Table 2.

Other Disorders to Consider in the Differential Diagnosis of Congenital Insensitivity to Pain (CIP)

Differential Diagnosis DisorderGene(s)MOIClinical Features of the Disorder
Overlapping w/CIPDistinguishing from CIP
Hereditary
Hypohidrotic ectodermal dysplasia EDA
EDAR
EDARADD 		XL
AR
AD
  • Lack of sweating (overlap w/NTRK1- & NGF-CIP)
  • Risk of hyperthermia
Insensitivity to pain not a feature
Lesch-Nyhan syndrome HPRT1 XLProgressive self-injurious behavior (biting fingers, hands, lips, cheeks; banging the head or limbs)
  • Hyperuricemia
  • Progressive, severe DD/ID
  • Abnormal involuntary movements
COL1A1/2-related osteogenesis imperfecta COL1A1
COL1A2 		ADMultiple fractures
  • Fractures cause pain
  • Fractures occur w/minimal or absent trauma
  • Assoc w/other features incl blue sclera, short stature, joint hypermobility, deafness
Familial dysautonomia (also known as HSAN III)ELP1 (IKBKAP)ARReduced pain from birthGastrointestinal dysfunction, vomiting crises, recurrent pneumonia, cardiovascular & temperature instability
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome MPV17 AR
  • Absent pain responses from birth
  • DD (can be seen in NTRK1 & NGF-CIP)
  • Infantile-onset liver dysfunction typically → liver failure
  • Failure to thrive, lactic acidosis, & hypoglycemia
  • More severe neurologic involvement; may incl white matter abnormalities on MRI & seizures
Acquired
Leprosy 1NANA
  • Insensitivity to pain
  • Painless injuries
  • Skin lesions (hypopigmented macules, nodules, plaques, or diffuse skin infiltration)
  • Enlargement of peripheral nerves
  • Localized (not universal) insensitivity to pain
Non-accidental / abusive injuryNANAMultiple unexplained injuries
  • Normal response to pain (although caregivers may deny this)
  • Different pattern of injuries (proportionate to size & development of child)

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable; XL = X-linked

1.

From: Congenital Insensitivity to Pain Overview

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