|Year : 2014 | Volume
| Issue : 1 | Page : 13-17
Congenital insensitivity to pain: Review with dental implications
A Vijay Kumar1, HP Jaishankar2, Purnachandrarao Naik1
1 Department of Oral Medicine and Radiology, SIBAR Institute of Dental Sciences, Takkellapadu, Guntur, Andhra Pradesh, India
2 Department of Oral Medicine and Radiology, Coorg Institute of Dental Sciences, Virajpet, Karnataka, India
|Date of Web Publication||15-Mar-2014|
A Vijay Kumar
Department of Oral Medicine and Radiology, SIBAR Institute of Dental Sciences, Takkellapadu, Guntur - 522 509, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Pain causes a reflex withdrawal from any stimuli that can cause actual or potential tissue damage. It is frequently an early symptom of a disease process and is often the impetus for a patient to seek medical treatment. In many disorders where pain appears late, patients are at risk of developing complications without getting noticed. 'Congenital insensitivity to pain' is a rare disorder. Traumatic injury and self-mutilation is an almost consistent feature in this disorder. Injuries most frequently involve the oral and paraoral structures such as teeth, lips, tongue, and also ears, eyes, nose, and fingers. Oral manifestations may be the presenting complaint. Thus, it is important for the clinicians to be familiar with the condition. The present article provides a brief review of the condition and its insinuation in dentistry.
Keywords: Congenital analgesia, congenital insensitivity to pain with anhidrosis, familial trophoneurosis, hereditary sensory and autonomic neuropathy, hereditary sensory autonomic neuropathy
|How to cite this article:|
Kumar A V, Jaishankar H P, Naik P. Congenital insensitivity to pain: Review with dental implications. Indian J Pain 2014;28:13-7
| Introduction|| |
Pain is a highly protective mechanism for the body. It is a distinctive sensory experience that may be described as an unpleasant awareness of a noxious stimulus or bodily damage. Painful stimuli indicate tissue damage or potential damage and cause a reflex withdrawal from the source of such damage.  In the absence of pain, patients are at risk of late presentation with systemic illnesses associated with pain, such as appendicitis or meningitis. Congenital insensitivity to pain is a rare disorder in which injuries of oral and paraoral structures may be the presenting complaint. These injuries often begin as the primary dentition erupts, and are self-inflicted. Frequently the tongue and lips are affected, with resultant scarring and deformation. Self-extraction of the teeth has also been reported. Self-mutilation is an almost invariable feature of this disorder. ,
The disorder affects the both myelinated and unmyelinated nerve fibers, and is characterized by diminished or absent sensitivity to pain, touch, and pressure on the extremities and other parts of the body. Although these patients are sensitive to thermal stimuli, they are not aware of the pain normally associated with high temperatures. Thus burns often occur, particularly in children. 
| History|| |
Reports of the individuals who seemed insensitive to pain from birth onwards have long history, but it was not until 1930 that this condition attracted medical attention. It was first described in 1932 by Dearborn as 'congenital pure analgesia'. Initially various terms were used to describe these individuals, over the time two terms began to predominate in descriptions of these individuals - 'congenital insensitivity to pain' and 'congenital indifference to pain'. Although these terms were often used interchangeably, in recent years they have acquired distinct meanings. 
Patients with congenital insensitivity to pain seem not to perceive sensations of pain, that is, they have markedly impaired ability to perceive the type, intensity, and quality of painful stimuli. In those with congenital indifference to pain, though, painful stimuli are perceived; but there is an absence of the affective response to pain, rather than a lack of signal transmission. These individuals report experiencing sensations of pain, but exhibit no repugnance to or withdrawal from painful stimuli. ,
In 1975 McMurray, proposed that impairment of pain perception caused by mental retardation or by peripheral neuropathies, infection, trauma, or toxic agents should not be considered as 'congenital universal insensitivity to pain'. ,
In 1983 Dyck et al., proposed the diagnostic criteria for the disease following sophisticated histological, microscopic, and morphometric methods for the assessment of nerve fiber pathology in which the presence of peripheral neuropathy became a criterion for diagnosing congenital insensitivity to pain and distinguishing it from congenital indifference to pain. Individuals with abnormal sensory nerves were classified as cases of congenital pain insensitivity arising from peripheral neuropathies of various types. ,
| Synonyms|| |
The patients suffering from this condition will have autonomic neuropathy with hereditary component, described as hereditary sensory autonomic neuropathy (HSAN). Historically, various terms have been used to describe the HSAN such as:
- Congenital pure analgesia.
