Congenital Insensitivity to pain with anhydrosis (CIPA) is a rare inherited disease. It is classified as hereditary sensory and autonomic neuropathy type IV. Pain insensitivity and autonomic deficits are present, but touch and pressure sensitivity are unimpaired. Mental retardation is usually present. We report a family case of a 5 years old girl and 2 years old boy with congenital insensitivity to pain, while discussing the clinical features and the anesthetic strategy of such patients. Patients with Congenital Insensitivity to Pain with anhydrosis may undergo surgery because of susceptibility to trauma due to absence of pain. The clinical features may intrinsically possess anesthetic challenges.
Keywords: Congenital insensitivity to pain, hereditary, neuropathy, sensory and autonomic neuropathy, family case, anesthesia
Congenital insensitivity to pain with anhydrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive neuropathy of the group of hereditary sensory and autonomic neuropathies (HSAN), first described in 1932 by Dearborn as “Congenital pure analgesia”  , and an exceedingly rare clinical disorder characterized by insensitivity to pain with intact tactile perception ,self mutilation, recurrent unexplained fever, anhydrosis, mental retardation and autonomic nervous system abnormality since infancy. Patients with CIPA often experience trauma, bony fractures, and osteomyelitis because of insensitivity to pain. Therefore, such patients may undergo surgery such as osteotomy and amputation. Since it is a rare condition, reports on the anesthetic conduct in patients with CIPA are not easily found in the literature. The objective of this report was to present family cases with CIPA, and to discuss the anesthetic strategy of such patients.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A 5 years old girl and a 2 years old boy, siblings, were born after a normal pregnancy and normal delivery. They were the only children of a healthy family and of a non-consanguineous marriage. There were no family history of neurologic or metabolic disorders and no other member of their family was diagnosed with CIPA.
They were brought by their parents looking for a therapy that could avoid injuries to their oral structures and the finger biting. Their physician had suggested full mouth extraction, but the parents did not agree because of the psychological and functional implications.
Their parents relate a history of self-mutilation from first months of life. After their teeth started to grow in, they began to chew their fingers and bit off the tip of their tongue, since eruption of the teeth there had been biting of their tongue, fingers, wrists, and feet, causing bleeding. They exhibited an absence of normal reaction to painful stimuli such as falls, cuts, and injections (e.g.: for vaccinations).
On admission, they were poorly developed and thin, their tongue and upper lip had been bitten off. They had scars from injuries and they had self-mutilation of interphalangeal joints of the fingers and toes (Figure 1 and Figure 2). The distal thumb and the tips of two fingers on the right hand and the toes were missing. Neurologic examination revealed depressed deep tendon reflexes and decreased tactile sensitivity. The patients seemed to respond appropriately to thermal stimuli. However, there was no reaction to painful stimuli. They showed normal lacrimation, salivation and corneal reflex, presence of a significant loss of tissue at the soles of the feet, toes and fingers. It was noted that their general development had continued normally, and they were of normal intelligence, the only difference in clinical presentation of the two siblings is that the girl had chronic diarrhea, probably related to autonomic dysfunction, with sphincter incontinence.
Self-mutilation of interphalangeal joints of fingers in a child suffering from congenital insensitivity to pain with anhydrosis
Self-mutilation of interphalangeal joints of toes in a child suffering from congenital insensitivity to pain with anhydrosis
Paraclinical investigations were common to both patients. Laboratory examination including white blood cell, hemoglobin, serum electrolytes, GOT, GPT, renal function value, uric acid, creatine kinase, were normal. Hands and feet radiograph showed destruction and amputation of fingers and toes (Figure 3).
X-ray showing destruction and amputation of fingers in a child suffering from congenital insensitivity to pain with anhydrosis
Once the diagnosis was confirmed, the patients benefited from a multidisciplinary management. Self-mutilation of the tongue, lips and fingers had posed difficult problems since the dental eruption; stomatologists tried to make a mouth guard, they estimate that extraction of all primary teeth was a radical alternative that should be considered only if all other possibilities failed or in extreme cases. Psychological support to the patients and the family were also necessary. Genetic counseling was indispensable given the seriousness of the disease. Parents were also advised to consult in cases of fever to eliminate a potential infection and in case of injury to detect an unnoticed fracture.
