growth factor (NGF), stimulates
homodimer formation, and activates its tyrosine kinase activity,
resulting in phosphorylation of specific tyrosine residues in the
intracellular domain. The lack of pain sensation and the
presence of anhidrosis in CIPA are caused by the absence of
NGF-dependent primary afferent neurons with unmyelinated C-
40)
fibers and sympathetic postganglionic neurons, respectively .
To date, more than 105 NTRK1 mutations have been reported in
41)
CIPA patients .
The signs and symptoms of CIPA appear early, usually at birth or

during infancy, but with careful medical attention, affected
individuals can live into adulthood. An inability to feel pain and
temperature often leads to repeated severe injuries.
Unintentional self-injury is common in people with CIPA,
typically by biting the tongue, lips, or fingers, which may lead to
spontaneous amputation of the affected area. In addition,
people with CIPA heal slowly from skin and bone injuries.
Repeated trauma can lead to chronic bone infections
(osteomyelitis) or a condition called Charcot joints, in which the
bones and tissue surrounding joints are destroyed.
5
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Normally, sweating helps cool the body temperature. However,
in people with CIPA, anhidrosis often causes recurrent,
extremely high fevers (hyperpyrexia) and seizures brought on by
high temperature (febrile seizures).
In addition to the characteristic features, there are other signs

and symptoms of CIPA. Many affected individuals have thick,
leathery skin (lichenification) on the palms of their hands or
misshapen fingernails or toenails. They can also have patches
on their scalp where hair does not grow (hypotrichosis). About
half of people with CIPA show signs of hyperactivity or
emotional instability, and many affected individuals have
intellectual disability. Some people with CIPA have weak muscle
tone (hypotonia) when they are young, but muscle strength and
tone become more normal as they get older.
CIPA is an extremely rare condition in most populations except

the Japanese and Israeli Bedouins. Of note, in 2009 the number
of Japanese with CIPA was estimated at between 130 and 210
42)
.
In the Japanese and Israeli Bedouin populations relatively

43)
common founder pathogenic variants have been reported :
Three variants – p.Phe284TrpfsTer36, p.Arg554GlyfsTer104, and

p.Asp674Tyr – account for roughly 70% of pathogenic NTRK1
alleles in the Japanese.
One variant – p.Pro621SerfsTer12 – accounts for 89% of
44)
pathogenic NTRK1 alleles among Israeli Bedouins .
Half of reported cases have occurred in offspring of

45)
consanguineous parents .
Specific
5 carrier frequencies are not available.
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The diagnosis of CIPA is suspected in infants and children with
recurrent fever and biting of the tongue, lips, or fingers after
eruption of the first teeth, and in older individuals with repeat
CONDITIONS D R46)U G S & S U P P L E M E N T S L I V I N G H E A LT H Y FO O D A D D I T I
traumatic injuries . Evaluation of sensory and autonomic
functions (including pharmacologic tests) and skin and nerve
biopsies were used in the past for clinical diagnosis, however,
the diagnosis can now be confirmed by identification of biallelic
pathogenic variants in NTRK1.
CIPA causes
Mutations in the NTRK1 gene cause CIPA. The NTRK1 gene
provides instructions for making a receptor protein that
attaches (binds) to another protein called NGFβ. The NTRK1
receptor is important for the survival of nerve cells (neurons).
The NTRK1 receptor is found on the surface of cells, particularly

neurons that transmit pain, temperature, and touch sensations
(sensory neurons). When the NGFβ protein binds to the NTRK1
receptor, signals are transmitted inside the cell that tell the cell
to grow and divide, and that help it survive. Mutations in the
NTRK1 gene lead to a protein that cannot transmit signals.
Without the proper signaling, neurons die by a process of self-
destruction called apoptosis. Loss of sensory neurons leads to
the inability to feel pain in people with CIPA. In addition, people
with CIPA lose the nerves leading to their sweat glands, which
causes the anhidrosis seen in affected individuals.
CIPA inheritance pattern

