Definition
Congenital Insensitivity to Pain with Anhidrosis (CIPA), also called Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), is an extremely rare condition that involves a disorder of the nervous system. CIPA has two characteristic features: the inability to feel pain and temperature, and decreased or absent sweating (anhidrosis).
Epidemiology
HSAN IV is extremely rare among most populations with the exception of the Japanese and Israeli-Bedouins. The prevalence is unknown, but it was seen the disorder is more diffused in cultures in which intermarriage is accepted.
Symptoms
Symptoms of Congenital insensitivity to pain with anhidrosis appear usually at birth or during infancy.
Because of the lack of pain and temperature sensations, patients with this disease are exposed to unintentional self-injury, for example, due to biting the tongue or burning fingers, which may lead to spontaneous ulcers, scars or even amputations. In this way, chronic infections of bones and joints, bone fractures, osteomyelitis and joint deformities are common in people who suffer from CIPA.
Other problems can affect eye, such as infections owing to hard rubbing, or skin that can be thickened.
Normally, sweating helps cool the body temperature. However, anhidrosis often causes hyperpyrexia and febrile seizures brought on by high temperature; there can be intellectual disabilities as a consequence.
We can also find patients with hyperactivity and emotional lability.
Diagnosis
The diagnosis is made clinically based on recognition of the following:
• lack of response to painful stimuli (pin prick; vigorous pressure on the Achilles tendons, testes, stylomastoid processes, and superior orbital rim);
• decreased perception of hot and cold (assessed quantitatively using standardized tests of thermal perception or through a history of unrecognized responses to burns);
• absence of the axon flare response after intradermal histamine phosphate injection;
• absence of sweating (ascertained through Quantitative sudomotor axon reflex test (QSART) or Sympathetic skin response (SSR)).
Histopathologically can be performed:
- skin biopsy (in CIPA patients there is absence of eccrine sweat gland innervation and small nerve fibers in the epidermis);
- sural nerve biopsy (CIPA sufferers have reduced numbers of myelinated small-diameter fibers and unmyelinated fibers associated with normal numbers of large-diameter fibers).
Mutations in NTRK1, the only gene known to be associated with CIPA, are identified by sequence analysis or deletion/duplication analysis in almost all individuals meeting HSAN IV diagnostic criteria.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation.
Congenital insensitivity to pain with anhidrosis may be misdiagnosed for leprosy because of similar symptoms.
Hereditary Sensory and Autonomic Neuropathy IV, 2009
Pathogenesis
HSAN IV is caused by a genetic mutation in the NTRK1 gene.
This gene is located on the long (q) arm of chromosome 1 between positions 21 and 22 and encodes the neurotrophic tyrosine kinase receptor type 1. The ntrk1 gene contains 17 exons and 16 introns spanning 25 kb of DNA.
NTRK1 protein (also known as high affinity nerve growth factor receptor or trasforming tyrosine kinase protein or Trk-A) is a membrane-bound receptor. It contains 796 amino acids and has an approximate molecular weight of 140 kDa. It is made of a signal peptide, an extracellular domain consisting of three tandem leucine-rich motifs flanked by two cysteine clusters and two Ig-like domains, a single transmembrane segment (1TM) and an intracellular domain possessing a tyrosine-kinase domain.
Protein Aminoacids Percentage
There are 3 major isoforms by alternative splicing of exon 9: TrkA I, TrkA II and Trka III. TrkA II is the longest ones and has been chosen as the canonical sequence; it is primarily expressed in neuronal cells. Isoform TrkA-I is found in non-neuronal tissues; it lacks an internal, in-frame exon, compared to variant II (resulting in a shorter isoform) and has enhanced responsiveness to NTF3 or neurotrophin -3. Isoform TrkA-III lacks an internal in-frame exon too and is specifically expressed by pluripotent neural stem and neural crest progenitors.
Common post-translational modifications can be ligand-mediated autophosphorylation, N-glycosylatation (Isoform TrkA-I is N-glycosylated), ubiquitination (regulates the internalization of the receptor).
Cellular functions: Receptor tyrosine kinase is involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. It has high affinity for NGF which is its primary ligand, it can also bind at low affinity and be activated by BDNF (Brain-Derived Neurotrophic Factor), NTF5 (Neurotrophin-4/5) and NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Homodimerization of the receptor is induced by binding of a NGF dimer and followed by autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation:
-SHC1 and FRS2 intracellular binding to the TrkA receptor leads to phosphorylation of its tyrosine residues and further recognition by the adapter protein Grb-2 (growth factor receptor bound protein-2) through SH3 (Src homology domain 3) domains. Grb-2 then binds to the factor sos (factor son of sevenless) to induce recruitment of the small G protein Ras to the cell membrane and its activation. This translocation to the cell membrane enables Ras-induced activation of the Raf kinase and therefore phosphorylation of Raf and activation of the MAPK (mitogen-activated protein kinase) ERK1/2 (extracellular-regulated protein kinase 1/2), leading to activation of survival mechanisms and proliferation (regulation of meiosis, mitosis, and postmitotic functions).
