Table 1.

Genes Associated with Congenital Insensitivity to Pain (CIP)

GeneProportion of Affected Individuals with Mutation of This GeneMOIDistinguishing Features
CLTCL1 1RareAR
  • Severe non-progressive learning disability
  • Delay in central nervous system myelination
  • One family reported
NGF 3RareAR
  • Variable phenotype
  • Individuals w/biallelic null variants may have anhidrosis, mild/moderate ID, prematurely aged appearance, ↑ Staphylococcus aureus infections, & Charcot joints.
  • Individuals w/a homozygous missense variant had impairment of pain/temperature sensation & Charcot joints, normal intellect & normal sweating. 4
NTRK1 5CommonAR
  • Anhidrosis
  • Tendency to develop corneal ulcers that heal poorly 6
  • ID in a majority; always less intellectually able than unaffected family members
  • Predisposition to Staphylococcus aureus infections
  • Charcot joints
  • Dry skin w/lichenification
  • Also known as HSAN IV
PRDM12 7IntermediateAR
  • Non-global pain insensitivity in some
  • Absent corneal reflex & impaired tear production
  • Staphylococcus aureus infections
  • No Charcot joints
  • Difficulties w/temperature regulation in some
  • Usually normal neurologic exam, development, intellect, & olfaction 8
  • Known as HSAN VIII
SCN9A 9, 10CommonAR
  • Anosmia 11
  • Charcot joints
  • Normal corneal reflex & tear production
SCN11A 12RareAD
  • Delayed motor development
  • Mild muscle weakness
  • Joint hypermobility
  • Gastrointestinal dysfunction (intestinal hypoperistalsis or diarrhea)
  • Pruritis
  • Hyperhidrosis in those w/c.2432T>C (p.Leu811Pro) variant
ZFHX2 13RareAD
  • 1 family reported
  • Non-global pain insensitivity w/lower back pain, headaches, & pain during childbirth perceived
  • Normal intelligence
  • Scarce or absent sweating
  • Variably reduced sensitivity to heat and cold
  • Low sensitivity to capsaicin – able to eat large amount of hot pepper w/out discomfort
  • Some autonomic features such as fainting & vomiting

AD = autosomal dominant; AR = autosomal recessive; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance

1.
3.
4.

Three individuals from a large northern Swedish family who were homozygous for the NM_002506​.2:c.661C>T, (p.Arg211Trp) pathogenic variant [Einarsdottir et al 2004]. 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 CIP.

5.
6.
7.
8.

Saini et al [2017] described a male age two years with a homozygous pathogenic splice site variant in PRDM12 who had global developmental delay, dolicocephaly, frontal bossing, and deep-set eyes as well as congenital insensitivity to pain.

8.
10.

Pathogenic variants are typically truncating, although one missense variant and one in-frame deletion have been described [Cox et al 2010].

11.
12.

Recurrent de novo variants have been reported: NM_014139​.2:c.2432T>C (p.Leu811Pro) and NM_014139​.2:c.3904C>T, (p.Leu1302Phe). Another pathogenic de novo variant, NM_014139​.2:c 1187T>C (p.Leu396Pro) has also been reported. Recurrent variants may be inherited. [Leipold et al 2013, Phatarakijnirund et al 2016, Huang et al 2017, King et al 2017].

13.

From: Congenital Insensitivity to Pain Overview

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