There are number of diseases that affect sensory function from birth. Dick  classified these congenital neuropathies into five types: sensory radicular neuropathy, congenital sensory neuropathy, familial dysautonomia or Riley-Day syndrome, congenital insensitivity to pain with anhydrosis (CIPA), and congenital indifference to pain. The differential diagnosis of these neuropathies is not straightforward because the clinical pictures overlap.
CIPA is characterized by insensitivity to superficial and deep painful stimuli with intact tactile perception, self-mutilation, recurrent unexplained fever in infancy, anhydrosis, mental retardation, absent or hypoactive deep tendon reflex, normal corneal reflex and lacrimation and autonomic nervous system abnormality.
Autonomic abnormalities include the inability to sweat in response to heat or chemical stimuli (pilocarpine) and the production of a wheal but not a flare after intradermal histamine injection . Individuals with HSAN IV show an absence of unmyelinated fibers and losses of small myelinated fibers . Skin biopsy show an absence of epidermal innervation and loss of most dermal innervations as well as accompanying loss of unmyelinated and thinly myelinated fibers from the sural nerve, sweat glands show no innervation . The condition is caused by autosomal recessive mutations and polymorphisms in the TRKA gene on chromosome 1 that encodes the receptor tyrosine kinase for nerve growth factor (NGF) . Patients with CIPA often experience trauma, bony fractures, and osteomyelitis because of insensitivity to pain. Therefore, such patients may undergo surgery such as osteotomy and amputation.
It may be thought that patients with CIPA do not need anesthesia to undergo surgical procedures because of the insensitivity to pain. However, the tactile sensation is intact and some patients have tactile hyperesthesia . Some patients have complained of pain in the postoperative period . Therefore, surgical stimulation may produce unpleasant sensations. Thus, it is possible that the use of anesthetics can prevent undue tactile discomfort . Also, anesthetics are useful to ensure cooperation and immobility during surgery for a pediatric patient with behavioral problems.
Some authors described the difference in concentration of inhaled anesthetics needed for orthopedic surgery and dental surgery. According to their report, the inhaled anesthetic was≥1 MAC for orthopedic surgery, and≤1.0 minimum alveolar concentration for dental surgery. They speculated that these differences were caused by the nociceptive stimulus of each operation. However, there have been few reports concerning the anesthetic management of patients with CIPA because it is a rare disease [8,9]. Patients with CIPA have autonomic and nociceptive dysfunction; therefore, the anesthetic conduct represents a challenge for the anesthesiologist.
Congenital hyposensitivity to pain is a rare disease, and there is limited information regarding anesthetic treatment of these patients. Okuda et al  reported 6 patients with HSAN IV who underwent 20 operations during general anesthesia without any adverse events. All patients received standard anesthesia management including inhalational agents in doses that are expected to be administered to patients with normal sensitivity to pain. No patient received opioids during operations, and no perioperative complications were noted.
Tomioka et al  reported that a variety of pre-anesthetic medications were given to the patients at the various medical facilities. In 19 of the 45 cases, atropine was given as a pre-anesthetic medication; despite the recommendations that avoid anticholinergic drugs because of the risk of hyperthermia , however, none of the patients displayed signs of heat. In 19 cases, sedatives such as a benzodiazepine or hydroxyzine, and meperidine were given as a preanesthetic medication. These medications all had a normal effect on the patients. All of the procedures were performed under general anesthesia. They reviewed 15 patients with HSAN IV who had 45 operations during general anesthesia using different inhalational agents (Halothane, Enflurane, and Sevoflurane) within wide range of anesthetic concentrations and intra venous anesthetic included barbiturates, benzodiazepine, propofol, and ketamine . Four patients received opioids intraoperatively, and two received fentanyl-supplemented inhalational.