-PLCG1 (phospholipase C gamma 1) catalyzes the calcium dependent breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). IP3 binds to particular calcium channels in the smooth endoplasmic reticulum (ER) increasing the cytosolic concentration of calcium. Calcium and DAG together work to activate several protein kinase C isoforms promoting transcription of genes involved in cell survival;
-SHC1 and SH2B1 activate the PI3 kinase. PI3K then induces synthesis of phosphatidyl-inositol 3,4-bisphosphate that recruits PDK-1 (phosphoinositide-dependent kinase-1) to the cell membrane activating PKB (protein-kinase B, also called Akt). PKB leads to gene transcription through small G protein Rac and the MAPK pathway. In addition, PKB can activate proteins belonging to the IAP (inhibitors of apoptosis), family that are involved in cell survival pathway.
In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.
Isoform TrkA III is resistant to NGF, does not interact with FRS2 but constitutively activates AKT1 and NF-kappa-B, is unable to activate the Ras-MAPK signaling cascade, promotes angiogenesis and has oncogenic activity when overexpressed.
CIPA-related mutations have been detected in almost every NTRK1 exon, as well as in several intervening intronic sequences (IVS). Some of the exonic mutations are nonsense and frameshift changes, which are likely to produce a truncated, non-functional, NTRK1 protein, or an aberrant mRNA that may be degraded by the nonsense-mediated decay system. In addition, most missense mutations in NTRK1 exons have been shown to completely abrogate receptor activity. IVS mutations, on the other hand, are commonly predicted to disrupt proper NTRK1 mRNA splicing, but the necessary RNA analyses to confirm this prediction have been carried out only in some of the studies. Without Ntrk1 proper signaling, neurons die by a process of self-destruction called apoptosis.
TrkA receptor, Wikipedia
High affinity nerve growth factor receptor, UniProt
Risk factors
There aren’t known specific risk factors for Congenital Insensitivity to Pain with Anhidrosis but a problem could be a family history of CIPA: this condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Each child of known carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Therapy
There is no specific treatment but parental supervising and medical attention can help affected individuals to live into adulthood. Common practices can be:
• prevention of self-mutilation by smoothing or extracting teeth;
• prevention of debilitating orthopedic problems by daily evaluation for early signs of unrecognized injury;
• prevention of neurotrophic keratitis with tarsorrhaphy, corneal patch graft, keratoplasty, and/or scleral bandage lens;
• control of hyperthermia with acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket;
• antibiotic therapy for local infections;
• using of antipsychotic in conjunction with behavior modification as needed;
• annual evaluations with ophthalmology, dentistry, and orthopedics;
• avoiding hot and dry climates, high-impact activities and sports, inadequate sedation in the postoperative period.
Hereditary Sensory and Autonomic Neuropathy IV, 2009
Bibliography
Congenital insensitivity to pain with anhidrosis, Wikipedia
CIPA, Genetics Home Reference
Congenital Insensitivity to Pain with Anhidrosis (HSAN Type IV), Extremely Rare Syndrome that Can Be Easily Missed by Bone and Joint Surgeons: A Case Report, 2012
See also
Interesting to mention is the recent discovery of the existence of patients suffering from what has been defined Congenital Absence of Pain with Hyperhidrosis (also called Congenital analgesia with hyperhidrosis or Congenital indifference to pain with hyperhidrosis), pathology somewhat opposite to note CIPA.
The prevalence is 1 in a million and its onset is during infancy.
It was also seen that sweating can be 3 to 8-fold greater than normal.
The CAPH patients have all normal types of sensory and autonomic innervation to the vasculature and sweat glands, but all other types of normal cutaneous C, Adelta and Abeta-fiber endings are absent.
No mutation has yet been found and much is still unknown, but the findings of the studies suggest three hypotheses:
1. development or maintenance of sensory innervation to cutaneous vasculature and sweat glands may be under separate genetic control from that of all other cutaneous sensory innervations;
2. the latter innervation is preferentially vulnerable to some environmental factor;
3. vascular and sweat gland afferents may contribute to conscious cutaneous perception.
Congenital insensitivity to pain with hyperhidrosis, Orphanet
Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation, 2009