Congenital insensitivity to pain with anhidrosis or CIPA is
inherited in an autosomal recessive pattern, which means both
copies of the gene in each cell have mutations. The parents of
an individual with an autosomal recessive condition each carry
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one copy of the mutated gene, but they typically do not show
signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions
within a family because if someone is a carrier for one of these
conditions, they would have to have a child with someone who
is also a carrier for the same condition. Autosomal recessive
conditions are individually pretty rare, so the chance that you
and your partner are carriers for the same recessive genetic
condition are likely low. Even if both partners are a carrier for
the same condition, there is only a 25% chance that they will
both pass down the non-working copy of the gene to the baby,
thus causing a genetic condition. This chance is the same with
each pregnancy, no matter how many children they have with or
without the condition.
If both partners are carriers of the same abnormal gene, they

may pass on either their normal gene or their abnormal gene to
their child. This occurs randomly.
Each child of parents who both carry the same abnormal gene
therefore has a 25% (1 in 4) chance of inheriting a abnormal
gene from both parents and being affected by the condition.
This also means that there is a 75% ( 3 in 4) chance that a child
will not be affected by the condition. This chance remains the
same in every pregnancy and is the same for boys or girls.
There is also a 50% (2 in 4) chance that the child will inherit just
one copy of the abnormal gene from a parent. If this happens,
then they will be healthy carriers like their parents.
Lastly, there is a 25% (1 in 4) chance that the child will inherit
both normal copies of the gene. In this case the child will not
have the condition, and will not be a carrier.
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These possible outcomes occur randomly. The chance remains
the same in every pregnancy and is the same for boys and girls.

Figure 3 illustrates autosomal recessive inheritance. The
example below shows what happens when both dad and mum
is a carrier of the abnormal gene, there is only a 25% chance
that they will both pass down the abnormal gene to the baby,
thus causing a genetic condition.
Figure 3. CIPA autosomal recessive inheritance pattern
People with specific questions about genetic risks or genetic

testing
5 for themselves or family members should speak with a
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genetics professional.
Resources for locating a genetics professional in your

community are available online:
The National Society of Genetic Counselors

(https://www.findageneticcounselor.com/) offers a searchable
directory of genetic counselors in the United States and Canada.
You can search by location, name, area of
practice/specialization, and/or ZIP Code.
The American Board of Genetic Counseling
(https://www.abgc.net/about-genetic-counseling/find-a-certified-
counselor/) provides a searchable directory of certified genetic
counselors worldwide. You can search by practice area, name,
organization, or location.
The Canadian Association of Genetic Counselors
(https://www.cagc-accg.ca/index.php?page=225) has a
searchable directory of genetic counselors in Canada. You can
search by name, distance from an address, province, or
services.
The American College of Medical Genetics and Genomics
(http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx)
has a searchable database of medical genetics clinic services in
the United States.
CIPA signs and symptoms

Congenital insensitivity to pain with anhidrosis (CIPA) is
characterized by profound sensory loss affecting pain and
temperature perception, absence of sweating (anhidrosis), and
intellectual disability.
Anhidrosis
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Because sweating plays an important role in maintaining normal
body temperature, anhidrosis (the failure to sweat) disturbs
thermoregulation in hot environmental conditions and
CONDITIONS DRUGS & SUPPLEMENTS L I V I N47)G H E A LT H Y FO O D A D D I T I
increases susceptibility to recurrent febrile episodes .
Recurrent episodic fevers, usually the first clinical sign of CIPA,

can begin in infancy or early childhood depending on
48)
environmental temperature . Recurrent febrile convulsions
are also observed in some affected infants.
49)
Occasionally, hypothermia is observed in cold environments .
Anhidrosis is present on the trunk and upper extremities in

50)
100% of cases and more variable in other areas of the body .
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
51)
evaporation of insensible water .
Insensitivity to pain
While impaired pain perception may not be apparent in early
infancy, parents may recall that their infant with CIPA did not cry
52)
during venipuncture or immunizations .
Tongue ulcers and fingertip biting, the characteristic self-

mutilation observed in infants with 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
53)
.
Biting of the fingers and ulcerated fingertips is common.

