Hereditary sensory and autonomic neuropathy type 4
General Information (adopted from Orphanet):
Synonyms, Signs:
NEUROPATHY, CONGENITAL SENSORY, WITH ANHIDROSIS
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY IV
FAMILIAL DYSAUTONOMIA, TYPE II
HSAN IV
HSAN4
NHSA4
CIPA
Insensitivity to pain - anhidrosis
Swanson et al. (1963, 1965) described 2 brothers with congenital insensitivity to pain and anhidrosis, despite normal-appearing sweat glands on skin biopsy. Temperature sensation was also defective. One of the brothers died after a 24-hour illness during which ... Swanson et al. (1963, 1965) described 2 brothers with congenital insensitivity to pain and anhidrosis, despite normal-appearing sweat glands on skin biopsy. Temperature sensation was also defective. One of the brothers died after a 24-hour illness during which his temperature reached 109 degrees F. Almost complete absence of the first order afferent system considered responsible for pain and temperature was found at autopsy (Swanson et al., 1965). Pinsky and DiGeorge (1966) described the same disorder in 3 mentally retarded children, 2 of whom were sibs, with recurrent episodes of unexplained fever, repeated traumatic and thermal injuries, and self-mutilating behavior. Sweating could not be elicited by thermal, painful, emotional, or chemical stimuli, and histamine evoked no axonal flare. Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children failed to do so in these patients, despite their occasional spontaneous lacrimation. Wolfe and Henkin (1970), who referred to the disorder in Pinsky and DiGeorge's sibs as type II familial dysautonomia, described unresponsiveness to methacholine despite the presence of taste buds. They suggested that it is the same as the disorder reported in 2 sibs of each of 2 families by Swanson (1963) and by Vassella et al. (1968). Yanagida (1978) found that naloxone, a specific antagonist of opiate receptors, was effective in CIPA, suggesting that overproduction of brain endorphins is involved in the disorder. Ishii et al. (1988) described a Japanese girl with CIPA who died at the age of 21 months. During the first few months of life, she suffered from recurrent episodes of unexplained high fever without sweating and hard breathing, and was found to lack sensation to pain. After the establishment of dentition, she bit off the apical part of her tongue and began self-mutilating her lips and the tips of her fingers. Courtney and Freedenberg (1990) described a patient who appeared to have HSAN4, but did not have developmental delay. Rosemberg et al. (1994) presented a 4-year-old girl, the second child of consanguineous parents, who had typical HSAN4. They provided a useful review of the literature, which included 31 patients, noting that 20% of the patients succumbed to hyperpyrexia, most of them before age 3. Most of the children were mentally retarded, with IQs varying from 41 to 78, the majority being in the 60s. Ismail et al. (1998) described an 8-year-old girl who was 1 of 2 affected sibs from healthy first-cousin Kuwaiti parents. She first presented at the age of 24 hours with fever, which persisted for 8 weeks. Extensive investigations revealed no cause for the fever. Recurrent febrile convulsions occurred, with fever of 42 degrees C induced by environmental temperature in Kuwait. She had mild hypotonia and hyporeflexia, did not cry during blood sampling, had never sweated, and never developed sphincter control. Pictures of the child demonstrated severe mutilation of the hands and feet as well as of the tongue and lips. Yagev et al. (1999) studied 15 Bedouin children with CIPA and found that all had absent corneal sensation, which led to corneal opacities in 10 (67%). Active corneal ulcers were found in 7 of the 15 children; 2 children had bilateral ulcers and 3 of the ulcers were recurrent. These corneal ulcers were characterized by very poor healing, and some required surgical interventions including lateral tarsorrhaphy, corneal patch graft, and/or penetrating keratoplasty. The authors concluded that congenital insensitivity to pain and anhidrosis, although rare, should be considered in the differential diagnosis of neurotrophic keratitis. Bonkowsky et al. (2003) studied a 1-year-old male with an atypical presentation of CIPA, whose diagnosis was confirmed by molecular analysis. The clinical features included an abnormally high pain threshold and heat intolerance, normal nerve conduction, and the absence of epidermal and sweat gland innervation in a skin biopsy. - Pathologic Findings In a biopsy of the cutaneous branch of the radial nerve from a 9-year old girl with CIPA, Rafel et al. (1980) found complete absence of small myelinated and unmyelinated fibers. They suggested that the disorder was not a hereditary sensory neuropathy, but rather a developmental defect. In a sural nerve biopsy from a 2-month-old boy with CIPA, Matsuo et al. (1981) found that unmyelinated fibers were essentially lacking, and that the number of small myelinated fibers was decreased. Langer et al. (1981) and Ismail et al. (1998) demonstrated absence of eccrine sweat gland innervation. In immunohistochemical studies of skin biopsies from a 10-year-old girl with CIPA, Verze et al. (2000) found greatly reduced numbers of nerve fibers compared to normal controls. In particular, the epidermis was free of nerve branches or endings, whereas rare nerve fibers were present in the dermis. No autonomic nerve fibers were visible around sweat glands or hair follicles, and blood vessel walls were completely devoid of nerve fibers. Degenerative changes were not found. Verze et al. (2000) concluded that HSAN4 patients have a hereditary developmental defect of nerve outgrowth.