The primary anesthetic concern in patients with HSAN type IV is impaired temperature control, which can cause death in about 20% of the affected patients within the first 3 years of life . Strict perioperative temperature control is recommended to maintain body temperature at about 37 °C [11,12]. The elevation of the temperature can be prevented by adequate monitoring, adjusting the temperature of the operating room, and using thermal mattresses. However, there is no association between malignant hyperpyrexia and CIPA. The genetic mechanisms of precipitating hyperpyrexia in the 2 conditions, malignant hyperpyrexia and CIPA, are different and previous reports do not reveal any episodes of malignant hyperpyrexia in these patients after exposure to suxamethonium and inhalational agents, including halothane, enflurane, isoflurane, and sevoflurane [4,7, 9,12].
There are reports of surgical procedures without anesthesia in patients with CIPA, such as the case of a patient who underwent amputation of both feet under sedation (20mg midazolam and thiopental over the 3 hours, but without analgesia (opioids) or general anesthesia. He did not show any response to incision of the skin or disarticulation, and he only reacted to clamping of a nerve trunk with flexion of a limb . An eight-year old patient with CIPA underwent reduction of a femur fracture with osteosynthesis under epidural block and sedation without complications during the procedure .
Congenital insensitivity to pain with anhydrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive neuropathy of the group of hereditary sensory and autonomic neuropathies (HSAN). Patients with CIPA may undergo surgery because of susceptibility to trauma due to absence of pain. The clinical features may intrinsically possess anesthetic challenges.
1. Dearborn G. A case of congenital pure analgesia. J Nerv Ment Dis. 1932;75:612–5.
2. Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Dyck PJ, Griffin PK, Low PA, Poduslo JF, editors. Peripheral neuropathy.
3. Swanson AG. Congenital insensitivity to pain with anhydrosis. A unique syndrome in two male siblings. Arch Neurol. 1963;8:299–306.[PubMed]
4. Rosemberg S, Marie SK, Kliemann S. Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV) Pediatr Neurol. 1994;11(1):50–6.[PubMed]
5. 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. Clin Neurophysiol. 2000;111(9):1596–601.[PubMed]
6. 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. Nat Genet. 1996;13(4):485–8.[PubMed]
7. Tomioka T, Awaya Y, Nihei K. Anesthesia for patients with congenital insensitivity to pain and anhidrosis: A questionnaire study in Japan. Anesth Analg. 2002;94(2):271–4.[PubMed]
8. Okuda K, Arai T, Miwa T. Anaesthetic management of children with congenital insensitivity to pain with anhydrosis. Paediatr Anaesth. 2000;10:545.[PubMed]
9. Mitaka C, Tsunoda Y, Hikawa Y. Anesthetic management of congenital insensitivity to pain with anhidrosis. Anesthesiology. 1985;63(3):328–9.[PubMed]
10. Pinsky L, DiGeorge AM. Congenital familial sensory neuropathy with anhidrosis. J Pediatr. 1966;68(1):1–13.[PubMed]
11. Yoshitake S, Matsumoto K, Miyagawa A. Anesthetic consideration of a patient with congenital insensitivity to pain with anhidrosis. Masui. 1993;42(8):1233–6.[PubMed]
12. Mori S, Yamashita S, Takasaki M. Anesthesia for a child with congenital sensory neuropathy with anhydrosis. Masui. 1998;47(3):356–8.[PubMed]
13. Layman PR. Anaesthesia for congenital analgesia-A case report. Anaesthesia. 1986;41:395–397.[PubMed]
14. Rodriguez Pérez MV, Fernandes Daza PL, Cruz-Villaseñor JA. Anestesia epidural a un niño con fractura de fémur e insensibilidad congénita al dolor. Rev Esp Anestesiol Reanim. 2002;49(10):555–7.[PubMed]
1The Neuro-Genetics Institute, 501 Elmwood Avenue, Sharon Hill, PA 19079, USA
2Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, Saint Francis Medical Center, 601 Hamilton Avenue, Trenton, NJ 08629, USA
Received 4 June 2014; Revised 5 September 2014; Accepted 5 September 2014; Published 18 September 2014
Copyright © 2014 Leema Reddy Peddareddygari et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutations in the SCN9A gene. We report a patient with the clinical features consistent with CIP in whom we detected a novel homozygous G2755T mutation in exon 15 of this gene. Routine electrophysiological studies are typically normal in patients with CIP. In our patient, these studies were abnormal and could represent the consequences of secondary complications of cervical and lumbosacral spine disease and associated severe Charcot’s joints.