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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

54)
serious complications of CIPA .
Frequent orthopedic complications are:
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 and even
55)
affects cranial nerves and visceral sensation .
Neurotrophic keratitis (degenerative disease of the corneal

epithelium resulting from impaired corneal sensation) manifests
initially as superficial punctate keratopathy which later can
56)
result in corneal ulceration and even perforation . Of note,
tearing (both overflow or emotional) is normal.
5
Intellectual disability
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Most individuals with CIPA have varying degrees of intellectual
57)
disability and show characteristic behaviors . Affected
individuals show defects in conceptual thinking, abstract
reasoning, and social behavior, as well as moderate to severe
58)
emotional disturbance . Some may exhibit rage. Assessments
of cognitive and adaptive behavior suggest that many children
with CIPA have intellectual disability (or learning disabilities) and
59)
severe attention-deficit-hyperactivity disorder (ADHD) .
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
60)
abrasions . Significant fissuring of the plantar skin is common.
Some affected individuals develop painless deep heel ulcers
61)
that are slow to heal .
Hypotonia is seen frequently in the early years, but strength and
tone normalize as the individual gets older; tendon reflexes are
62)
normal .
Gastrointestinal dysmotility is mild or absent.
Vomiting is not a feature, but can be observed in some affected
individuals.
Speech is usually clear.
63)
Gao et al have reported oral and craniofacial manifestations,
including nasal malformation, submucous cleft palate, and
developmental abnormalities of the teeth.
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CIPA diagnosis
The diagnosis of congenital insensitivity to pain with anhidrosis
CONDITIONS DRUGS & SUPPLEMENTS LIVING HEA 64)LT H Y FO O D A D D I T I
(CIPA) is made clinically based on presence of the following :
Impaired perception of pain and temperature, manifest in

infants by biting of the tongue, lips, or fingers after the first
teeth erupt; and in older individuals by repeated traumatic
injuries including bruising, bone fractures and painless joint
dislocations often associated with neurogenic arthropathy
(Charcot joint) of the knees and ankles. There may be a history
of failure to recognize burns and other injuries.
Anhidrosis (absence of sweating), manifest as recurrent febrile
episodes beginning in early infancy
Intellectual disability.
The diagnosis of CIPA is confirmed by identification of biallelic

65)
pathogenic variants in NTRK1 (TRKA) . Mutation of NTRK1
accounts for all cases of properly classified CIPA.
Neurologic examination supports the diagnosis:
Insensitivity to superficial and deep painful stimuli is confirmed

when painful stimuli fail to evoke either withdrawal or
emotional change [Swanson 1963]. For example, no tenderness
or pain sensation is elicited even when apparently injured joints
or broken bones are moved passively or actively. See also
Special studies.
Impaired temperature perception is confirmed when:
Consistent errors are made in distinguishing between hot and
cold moist substances.
Extreme cold or heat fails to elicit the usual withdrawal
5 response. See also Special studies.
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Visceral pain perception is also impaired.
Impairment of the autonomic nervous system may be evident
C O N Dby
I Tthe
I O Npresence
S D R UofG SHorner
& S U Psyndrome
P L E M E N Tand
S the
L Icold
V I N Gpressor
H E A LTtest.
HY FO O D A D D I T I
Normal findings are:
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. Note: No pathologic reflexes are observed.
Additional tests supporting the diagnosis of CIPA:
Skin tests demonstrating abnormalities in sweating and the lack

of the axon reflex. See Special studies for more details
(https://www.ncbi.nlm.nih.gov/books/NBK1769/bin/hsan4-
special-studies.pdf).
Note: Skin and nerve biopsies were used to confirm the

diagnosis in the past; however, molecular genetic testing is now
preferred.
CIPA treatment
To establish the extent of disease and needs in an individual
diagnosed with congenital insensitivity to pain with anhidrosis
(CIPA) (also known as hereditary sensory and autonomic
neuropathy type IV [HSAN IV]), the following evaluations are
recommended:
General physical examination for evidence of self-mutilation of

tongue, lips, buccal mucosa; skin injury including infection
and/or palmoplantar hyperkeratosis, bone injury including old
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poorly healing fractures and/or joint injury including
dislocations, as well as behavioral and developmental problems
C O N DOrthopedic
I T I O N S consultation
D R U G S & S regarding
U P P L E M Eassessment
NTS L I Vof
I N injuries ofHthe
G H E A LT Y FO O D A D D I T I
extremities and weight-bearing joints, including radiographs as
necessary
Dental examination to assess for auto-extraction of teeth,
evidence of dental caries and/or abscess, as well as overall
dental health
Ophthalmologic examination to assess for evidence of
neuropathic keratitis and its sequelae (corneal infection,
ulceration, and/or perforation)
Consultation with a clinical geneticist and/or genetic counselor
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 dry
eyes, prevention of corneal infection, and daily observation of
5 the ocular surface. Interventions for behavioral, developmental,
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and motor delays as well as educational and social support for
school-age children and adolescents are recommended.