- Congenital general pure analgesia (Dearborn, 1932).
- Congenital universal insensitiveness to pain (Ford and Wilkins, 1938).
- Congenital universal indifference to pain (Boyd and Nie, 1949).
- Congenital absence of pain (Winkelmann, 1962).
- Familial trophoneurosis.
- Familial syringomyelia.
- Morvan syndrome.
- Mal perforant du pied.
Thrush suggested three criteria for precise definition of congenital insensitivity to pain: 
- Pain should be absent from birth.
- The entire body should be affected.
- All other sensory modalities should be intact or minimally impaired and tendon reflexes present.
Various classification systems have been proposed based on the mode of inheritance, natural history, pathological alterations, neurophysiologic characteristics, and biochemical disorders. Those more widely accepted were proposed by Pinsky and DiGeorge in 1966 and more recently by Dyck in 1984 who divided these neuropathies into five types [Table 1]. ,
| Genetics of HSAN|| |
All HSAN that produce abnormalities of pain sensation have involvement of the small-diameter C and A-delta fibers that transmit pain sensation. Although each HSAN is characterized by a different pattern of sensory and autonomic dysfunction, the field is currently moving away from classification based on clinical presentation towards the underlying genetic abnormality.
Recent advances in molecular genetics have led to the identification of gene loci and disease causing genes for autosomal-dominant and autosomal-recessive hereditary sensory neuropathy (HSN). These genes have been shown to play roles in lipid metabolism and the regulation of intracellular vesicular transport, but also a presumptive transcriptional regulator, a nerve growth factor (NGF) receptor and a NGF have also been described among the causative genes in HSN. Nevertheless, it remains unclear how mutations in the known genes lead to the phenotype of HSAN [Table 2]. ,
It is a relatively mild condition mainly affecting the lower limbs. It occurs due to mutation in the SPTLC1 gene at locus 9q22.1-q22.3. Serine palmitoyltransferase (SPT) is a pyridoxal-5'-phosphate dependent enzyme, which is suggested to be a key enzyme for the regulation of sphingolipid levels in cells. Regulation of sphingolipid synthesis at the SPT step prevents a harmful accumulation of metabolic sphingolipid intermediates including sphingoid bases and ceramide. Dawkins et al., showed that specific missense mutations in the human gene SPTLC1 cause autosomal-dominant HSAN type 1. ,
The disease onset varies between the 2 nd and 4 th decade of life. Initial signs frequently consist of loss of pain and temperature sensation in the distal parts of the lower limbs, which spread to more proximal parts, but also to the hands with progression of the disease. Later on, there may be loss of pinprick and surface sense, while there is a relative preservation of vibration sense has been reported in some families. 