Based on the phenotypic features of a mouse model lacking the gene encoding the receptor tyrosine kinase (NTRK1; 191315) for nerve growth factor (NGF; 162030) (Smeyne et al., 1994), Indo et al. (1996) studied human NTRK1 as a ... Based on the phenotypic features of a mouse model lacking the gene encoding the receptor tyrosine kinase (NTRK1; 191315) for nerve growth factor (NGF; 162030) (Smeyne et al., 1994), Indo et al. (1996) studied human NTRK1 as a candidate gene for the site of the mutation in CIPA. In 3 unrelated patients with CIPA, each of whom had consanguineous parents, Indo et al. (1996) identified a deletion (191315.0001), a splice site aberration (191315.0002), and a missense mutation (191315.0003) in the tyrosine kinase domain of NTRK1. Their findings strongly suggested that defects in NTRK1 cause CIPA and that the NGF-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. The results also implicated genes encoding other TRK and neurotrophin family members as candidates for developmental defects of the nervous system. In patients with CIPA from an isolate of Bedouins in northern Israel, Shatzky et al. (2000) identified 2 mutations (191315.0010; 191315.0011) in the NTRK1 gene. They made the prenatal diagnosis in 8 cases, 2 by linkage analysis and 6 by direct checking for one of the novel mutations.
The diagnosis of hereditary sensory and autonomic neuropathy type IV (HSAN IV; also known as congenital insensitivity to pain with anhidrosis; CIPA) is made clinically based on recognition of the following:...
DiagnosisClinical DiagnosisThe diagnosis of hereditary sensory and autonomic neuropathy type IV (HSAN IV; also known as congenital insensitivity to pain with anhidrosis; CIPA) is made clinically based on recognition of the following:Profound sensory loss affecting pain and temperature perceptionLack of response to painful stimuli (including 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 burnsAbsence of the axon flare response after intradermal histamine phosphate injection. After intradermal injection of 0.1 ml histamine phosphate (1:10,000 dilution or 0.275 mg histamine phosphate/mL) usually an initial local area of erythema appears, followed within three to five minutes by a central wheal surrounded by a diffuse flare with irregular borders. In HSAN, the wheal is surrounded by a sharply circumscribed border. Note: (1) The histamine test is rapid, relatively inexpensive, and sensitive. (2) When used by itself the histamine test cannot distinguish the various HSAN types; however, when other clinical findings are considered, the histamine test is helpful in patient classification.Absence of sweating. Abnormalities in the postganglionic sympathetic cholinergic pathways that regulate sweating can be identified by the following tests:Quantitative sudomotor axon reflex test (QSART). In this test acetylcholine (ACh) iontophoresed through the skin using a constant 2 mA anodal current induces sweating by eccrine sweat glands and activates postganglionic sympathetic sudomotor axons. The axon reflex-mediated sweat response is quantified by a hygrometer and a multicompartmental sweat cell.Sympathetic skin response (SSR). The SSR, resulting from transient electrical activity of sweat glands and adjacent epidermal tissue, can be induced by a stimulus that elicits arousal of and consecutive discharges of sympathetic sudomotor fibers, i.e., preganglionic B-fibers and postganglionic unmyelinated C-fibers. Stimuli include electrical, acoustic, and inspiratory gasp. Usually the SSR is recorded simultaneously from the dorsum of the hands and feet.Severe learning disabilities and cognitive impairment are common [Indo 2002] but not universal [Ohto et al 2004; Oddoux et al, in preparation].TestingHistopathologySkin biopsy. Absence of eccrine sweat gland innervation and small nerve fibers in the epidermisSural nerve biopsy. Reduced numbers of myelinated small-diameter fibers and unmyelinated small-diameter fibers associated with normal numbers of large-diameter fibersMolecular Genetic TestingGene. NTRK1 (TRKA), the only gene in which mutation is known to cause HSAN IV [Indo et al 1996], accounts for all cases of properly