Autosomal recessive congenital insensitivity to pain (CIP) is a rare condition, affecting very few individuals, but with a worldwide distribution. CIP is clinically characterized by the ability to feel a given stimulus but also the inability to perceive pain. This is in contrast to congenital “indifference” to pain which implies a lack of concern to a painful stimulus that is received through normal sensory pathways and may be associated with central nervous system disorders such as schizophrenia or pervasive development disorder .
CIP is genetically and clinically heterogeneous caused by mutations in several different genes. For example, mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) and nerve growth factor-β (NGFB) result in CIP with an anhidrosis phenotype [2, 3]. In contrast, homozygous loss of function mutations in sodium channel voltage-gated type IX, alpha subunit (SCN9A) gene has been reported to result in the CIP with an anosmia phenotype . Although this condition is rare, genotype phenotype studies of such patients are important.
We report the results of our analysis of a patient who we encountered in our neurology clinic with a history of insensitivity to pain.
2. Case Report
This 58-year-old woman presented with a long history of insensitivity to pain since childhood and increased numbness in her legs for several years. As a child, she recalled developing cuts on her feet that she could not feel. She could distinguish between hot and cold temperature although there was no uncomfortable sensation associated with extremes of either one. Since the age of 15 years she started to develop frequent fractures involving multiple bones which were also painless. In addition, she has two children and suffered no pain during childbirth. She also had anosmia. Over the ten years prior to evaluation, she had started to develop sensory loss in her legs. She had previously been diagnosed with cervical and lumbar spine disease and had undergone surgical treatment of both of these regions of her spine. She is of Caucasian English descent and the product of a nonconsanguineous marriage. She has a healthy brother and two healthy children. There is no indication that either her parents or any other relative was affected by symptoms suggestive of CIP suggesting an autosomal recessive form of inheritance. The remainder of the general medical history was significant for absence of diabetes, cancer, or rheumatologic disease. Neurological examination revealed normal mental status and cranial nerve examination except for anosmia. She was diffusely areflexic with flexor plantar responses. She had multiple joint deformities involving both ankles, elbows, and knees (Charcot’s joints) which limited the testing of power. When she could provide a good effort, she had good strength. She had decreased sensation to pin prick, proprioception, and vibration distally in her feet. She could not perform a tandem walk and had a positive Romberg’s test.
An electromyogram (EMG) was performed; the motor nerve conduction parameters were normal in the right tibial nerve but showed a markedly reduced response amplitude in the right peroneal nerve recording the extensor digitorum brevis muscle (this was severely atrophied). No evoked response could be elicited with stimulation of the peroneal nerve at the fibular head. No evoked sensory nerve action potentials were obtained in the right ulnar, sural, and superficial peroneal nerves. Needle electromyogram showed no abnormal spontaneous activity in any muscle sampled and the presence of high amplitude polyphasic units in the distal muscles of the right arm and legs associated with a mildly reduced interference pattern with maximal effort. Overall the study was interpreted as showing chronic neurogenic changes with a superimposed entrapment neuropathy of the right ulnar nerve. The other abnormalities noted in the nerve conductions were interpreted as partly secondary to Charcot’s joints and technical factors such as increased subcutaneous tissues.
