Congenital Insensitivity to Pain and Anhidrosis (CIPA)

Original Editor - Reem Ramadan Top Contributors - Reem Ramadan and Carina Therese Magtibay

Introduction[edit | edit source]

Congenital Insensitivity to Pain and Anhidrosis (CIPA) is a rare genetic disorder affecting the autonomic nervous system and is described as hereditary sensory and autonomic neuropathy type IV (HSAN IV). It is characterized by the inability to perceive pain and temperatures sensations and the inability to sweat[1]. It's incidence varies among populations but is estimated to occur in 1 in 125 million newborns[2].

Pathological Process[edit | edit source]

CIPA is a genetic disorder, inherited in an autosomal recessive pattern which means that the parents of the individual diagnosed with CIPA each carry one copy of the mutated gene and don't show symptoms or signs of the condition[3]. It is caused by mutations in neurotrophic tyrosine kinase receptor 1 ( NTRK1 ) gene. The NTRK1 gene is responsible for giving instructions for the synthesis of a receptor protein that binds to another protein called nerve growth factor beta (NGFβ). The NTRK1 is found on the surface of sensory neurons that transmit pain, temperature and touch sensations and when the NGFβ protein binds to this receptor, the process of autophosphorylation is activated which means that NTRK1 is activated and cells are signaled to grow and divide maintaining the survival of nerve cells[4]. Mutations in the NTRK1 gene lead to dysfunctions in the NGFβ protein and thus errors in transmitting signals which eventually lead to apoptosis of neuronal cells leading to inability to feel pain and temperature sensations in addition to inability to sweat due to the loss of neuronal connections to the sweat glands[5].

Clinical Presentation[edit | edit source]

Clinical manifestations affecting the[6]:

  1. Sensory Nervous System: lip biting, corneal scarring, autoamputation of digits, loss of temperature sensation and hypoalgesia.
  2. Autonomic Nervous System: anhidrosis and hyperpyrexia.
  3. Cognition: intellectual disability, impulsivity, hyperactivity and delayed maturation.
  4. Gastrointestinal System: uncoordinated swallowing, recurrent misdirection, nausea and vomiting.
  5. Respiratory System: pneumonia and hypoxemia.
  6. Cardiovascular System: circulatory lability, postural hypotension and blotchy erythema.
  7. Musculoskeletal System: delayed cutaneous healing, periungual lesions, early loss of teeth, fractures caused by minor traumas, delayed bone union, staphylococcus aureus osteitis, septic fistulated pseudarthrosis, multiple dislocations and neuroarthropathic complications.

Diagnostic Procedures[edit | edit source]

The diagnosis of CIPA is mainly clinically where the main symptoms necessary for diagnosis include the insensitivity to pain and temperature, anhidrosis and intellectual disabilities. In addition to that, some tests may be needed to confirm the diagnosis including a skin biopsy which reveals the lack of eccrine sweat gland innervation. Sural nerve biopsy may also be needed to reveal reduced numbers of myelinated and unmyelinated small diameter fibers with normal numbers of large diameter fibers[7]. Furthermore, an axonal flare test may be needed where a small amount of diluted histamine is injected in the skin and in the case of patients with CIPA there will be no flare around the site of injection[8]. Genetic testing may also aid in the diagnosis[5]. It's also important to note that laboratory findings may also help in diagnosis where in patient diagnosed with CIPA, the plasma norepinephrine is very low and fails to increase in upright position despite the blood pressure being normal in that position whereas the plasma epinephrine levels are normal and increase when the patient is upright[9].

Management/Interventions[edit | edit source]

The therapeutic approach for CIPA is still evolving and there's no definite agreement regarding its management. Managing CIPA typically requires a team of healthcare professionals, including geneticists, neurologists, orthopedists, dentists, and psychologists, who can work together to address various aspects of the condition. Geneticists and neurologists are responsible for the early diagnosis of the condition and the prescription of adequate medications to avoid complications and to manage the condition more effectively. In addition to that, dentists play a crucial role in the treatment for patients diagnosed with CIPA may not feel toothaches or gum problems which explains why it's necessary to do regular checkups to prevent dental problems. Furthermore, psychologists play an important role in providing emotional support and counseling for these patients due to how challenging it is to suffer from such a disorder. Physical Therapists also play an important role where they provide mobility and strength training to help CIPA patients maintain a better posture, balance and coordination and reduce the risk of falls. In addition to that, physical therapists can help through sensory integration techniques in improving the patient's awareness of his surrounding and educate and teach the patient how to use assistive devices helping promote independence of the patient and his mobility.

Differential Diagnosis[edit | edit source]

  • Radicular hereditary sensory neuropathy (HSN I)
  • Hereditary sensory and autonomic neuropathy (HSN II)
  • Familial dysautonomia or Riley-Day syndrome (HSN III)
  • Congenital indifference to pain (HSN V)
  • Lesch-Nyhan syndrome
  • Neurotrophic keratitis

Reference[edit | edit source]

  1. ↑ Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet journal of rare diseases. 2007 Dec;2(1):1-2.
  2. ↑ Daneshjou K, Jafarieh H, Raaeskarami SR. Congenital insensitivity to pain and anhydrosis (CIPA) syndrome; a report of 4 cases. Iranian journal of pediatrics. 2012 Sep;22(3):412.
  3. ↑ Verpoorten N, De Jonghe P, Timmerman V. Disease mechanisms in hereditary sensory and autonomic neuropathies. Neurobiology of disease. 2006 Feb 1;21(2):247-55.
  4. ↑ Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Human mutation. 2001 Dec;18(6):462-71.
  5. ↑ 5.0 5.1 Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nature genetics. 1996 Aug 1;13(4):485-8.
  6. ↑ Nabyev VN, Seneran H, Aksoy MC. Congenital insensitivity to pain syndrome with anhidrosis. Review of literature. Journal of Pediatrics and Pediatric Medicine. 2018 Aug 1;2(3).
  7. ↑ Nolano M, Crisci C, Santoro L, Barbieri F, Casale R, Kennedy WR, Wendelschafer-Crabb G, Provitera V, Di Lorenzo N, Caruso G. Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clinical Neurophysiology. 2000 Sep 1;111(9):1596-601.
  8. ↑ Grills BL, Schuijers JA. Immunohistochemical localization of nerve growth factor in fractured and unfractured rat bone. Acta Orthopaedica Scandinavica. 1998 Jan 1;69(4):415-9.
  9. ↑ Norcliffe‐Kaufmann L, Katz SD, Axelrod F, Kaufmann H. Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis. Annals of neurology. 2015 May;77(5):743-52.
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