Orthopedic
Bone fractures of weight-bearing bones and joints can lead to

failure of bone union and hypertrophic osseous callous
66)
formation, as well as neurogenic arthropathy (Charcot joint) .
Because such injuries and their sequelae are difficult to treat,
the goal of orthopedic management is to prevent severe
articular destruction and the need for surgical amputation.
Although the parents and caregivers of an affected child are

advised to modify the child’s activities to prevent injuries, it is
often very difficult due to the child’s inability to perceive pain.
While protective appliances, such as braces to prevent injury to
the lower limbs can be tried, they are associated with a high risk
of secondary skin injury and, thus, infection.
Careful daily evaluation by parents and caregivers for early signs

of otherwise unrecognized injury is important for early
detection and treatment of injuries.
Appropriate footwear and periods of non-weight-bearing are

important in the prevention and early treatment of ulcerating
67)
foot lesions .
In the treatment of various injuries the absence of pain

perception makes immobilization difficult, often resulting in
delayed healing. Additionally, infection is a serious potential
complication of any invasive procedure, such as treatment of
68)
bone fractures with an external fixator .
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Of note, longstanding infections require wide surgical
debridement.

Bone and joint deformities can be managed by corrective
osteotomy; leg length discrepancy can be managed by shoe lifts
69)
and/ or epiphysiodesis ; however, the value of surgical
intervention needs to be weighed against non-surgical
70)
approaches including close monitoring . Joint dislocations are
best treated conservatively.
Dental
Early and routine preventative oral/dental care and timely

treatment of the dental and oral conditions associated with CIPA
can help reduce the characteristic oral and dental
71)
manifestations .
In infants, the incisal edges of newly erupted mandibular

primary incisors traumatize the ventral surface of the tongue
with sucking and nursing. This ulceration of the tongue can lead
to bleeding and infection of the tongue, and halitosis, as well as
systemic problems such as poor weight gain and failure to
thrive.
The oral self-mutilation (i.e., the severe biting injuries [and

resultant scarring] of the fingertips and/or oral soft tissues
[tongue, lip, and buccal mucosa]) is found in most affected
individuals. Although self-mutilation appears to decrease with
age and with intellectual, social, and/or emotional development,
such behaviors cannot be completely eliminated.
Methods used to prevent injuries to the lips, buccal mucosa,

tongue, and teeth include tooth extraction, and/or filing
72)
(smoothing) of their sharp incisal edges , and/or use of a
5
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mouth guard, a protective plate of thermoplastic resin ~0.6-0.8
73)
mm thick . Mouth guards must be refashioned as new teeth
erupt and the jaw grows. Although use of a mouth guard is a
reasonable approach, mouth guards can be difficult to prepare
and/or retain.
The high rate of missing teeth and untreated carious teeth

observed in individuals with CIPA suggests that dental
examination and/or care is underutilized or that tooth decay
may be overlooked because of the insensitivity to pain. Serious
tooth decay can cause osteomyelitis that can lead to mandibular
bone fracture.
Eye
Care for dry eyes, prevention of corneal infection, and daily

observation of the ocular surface are crucial for maintaining
74)
good visual function . Of note, surgical treatment of
neurotrophic keratitis has not been successful as poor
outcomes of lateral tarsorrhaphy, corneal patch graft, and
75)
penetrating keratoplasty have been reported .
Skin
Daily care with a skin moisturizer is recommended to prevent or

reduce skin cracking which can lead to bruising, and skin
infections, which can progress to more significant infections
such as cellulitis or osteomyelitis.
Parents or guardians should practice skin care to prevent

serious infections, including daily observation of the whole skin
surface and early treatment of even minor skin lesions.
Behavior
5
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Interventions for behavioral, developmental and motor delays
as well as educational and social support for school-age children
and adolescents are important.
Although irritability, hyperactivity, impulsivity, and acting-out

behaviors typically improve with age, medications for
antipsychotic and/or attention-deficit/hyperactivity disorder
(ADHD) in conjunction with behavior modification may be
beneficial. The advantages and disadvantages should be
weighed for each individual with CIPA.