3. Genetic Analysis
Following IRB approved policies and procedures, a blood sample was obtained and DNA was extracted. Whole exome sequencing was performed by commercial sequencing company. Exome capture was performed by HiSeq2000 using a paired-end (2 × 100) protocol, Illumina raw data processing, and Agilent SureSelect exome kit for exome enrichment. The sequences were aligned to human genome reference (UCSC version hg 19). Nucleotide-level variation analysis of the exome sequence data was performed using the DNA nexus platform (https://dnanexus.com/). The variants obtained with this platform were further annotated using Ensembl variant effect predictor tool (Ensembl release 75, February 2014) (http://useast.ensembl.org/info/docs/tools/vep/index.html) . Since CIP is a rare disorder, the minor allele frequency was assigned at less than 1%. These results were further filtered for homozygous, nonsynonymous variants with deleterious, possible damaging and unknown effect using SIFT and Polyphen analysis. This narrowed down the list of variants to 584.
Those single nucleotide polymorphisms (SNPs) involving genes known to cause insensitivity to pain were then analyzed. A potentially significant variant was identified on chromosome 2 at position 167133579, a homozygous A/A variant (Figure 1(a)). This homozygous c. G2755T mutation in exon 15 of SCN9A gene results in a stop mutation, causing premature truncation of the protein p. E919X. This SNP was reconfirmed by amplification and Sanger’s sequencing (Figure 1(b)).
Figure 1: Image showing the homozygous variant on chromosome 2. (a) Image identifying the homozygous A/A mutation on chromosome 2 at position 167133579 using the DNA nexus platform. (b) Image showing the homozygous c. G2755T mutation in exon 15 of SCN9A gene following amplification and Sanger’s sequencing.
The SCN9A gene is expressed in all sensory neurons and is a key molecule in the processing of peripheral pain. This gene encodes a voltage-gated sodium channel (Nav 1.7) which plays a significant role in nociceptive signaling and both gain and loss of function mutations have been reported. Interestingly, depending upon the specific mutation, there is a marked diversity of resulting phenotype. For example, gain of function mutations causes inherited erythromelalgia and paroxysmal extreme pain disorder which follow an autosomal dominant pattern of inheritance [6, 7]. More recently there have been reports of mutations causing seizures or a small fiber neuropathy [8, 9].
Studies in individuals with CIP from seven different populations identified homozygous mutations in SCN9A gene . Loss of function mutations in SCN9A gene causes truncation of the encoded sodium channel Nav 1.7 protein, resulting in channelopathy-associated autosomal recessive congenital insensitivity to pain. Twenty-seven different SCN9A gene mutations have been reported in CIP patients so far (Table 1). Given the predicted consequences of the novel change in the SCN9A gene in our patient, it is likely to be a disease producing mutation and brings the total number of mutations to twenty-eight.
Table 1: SCN9A mutations causing congenital indifference to pain.
Although the primary consequence of the homozygous SCN9A mutation is the absence of pain sensation, there are associated conditions including anosmia, self-mutilation resulting in oral and digit lesions, multiple injuries due to repeated trauma, burn-related injuries, orthopedic complications that include bone deformities from untreated fractures, osteomyelitis, and neuropathic joints later in life [4, 8, 9, 11–14]. Although Charcot’s joints are commonly reported in patients with CIP, bony involvement of the spine as seen in our patient is rare; however, anosmia and Charcot’s joints noted in our patient are comorbidities that were previously reported associated with CIP [4, 8, 9, 14].
Routine EMG studies of patients with CIP are typically normal. In our patient, it is likely that the abnormalities detected on both the nerve conduction studies and needle examination are secondary to cervical and lumbosacral spine disease, joint deformities, and muscle wasting associated with Charcot’s joints. However, a sensory motor peripheral neuropathy is not excluded by this examination. It is possible that the patient has an associated large fiber neuropathy which may be related to the G2755T mutation or alternatively to another unrelated etiology. A possible relationship between mutations in the SCN9A and a large fiber neuropathy could be supported by genotype/phenotype analysis in further patients with CIP.
The study of our patient expands the spectrum of mutations that have been reported to cause this disorder. In addition, our analysis demonstrates the power of next generation sequencing that can enable genetic confirmation of a suspected diagnosis of a rare disorder.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.