It follows autosomal-recessive trait. It is a more severe form presenting in infancy or early childhood. It occurs due to mutations in the HSN2 gene at locus 12p13.33 which codes for an unknown protein, predicted to have 434 amino acids. It is suggested that the protein may play a role in the development or maintenance of peripheral sensory neurons or their supporting cells. ,
The condition is characterized by early-onset sensory neuropathy in the first 2 decades. At the beginning of the disease, affected individuals complain of distal numbness in the upper and lower limbs. Later on, they develop impairment of pain, temperature, and touch sensation then also involving the trunk. Mental development will be normal. Sensory nerve action potentials will be absent, but motor nerves may be in the normal range. Sweating will be absent, temperature and regulation of blood pressure may be normal. ,
It is also known as familial dysautonomia (FD) or Riley-Day syndrome. It is a multisystem disease affecting mainly Ashkenazi Jews. The IKBKAP gene at locus 9q31 is the site of mutation. The gene encodes a protein termed ikb kinase complex-associated protein (IKAP), which is likely a component of the elongator complex and/or is a c-junction n-terminal kinase-associated protein. It is still unclear how mutations in the IKBKAP gene predispose or cause FD. ,
Early signs are prominent autonomic disturbances consisting of feeding difficulties owing to poor oral coordination and hypotonia. The clinical features include diminished pain sensation, unexplained fevers, hypertension, and postural hypotension caused by defective control mechanisms of temperature and blood pressure. Patients suffer from oropharyngeal in-coordination and abnormal gastroesophageal motility. These cause feeding difficulties, vomiting and recurrent aspiration pneumonia leading to chronic lung disease. Musculoskeletal manifestations include ataxic gait, severe kyphoscoliosis, and deformities of the feet leading to increased incidence of fractures. ,
According to few studies taste in the tongue is decreased, especially affecting the recognition of sweet and corresponds to the absence of fungiform papillae on the tip of the tongue, which is a hallmark feature of FD. These characteristic episodes are also called "dysautonomic crisis". 
It is the most prevalent type and is referred to as congenital insensitivity to pain with anhidrosis (CIPA). It was recently reported that genomic defects in tyrosine kinase can cause this disorder and that the "NGF-tyrosine kinase system" has a crucial role in the development and function of nociceptive reception, as well as in the establishment of thermoregulation by means of sweating in humans. It was first reported by Nishida in 1951. 
The condition is caused by autosomal recessive mutations and polymorphisms in the TRKA gene on chromosome 1 that encodes the receptor tyrosine kinase for NGF. TRKA protein is a receptor tyrosine kinase, which is phosphorylated in response to NGF. NGF supports the survival of sympathetic ganglion neurons and nociceptive sensory neurons in the dorsal root ganglia. 
Indo et al., suggested that the NGF-neurotrophic tyrosine kinase receptor (NTRK) system has a crucial role in the development and function of the nociceptive reception system, as well as establishment of thermal regulation via sweating in humans. 
Individuals with HSAN IV may demonstrate an absence of unmyelinated fibers and loss of small myelinated fibers. In several studies skin biopsy has shown 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. 
HSAN type IV is characterized by recurrent episodes of unexplained fever, failure to thrive, absence or decline of perspiration despite the presence of normal sweat glands, insensitivity to pain, self-mutilation, and mild mental retardation. The lack of pain sensation often results in severe oral mutilation. Bite wounds have been reported to cause laceration and ulceration of the tongue, lips, and other oral mucosa. Tooth luxation and severe dental attrition have also been observed. ,
The typical and common feature in the infantile patients with HSAN type IV was found to be a decubital ulcer on the ventral surface of the tongue. The incisal edges of erupting mandibular primary incisors may cause this tongue injury during sucking or nursing. The condition is same as that found in Riga-Fede disease, caused by mechanical irritation by the incisal edge of the natal or neonatal mandibular incisors. With the eruption of upper and mandibular primary incisors, further oral trauma, such as tongue or lip biting, is induced in an infant with HSAN type IV. Repeated and uncontrolled tongue biting with the primary incisors is one of the important diagnostic signs of HSAN IV. The tongue is severely injured by biting, and the result is tissue laceration with excessive bleeding, infection, fever, or malnutrition. ,
Although no disorder exactly mimics HSAN type IV, several progressive sensory neuropathies have similar features. Severe oral self-mutilation has been reported in some syndromes, in which pain sensation is impaired, such as Lesch-Nyhan syndrome, Tourette's syndrome and de Lange's syndrome. 
It is an autosomal recessive disorder, caused by a mutation in the NGF beta gene (NGFB gene at locus 1p13.2-p11.2). NGF-β mutation results in a substitution of tryptophan for arginine on position 211 in a highly conserved region of the protein. The mutation seems to separate the effects of NGF involved in development of central nervous system functions (such as mental abilities) from those involved in peripheral pain pathways. 