classified HSAN IV.Clinical testingSequence analysis. Sequencing of the coding region and flanking intronic regions of NTRK1 detects more than 90% of causative mutations [Oddoux et al, in preparation]. This estimate is based on results of sequence analysis in approximately 75 individuals who either fit the clinical diagnostic criteria for HSAN IV or had overlapping phenotypic characteristics but were not classified as having HSAN IV.Deletion/duplication analysis. Deletion of an NTRK1 exon(s) or whole gene would be detected by this analysis, including the multiexonic deletion of exons 12 and 13 and flanking regions [Huehne et al 2008] See Molecular Genetics.Linkage analysis of the NTRK1 locus has been performed successfully [Shatzky et al 2000]; however, it should be used with caution. Data from the International HapMap Consortium [2003] reveal that the gene is positioned in a recombination hot spot, making the likelihood of inconclusive or inaccurate results much higher than expected.Table 1. Summary of Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy IVView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 1, 2Test AvailabilityNTRK1Sequence analysisSequence variants 3, 4, 5>99%ClinicalDeletion / duplication analysis 6Partial- and whole-gene deletionsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. In individuals with impaired pain and temperature perception and anhidrosis3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. In affected Israeli-Bedouins, p.Pro621Serfs*12 accounts for 89% of mutations [Shatzky et al 2000].5. In affected Japanese, p.Arg554Glyfs*104 accounts for more than 50% of mutations, p.Phe284Trpfs*36 for 13%, and p.Asp674Tyr for 10% [Indo 2001].6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyDiagnosis of a proband is made primarily from the clinical findings of impaired pain and temperature perception and anhidrosis. The diagnosis may be confirmed by molecular genetic testing [Indo 2001, Indo 2002].Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Given the rarity of the disorder and the likelihood of detecting variants of unknown clinical significance, full gene sequencing of reproductive partners of carriers who do not themselves have a family history of HSAN IV is not recommended.Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family [Oddoux et al, in preparation].Genetically Related (Allelic) DisordersControversy about the clinical criteria used to classify the individual hereditary sensory and autonomic neuropathies (HSANs) has led to the suggestion that NTRK1 mutations may also be associated with HSAN V [Houlden et al 2001].The finding that a boy diagnosed with HSAN V was homozygous for a mutation in NTRK1 suggested that HSAN IV and HSAN V may be allelic [Houlden et al 2001]; however, no other examples have been reported. The report of a child with HSAN V with no mutations in NTRK1 has further suggested that another gene or genes are causative in some individuals [Toscano et al 2002].Somatic gain-of-function mutations that lead to constitutive tyrosine kinase activity that occurs as a result of genetic rearrangements between NTRK1 and either TPM3, TPR, or TFG have been described in papillary thyroid carcinomas [Greco et al 2004, DeLellis 2006]. Constitutive activation of NTRK1 has also been detected as a result of altered expression patterns of splice variants in neuroblastoma [Tacconelli et al 2004] and by induction of autocrine stimulation by nerve growth factor in breast and prostate cancers [Djakiew et al 1991, Dollé et al 2004].
The profound sensory loss affecting pain and temperature perception and absence of sweating characteristic of hereditary sensory and autonomic neuropathy type IV (HSAN IV) are evident in infancy when the child fails to respond appropriately to painful stimuli such as the injections associated with routine pediatric immunizations. Because sweating plays an important role in maintaining normal body temperature, anhidrosis disturbs thermoregulation in hot environmental conditions and increases susceptibility to recurrent febrile episodes [Loewenthal et al 2005]. Hyperthermia in neonates can be the first sign of the disorder....
