Insensitivity to Pain, Congenital, with Anhidrosis

Alternative Names

  • CIPA
  • Neuropathy, Congenital Sensory, with Anhidrosis
  • Hereditary Sensory and Autonomic Neuropathy IV; HSAN4
  • HSAN IV
  • Familial Dysautonomia, Type II
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations of the nervous system

OMIM Number

256800

Mode of Inheritance

Autosomal recessive

Gene Map Locus

1q23.1

Description

Congenital insensitivity to pain with anhidrosis is a rare autosomal-recessive disorder of the nervous system. Lack of pain sensation, painless injuries of the extremities and oral structures with self mutilation, fever secondary to anhidrosis (lack of sweating) during hot weather, mental retardation, and loss of unmyelinated and diminution of small myelinated fibers in sural nerve specimens are the main features of the disease. Infection and scarring of the tongue, lips, and gums occur frequently, and keratoderma palmo-plantaris is a typical feature in older patients. Chronic infections of bones and joints represent additional complications.

In congenital insensitivity to pain with anhidrosis the insensitivity to pain is associated with the defective development of the small, nociceptive neurons in the dorsal root ganglia. These nociceptive neurons and the cells of the sympathetic ganglia derive from the neural crest, and their survival is stimulated by the nerve growth factor through the neuronal tyrosine kinase receptor. Mutations in the tyrosine kinase receptor A gene, described recently in patients with congenital insensitivity to pain with anhidrosis, correlate well with the defective development of the nociceptive neurons. Human tyrosine kinase receptor A is a receptor tyrosine kinase which is phosphorylated in response to nerve growth factor. The binding of the nerve growth factor to tyrosine kinase receptor A stimulates homodimer formation and activation of tyrosine kinase activity. Phosphorylated tyrosine residues in tyrosine kinase receptor A cytoplasmic domain serve as anchors for binding downstream signaling molecules.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
256800.1LebanonMaleYes Self-mutilation; Motor delay; Joint hy...NM_002529.3:c.2205+1G>AHomozygousAutosomal, RecessiveNair et al. 2018
256800.2United Arab EmiratesMaleYesYes Pain insensitivity; Fever; Aganglionic m...NM_002529.4:c.429-1G>CHomozygousAutosomal, RecessiveSaleh et al. 2021 Affected cousins
256800.3.1United Arab EmiratesMaleNoYes Pain insensitivity; Anhidrosis; Failure ...NM_002529.4:c.429-1G>C, NM_002529.4:c.253C>AHomozygousAutosomal, RecessiveMardy et al. 2001; Sztriha et al. 2001; Mardy et al. 1999 Patient from 'family...
256800.4.1KuwaitFemaleYes Pain insensitivity; AnhidrosisNM_002529.4:c.284delHomozygousAutosomal, RecessiveMardy et al. 1999 Patient from 'family...
256800.4.2KuwaitFemaleYes Pain insensitivity; AnhidrosisNM_002529.4:c.284delHomozygousAutosomal, RecessiveMardy et al. 1999 Sister of 256800.4.1
256800.5.1KuwaitFemaleYes Pain insensitivity; AnhidrosisNM_002529.4:c.850+1G>AHomozygousAutosomal, RecessiveMardy et al. 1999 Patient from 'family...
256800.5.2KuwaitFemaleYes Pain insensitivity; AnhidrosisNM_002529.4:c.850+1G>AHomozygousAutosomal, RecessiveMardy et al. 1999 Sister of 256800.5.1

Other Reports

Morocco

Vardy et al. (1979) described two girls with CIPA, born to consanguine Jewish parents of Moroccan origin. An immunologic investigation on one of the cases showed only an early and transient deficiency of IgA. the presence in the family of a brother with ataxia telangiectasia and complete absence of IgA led Vardy et al. (1979) to speculate that the parents were probably heterozygotic for two disparate autosomal recessive syndromes.

Saudi Arabia

Jarade et al. (2002) reported a case of a 6 year-old boy patient with congenital insensitivity to pain with anhidrosis. The patient presented a bilateral central corneal sterile ulcer, decreased corneal sensitivity, moderately altered corneal reflex and normal tearing response. Jarade et al. (2002) concluded that congenital insensitivity to pain with anhidrosis may present as neurotrophic corneal ulcer.

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