Regular dental examinations and restriction of sweets to
prevent dental caries; early treatment of dental caries and
periodontal disease to prevent osteomyelitis of the mandible.
During and following surgical procedures, potential
complications to identify and manage promptly include hyper-
or hypothermia and inadequate sedation, which may trigger
unexpected movement and result in secondary injuries.
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 are recommended to help prevent serious
injuries and initiate early treatment. Annual follow up at a
center that fosters comprehensive care and communication
between the various subspecialties that are needed for optimal
care.
Agents and circumstances to avoid
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Hot or cold environments; hot or cold foods; hot showers or
baths; jumping or high-impact activities and sports.
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CONDITIONS DRUGS & SUPPLEMENTS L I V I N G H E A LT H Y FO O D A D D I T I

Congenital insensitivity to pain

Congenital insensitivity to pain is considered a form of

Congenital insensitivity to pain is a rare condition; about 20

Figure 1. Congenital insensitivity to pain

Footnote: (A) Typical loss of fingertips secondary to trauma,

1. Three individuals from a large northern Swedish family who

Congenital insensitivity to pain causes

The SCN9A gene mutations that cause congenital insensitivity to

Congenital insensitivity to pain

It is rare to see any history of autosomal recessive conditions

If both partners are carriers of the same abnormal gene, they

CONDITIONS DRUGS & SUPPLEMENTS L I V I N G H E A LT H Y FO O D A D D I T I

Figure 2. Congenital insensitivity to pain autosomal

Resources for locating a genetics professional in your

The National Society of Genetic Counselors

Congenital insensitivity to pain

All affected individuals are at risk for corneal injuries due to

Apparent selectively reduced immunity to Staphylococcus

Temperature Regulation, Anhidrosis, and Hyperhidrosis

Some individuals have anhidrosis (lack of sweating), which

Marked hyperhidrosis may be seen in those affected individuals

Hypothermia can occur in cold conditions.

Development and Intellect

Development and intellect may be normal or delayed/disabled

Individuals with congenital insensitivity to pain caused by

Chronic anemia of unknown cause was observed in 22/28 Israeli

A few individuals have neuropathic pain, although this does not

Congenital insensitivity to pain

The technique should not damage/scar prior to significant pain

Assessment of the remainder of the peripheral and central

CONDITIONS DRUGS & SUPPLEMENTS L I V I N G H E A LT H Y FO O D A D D I T I

For more information about autonomic function testing for

Targeted gene testing requires the clinician to develop a

Serial single-gene testing

The phenotype may guide the choice of which gene(s) to analyze

SCN11A first in a newborn with severe intestinal hypomotility.

If no pathogenic variant in SCN11A is found through sequence

Note: Whole-gene deletions have been reported in individuals

A multigene panel that includes genes for congenital

Note: The genes included in the panel and the diagnostic

Comprehensive genomic testing (when available) including

Congenital insensitivity to pain

Individuals with congenital insensitivity to pain typically learn

The possibility that naloxone may temporarily relieve congenital

Jumping, high-impact/contact sports, pastimes and jobs that

Women with congenital insensitivity to pain are able to become

Table 2. Treatment of manifestations in individuals with

Manifestation/Concern Treatment Considerations/Other

Treatment w/an external

Prolonged & intensive

The value of surgical

Longstanding Wide surgical

Appropriate footwear &

Direct cooling in a Control of environmental

Untreated dry skin can →

Developmental delay and intellectual disability

The following information represents typical management

Developmental delay and intellectual disability educational

Ages 0-3 years. Referral to an early intervention program is

Developmental Disabilities Administration (DDA) enrollment is

Social and behavioral concerns

Consultation with a developmental pediatrician may be helpful