Natural HistoryThe profound sensory loss affecting pain and temperature perception and absence of sweating characteristic of hereditary sensory and autonomic neuropathy type IV (HSAN IV) are evident in infancy when the child fails to respond appropriately to painful stimuli such as the injections associated with routine pediatric immunizations. Because sweating plays an important role in maintaining normal body temperature, anhidrosis disturbs thermoregulation in hot environmental conditions and increases susceptibility to recurrent febrile episodes [Loewenthal et al 2005]. Hyperthermia in neonates can be the first sign of the disorder.Decreased pain perception does not spare any area and even affects cranial nerves and visceral sensation [Yagev et al 1999, Shorer et al 2001]. Self-mutilation is common. Oral self-mutilation, such as biting injuries and scarring of soft tissues (tongue, lip and buccal mucosa), is very common. In infants oral self-mutilation is typically characterized by tongue ulcers. Most affected infants also exhibit fingertip biting that begins when the primary incisors erupt.Radiographs demonstrate evidence of repeated fractures, joint deformities, joint dislocations, osteomyelitis, avascular necrosis, and acro-osteolysis [Schulman et al 2001]. Fractures are slow to heal and large weight-bearing joints appear particularly susceptible to repeated trauma and frequently become Charcot joints (i.e., neuropathic arthropathy). Osteomyelitis occurs frequently.Anhidrosis, present on the trunk and upper extremities in 100% of cases, is more variable in other areas of the body [Ismail et al 1998, Axelrod 2002].Often the skin is dry with lichenification of the palms; the nails are dystrophic; and the scalp has areas of hypotrichosis.Speech is usually clear. Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [Axelrod 2002]. Defects are evident in conceptual thinking and abstract reasoning. Because a large proportion of individuals have severe learning disabilities, some have stated that HSAN type IV is characterized by cognitive impairment [Indo 2002].Hyperactivity and emotional lability are common; approximately 50% of affected individuals exhibit rages.In most individuals baseline tear flow is diminished resulting in superficial punctate keratopathy which predisposes to corneal ulcerations and infection [Yagev et al 1999, Amano et al 2006].Other autonomic perturbations are mild to absent:Overflow or emotional tearing is normal.Postural hypotension with compensatory tachycardia may be present but episodic hypertension is not observed, suggesting that blood pressure problems in HSAN IV are secondary to disuse atrophy or deconditioning rather than sympathetic dysfunction [Axelrod 2002].Gastrointestinal dysmotility is mild or absent.Vomiting is not a feature.Cyclical crises do not occur.Insensitivity to hypoxia and hypercapnia has not been noted.In some individuals, subnormal adrenal function and abnormalities in the first-phase insulin response to glucose challenge are observed [Toscano et al 2000, Schreiber et al 2005].The prognosis for independent function depends on the degree of expression and the ability to control secondary clinical problems.NeurophysiologyTraditional electrophysiologic studies such as motor and sensory conduction velocities by electrical and mechanical stimuli are usually normal as are somatosensory, visual, and brain stem evoked potentials [Shatzky et al 2000, Shorer et al 2001].Microneurography shows neural activity from A-beta sensory fibers connected to low-threshold mechanoreceptors; however, pain and skin sympathetic C fiber nerve activity are absent [Indo 2002].Intraneural electrical stimulation that produces unbearable pain in normal controls does not evoke any painful sensation.Neuropathologic studies demonstrate decreased numbers of unmyelinated and small myelinated fibers in sensory nerves, including the sural nerve and the cutaneous branch of the radial nerve [Swanson et al 1965, Goebel et al 1980, Itoh et al 1986].Studies of the skinHistology demonstrates normal sweat glands, sebaceous glands, and hair follicles.Silver stain light microscopy shows normal number and appearance of dermal nerves.Electron microscopy reveals lack of innervation of the eccrine sweat glands with loss of unmyelinated sudomotor fibers, possibly accounting for the anhidrosis [Langer et al 1981].Immunohistochemistry demonstrates absent innervation of skin and sweat glands. The lack of C- and A-delta fibers in the skin is consistent with the loss of unmyelinated and small myelinated fibers in sural nerve biopsies [Nolano et al 2000] and provides a morphologic basis for insensitivity to pain as well as anhidrosis. Nolano et al [2000] also reported an almost complete absence of dermal fibers to blood vessels and erector pilomotor muscles.The anhidrosis is probably secondary to decreased neuronal supply from thoracolumbar sympathetic outflow.Autopsy has demonstrated absence of small neurons in the dorsal ganglia, lack of small fibers in the dorsal roots, absence of Lissauer’s tract, and reduction in size of the spinal tract of the trigeminal nerve with paucity of small fibers [Swanson 1963, Swanson et al 1965]. These findings represent almost complete absence of the first-order afferent system generally considered responsible for pain and temperature sensation.