Skin biopsy has demonstrated severe loss of small myelinated fibers with a possible decrease in the number of unmyelinated fibers. Because of the selectivity of the deficits in HSAN V, it has been argued that these individuals would have been considered cases of congenital indifference to pain prior to the ability to assess peripheral nerve morphology. 
In HSAN V, pain and temperature insensitivity are evident in childhood, with the occurrence of painless fractures, ulcers, and burns. Self-mutilation, typically manifesting as biting of the lips and tongue, has also been observed in these patients. Although pain and temperature sensitivity are deficient, proprioception and sensitivity to touch, pressure, and vibration are unaffected. The autonomic manifestations are variable, with minimal autonomic abnormalities and blotching, abnormal sweating, difficulties with feeding, and elevated temperatures. ,
| Oral Manifestations of HSAN|| |
As the condition is very rare, no studies have been done at large scale level regarding oral manifestations, though diverse individual case reports and case studies have been documented in the literature. In the majority of the cases, oral manifestations were the presenting complaint of these patients. In precise, the various oral manifestations that are commonly seen in HSAN patients includes:
- Trauma to tongue leading to chronic nonhealing ulcers.
- Trauma to lower lip.
- Reduced mouth opening due to thick fibrous scars as a result of severe cheek biting.
- Premature loss of teeth due to self-extraction or dental sepsis.
- Insensitivity to dental pain, leading to space infections or dental sepsis.
- Loss of taste sensation, especially failure to identify sweet taste.
- Increased incidence of fractures and osteomyelitis of jaws.
- Increased incidence of traumatic ulcers of oral mucosa.
- Dryness or fissuring of vermillion border of lip due to anhidrosis.
- Severe dental attrition and cervical abrasions.
- Erosion of teeth due to regurgitation of fluids because of defective gastroesophageal motility.
- Abnormal gastroesophageal motility may cause feeding difficulties and recurrent vomiting in children.
- Recurrent fever may lead to xerostomia and increased incidence of dental caries, oral infections such as candidiasis.
- Patients are sensitive to thermal stimuli, but they may not be aware of the pain normally associated with high temperatures, thus leading to burns of oral mucosa especially palate, due to hot food or beverages, etc.
No gene-based therapies are available till date for any variant of HSN. Yet, accurate diagnosis is important, thus the patients and the family members are subjected to appropriate genetic counseling. 
The degree of self-injury must be taken into account when deciding on appropriate management. Several methods can be instilled for prevention of the oral mucosal injuries in these patients, such as:
- Elimination of sharp surfaces of the teeth by grinding (enameloplasty) or addition of composite restorations.
- Use of mouth guards or tongue guards and other appliances to prevent injury to the tongue.
- Extraction of offending teeth.
The use of intraoral appliances is often difficult or impossible to implement in few cases, because the mutilation may begin in infancy with the eruption of the primary incisors. Thus, extractions of teeth may be unavoidable in cases in which the mutilation is particularly severe. ,
Prevention of dental disease is very important in these patients, as caries can progress to involvement of dental pulp without causing pain and may lead to chronic infection and tooth loss due to dental abscesses. 
Thus, the dental team should therefore be involved in the management of these patients as soon as the diagnosis is made and careful monitoring should continue throughout the lifetime of the patient.
Recent advances in molecular genetics, about the sensory and autonomic neuropathies have brought about improved methods for diagnosis of the conditions and genetic counseling for affected families. Prenatal genetic testing is also now available for these disorders, with reported 98% of diagnostic accuracy. 
| Conclusion|| |
Congenital insensitivity to pain is a rare disorder in which oral manifestations may be the presenting complaint. The most important characteristic is the self-mutilating behavior, which leads the child to oral ulcerations on lips, tongue, and cheeks and also finger and hand biting. This condition represents a challenge to the dentist, who is concerned with the early intervention, and as the patients are below normal in intellect, development, and psychological aspects. As oral ulcerations and premature loss of teeth along with signs of self-mutilation may represent early manifestations of this rare disorder, clinicians should always keep in mind that these clinical signs can be because of HSAN. An early diagnosis and appropriate dental approach is indispensable to avoid severe injuries to the oral and other regions of the body.
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[Table 1], [Table 2]
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