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:
1. Nociceptive neurons - cannot detect pain
2. Sympathetic postganglionic neurons - no innervation to sweat glands (hence anhidrosis)
3. 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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