Expression varies widely even among individuals with the same two deleterious mutations [Shatzky et al 2000], suggesting that interaction with other genetic and environmental factors may contribute to the phenotype....
Genotype-Phenotype CorrelationsExpression varies widely even among individuals with the same two deleterious mutations [Shatzky et al 2000], suggesting that interaction with other genetic and environmental factors may contribute to the phenotype.Mutations occur in portions of the gene that encode the intracellular or extracellular domains of the protein, which may further affect the variability in presentation. Individuals who are compound heterozygotes (i.e., have two different abnormal NTRK1 alleles, one on each chromosome of a pair) may in some cases have unusually mild presentations [Ohto et al 2004; Oddoux et al, in preparation]. A mild phenotype has been observed when one of the alleles is a missense mutation in the portion of the gene encoding in the carboxy terminus of the protein, suggesting that aspects of the signal transduction pathway interacting with the carboxy terminus of the protein may be tissue-specific and that this allele may function normally in some, but not all, tissues, thereby leading to the milder presentation.
Hereditary sensory and autonomic neuropathies (HSANs). HSAN IV belongs to the family of HSANs [Hilz 2002]. Five HSANs are recognized. HSAN type IV is the only HSAN that is associated with widespread anhidrosis....
Differential DiagnosisHereditary sensory and autonomic neuropathies (HSANs). HSAN IV belongs to the family of HSANs [Hilz 2002]. Five HSANs are recognized. HSAN type IV is the only HSAN that is associated with widespread anhidrosis.Hereditary sensory neuropathy type I (HSAN I) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. HSAN1 is often associated with progressive sensorineural deafness. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles so that in later life a wheelchair may be required for mobility. Drenching sweating of the hands and feet is sometimes reported and rare individuals have pupillary abnormalities; visceral signs of autonomic involvement are not present. Inheritance is autosomal dominant. Mutations in SPTLC1 are identified in approximately 90% of individuals with a positive family history and approximately 10% of simplex cases (i.e., a single occurrence in a family).Hereditary sensory neuropathy type II (HSAN II) (Morvan's disease; acrodystrophic neuropathy). Symptoms occur in infancy or early childhood. Affected individuals have acral anhidrosis; ulcers, paronychia, whitlows, or other trophic changes of the fingers and toes; and other autonomic dysfunction including tonic pupils, oromotor incoordination, constipation from gastrointestinal dysmotility, bladder dysfunction, intermittent fevers, impaired sensory perception, hypotonia, and apnea. Unrecognized injuries and neuropathic arthropathy (Charcot joint) occur. Except for decreased or absent tendon reflexes, general neurologic examination is normal. Inheritance is autosomal recessive.HSAN III (familial dysautonomia, FD) is a developmental disorder affecting small myelinated and unmyelinated neurons resulting in sensory and autonomic dysfunction. Symptoms are present from birth with the earliest signs being poor suck and hypotonia. The sensory dysfunction affects pain and temperature perception, but is not as profound as that in HSAN type IV, sparing the hands and feet. Autonomic dysfunction results in absent emotional tears, oromotor incoordination, and cardiovascular lability with postural hypotension and episodic hypertension. Patients are also prone to periodic vomiting crises comprising nausea, retching, hypersalivation, bronchorrhea, hypertension, tachycardia, and erythematous blotching of the skin. Clinical diagnostic criteria include absent lacrimation, absent deep-tendon reflexes, and absent lingual fungiform papillae. Inheritance is autosomal recessive. FD is caused by mutations in IKBKAP (RefSeq NM_003640.3), with the most common being a tissue-specific missplicing mutation in intron 20 (c.2204+6T>C) [Anderson et al 2001, Slaugenhaupt et al 2001]. More than 99% of affected patients are of Ashkenazi Jewish extraction and homozygous for the c.2204+6T>C mutation. Inheritance is autosomal recessive.HSAN IV is hereditary sensory and autonomic neuropathy type IV or CIPA, the subject of this GeneReview.HSAN V is characterized by selective loss of pain perception but normal response to tactile, vibratory, and thermal stimuli. Neurologic examination is otherwise normal. Three severely affected individuals with HSAN V born to consanguineous parents in a large Swedish family were homozygous for a mutation in NGFB [Einarsdottir et al 2004]. Inheritance is autosomal recessive.
