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Cipa
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What are you referring to by 'CIPA'?
CIPA (Congenital Insensitivity to Pain with Anhidrosis) is a rare hereditary sensory and autonomic neuropathy (HSAN type IV) caused by mutations in the NTRK1 gene, which encodes the nerve growth factor receptor TrkA. It results in complete inability to feel pain, absence of sweating, and intellectual disability in some cases.
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Here is a thorough overview of CIPA:
Congenital Insensitivity to Pain with Anhidrosis (CIPA)
What is it?
CIPA (also called HSAN type IV - Hereditary Sensory and Autonomic Neuropathy type IV) is a rare autosomal recessive disorder characterized by four core features:
| Feature | Description |
|---|---|
| Pain insensitivity | Complete inability to feel noxious/painful stimuli from birth |
| Anhidrosis | Inability to sweat (no eccrine sweat gland function) |
| Recurrent hyperpyrexia | Life-threatening fever episodes due to inability to thermoregulate |
| Intellectual disability | Variable degrees of mental retardation |
| Self-mutilating behavior | Secondary to not feeling pain - biting lips/fingers, eye gouging |
Genetics & Pathophysiology
- Gene: Loss-of-function mutations in the NTRK1 gene (Neurotrophic Tyrosine Receptor Kinase 1), which encodes the TrkA receptor - the high-affinity receptor for nerve growth factor (NGF).
- Mechanism: Defective NTRK1 signaling disrupts the development of three key neuronal populations:
- Nociceptive neurons - cannot detect pain
- Sympathetic postganglionic neurons - no innervation to sweat glands (hence anhidrosis)
- Central cholinergic neurons - contributing to cognitive involvement
- Inheritance: Autosomal recessive; more common in consanguineous populations (notably Israeli Jewish and Japanese families).
Clinical Features
- From birth: no response to painful stimuli, recurrent unexplained fevers
- Childhood: repeated injuries (fractures, burns, joint damage) without complaint; corneal ulcers from eye rubbing; poor dentition from biting
- Skin: dry skin, no sweating even in heat
- Joint/bone complications: Charcot joints, osteomyelitis, repeated fractures
- Thermoregulation failure is the most life-threatening aspect - patients can develop hyperthermia rapidly in warm environments or during infections
Diagnosis
- Clinical diagnosis based on the tetrad of features
- Skin/nerve biopsy: absence of unmyelinated C fibers and small myelinated A-delta fibers; absent or abnormal sweat glands
- Genetic testing: NTRK1 mutation confirmation
- Sweat testing (pilocarpine iontophoresis, starch-iodine test) - confirms anhidrosis
- Histamine skin test: absent axon flare response
Management
There is no cure. Management is entirely supportive:
- Temperature monitoring and cooling measures (fans, cool environments, wet cloths) - preventing hyperthermia is the top priority
- Injury prevention: protective gear, regular joint/bone surveillance, ophthalmologic check-ups
- Orthopedic care: aggressive management of fractures and Charcot joints
- Dental surveillance: regular exams, protective mouthguards
- Behavioral management for self-mutilation
Prognosis
- Prognosis is guarded, particularly in early childhood - hyperpyrexia is the leading cause of death
- Survival into adulthood is possible with careful management
- Accumulating joint and bone damage can significantly limit quality of life
Recent Research (2024)
Recent reviews (PMID 39493574) have explored stem cell therapy as a potential future treatment approach, targeting restoration of NGF/TrkA signaling. A 2024 systematic review (PMID 38929791) confirmed the rarity and management challenges of the condition.
Sources: Fitzpatrick's Dermatology, 9th ed.; Adams and Victor's Principles of Neurology, 12th ed.
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