To establish the extent of disease in an individual diagnosed with hereditary sensory and autonomic neuropathy type IV (HSAN IV), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hereditary sensory and autonomic neuropathy type IV (HSAN IV), the following evaluations are recommended:Radiographs of extremities and weight-bearing jointsOphthalmologic examination to detect keratoconjunctivitisDental examinationTreatment of ManifestationsThe treatment of this disorder remains supportive and is oriented to (1) prevention of self-mutilation and orthopedic problems that potentially can cause severe and debilitating deformities and (2) control of hyperthermia. It is important to provide assistance and encourage therapies for behavioral, developmental, and motor delays that are appreciated during infancy and early childhood as well as to provide educational and social support for school-age children and adolescents.Hyperthermia. Febrile spikes respond to use of acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket [Axelrod 2002].OrthopedicCareful daily evaluation for early signs of unrecognized injury is important.Braces may be required on the ankles to prevent injury to these weight-bearing joints.Sufficient sedation is necessary to avoid accidental fractures in a postoperative period.Self-mutilation. Some children require smoothing of the teeth or extraction of the teeth to prevent self-mutilation of the tongue and lips caused by rubbing or chewing [Bodner et al 2002].Dental. Absence of some teeth is common either as a result of self-extraction or prophylactic extraction in order to prevent injury. Early diagnosis and specific dental care for patients with HSAN IV can help prevent the fingertip biting and orofacial manifestations [Bodner et al 2002]. Management of the fingertip biting that begins as soon as the primary dentition erupts has required either smoothing of teeth edges or even dental extractions to prevent extreme consequences such as self-amputation of digits [Bodner et al 2002].Eye. Neurotrophic keratitis is a frequent complication caused by the combination of decreased baseline moisture and corneal hypesthesia, resulting in deficient blink reflex and optimal wetting of the cornea. Treatments can include tarsorrhaphy, corneal patch graft, keratoplasty, and scleral bandage lens [Yagev et al 1999].Behavior. Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age. Pharmacologic treatments with antipsychotic and/or attention-deficit/hyperactivity disorder (ADHD) medications in conjunction with behavior modification may be beneficial.Prevention of Secondary ComplicationsTemperature needs to be monitored carefully during the perioperative period; the patient should not be put on a heating blanket.Of note, the use of muscle relaxants is not a problem and malignant hyperthermia is not associated with HSAN [Tomioka et al 2002].SurveillanceIndividuals with HSAN type IV should be followed annually at a center that fosters comprehensive care and communication between the various subspecialties that are needed for optimal care. Clinical specialties that are essential are ophthalmology, dentistry, and orthopedics.Agents/Circumstances to AvoidAvoid the following:Hot, dry climatesJumping or high-impact activities and sportsInadequate sedation in the postoperative period. The decreased number of peripheral pain fibers may not be adequate to result in conscious awareness of pain yet may be sufficient to trigger an unconscious physiologic response to pain. Therefore, if tachycardia and hypertension occur in the postoperative period, the possibility of inadequate analgesia should be considered.Evaluation of Relatives at RiskOnce the disease-causing mutations for a given family are known, molecular genetic testing may be used to evaluate at-risk infants, so that those who are affected can be monitored to avoid hyperpyrexia and its potential complications, including febrile seizures.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Sensory and Autonomic Neuropathy IV: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNTRK11q23.1High affinity nerve growth factor receptorCatalogue of Somatic Mutations in Cancer (COSMIC) IPN Mutations, NTRK1 NTRK1 homepage - Leiden Muscular Dystrophy pagesNTRK1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Sensory and Autonomic Neuropathy IV (View All in OMIM) View in own window 191315NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1 256800INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS; CIPAMolecular Genetic PathogenesisIndividuals with HSAN type IV have loss-of-function mutations in NTRK1, which encodes the nerve growth factor (NGF) receptor. NGF supports the survival of nociceptive neurons and embryonic sensory and sympathetic neurons from the neural crest and ascending cholinergic neurons of the basal forebrain. Persons with HSAN IV have decreased development, survival, and maintenance of various NGF-dependent neurons [Mardy et al 1999, Indo 2002].Subnormal adrenal function and abnormalities in the first-phase insulin response to glucose challenge emphasize the importance of the NGF-TrkA pathway in the physiology of the neuroendocrine system and its response to stress [Toscano et al 2000, Schreiber et al 2005]. Presence of a TrkA mutation in B cells can result in a lymphocyte signaling defect [Melamed et al 2004], which may explain some of the delayed healing observed in this disorder.Normal allelic variants. NTRK1 comprises 17 exons and 16 introns and spans at least 23 kb. Two main isoforms have been characterized coding for a protein of 790 or 796 amino acid residues, respectively. The longer isoform is neuronal specific and includes six amino acid residues encoded by exon 9 that form part of the extracellular domain of the neuronal-specific receptor. Additional isoforms have been detected but have yet to be fully characterized. An isoform lacking exons 6, 7, and 9 appears to be stimulated by hypoxic conditions in neuronal tissue and has been implicated in progression of neuroblastoma [Tacconelli et al 2004].Mardy et al [1999] originally discovered the putative mutations p.His604Tyr and p.Gly613Val in cis with p.Gln9X. Subsequent analyses demonstrated that p.His604Tyr and p.Gly613Val are normal allelic variants; in vitro expression analysis showed normal activity of the expressed proteins carrying the variants p.His604Tyr or p.Gly613Val [Mardy et al 2001], and healthy individuals homozygous for p.Gly613Val have also been described [Shatzky et al 2000].Pathologic allelic variants. A variety of intragenic mutations have been described including frameshift, nonsense, missense, and splicing defects, but no large insertions, deletions, or rearrangements. The mutations are not localized to any particular domain and span both the extracellular and intracellular domains. A multiexonic deletion of 1381 bp has been reported in an affected individual [Huehne et al 2008]. The frequency of such deletions is not known.The mutation p.Pro621Serfs*12 is a common founder mutation among Israeli-Bedouins, in whom it accounts for approximately 89% of HSAN IV alleles [Shatzky et al 2000].Among Japanese individuals affected with HSAN IV, common founder mutations are responsible for roughly 70% of cases [Indo 2001]. The most common of these founder mutations, found on more than 50% of HSAN IV-causing Japanese alleles, is the frameshift mutation p.Arg554Glyfs*104. The missense mutation p.Asp674Tyr and the splice site mutation c.851-33T>A each account for an additional 10% of cases. Multiple additional private mutations have been described in individuals from Japan.Among other populations, a wide variety of private mutations have been described.Table 2. Selected NTRK1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.1810C>T (c.1876C>T)p.His604Tyr (p.His598Tyr)NM_002529.3 NP_002520.2c.1838G>T (c.1904G>T)p.Gly613Val (p.Gly607Val)Pathologicc.25C>Tp.Gln9Xc.851-33T>A (IVS7-33T>A)p.Phe284Trpfs*36 (r934_935ins137)c. 1660delC (c.1726delC)p.Arg554Glyfs*104 (Arg548fs)c.1860_1861insT (c.1926_1927insT)p.Pro621Serfs*12 (Pro615fs)c.2020G>T (c.2086G>T)p.Asp674Tyr (p.Arg668Tyr)(1381-bp deletion) 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions. For NTRK1, variant designations are based on the shorter isoform that is not neuronal specific.2. Huehne et al [2008]Normal gene product. The longer neuronal-specific isoform (RefSeq NM_002529.3, NP_002520.2) encodes a 796-amino-acid membrane protein, whereas the shorter isoform expressed in non-neuronal tissues is 790 amino acids long. The gene encodes the receptor tyrosine kinase for NGF. The extracellular domain is responsible for specific binding to NGF. Binding of NGF results in dimerization of the receptor followed by autophosphorylation of the intracellular tyrosine kinase domain and C-terminal tail, which in turn is responsible for intracellular signaling. Mutations in many domains of the protein ultimately interfere with the signal transduction by the receptor.Abnormal gene product. Mutations occur across the entire protein sequence and give rise to altered full-length products, or truncated or deletion products of varying lengths, some of which may be too short to be expressed or properly targeted in the cell.