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Year : 2014  |  Volume : 15  |  Issue : 3  |  Page : 140-143

The child who felt no pain: A case of hereditary sensory autonomic neuropathy (HSAN) type IV

Department of Dermatology and STD, Government Medical College, Srinagar, Jammu Kashmir, India

Date of Web Publication30-Oct-2014

Correspondence Address:
Imran Majid
Shri, SMHS Hospital, Karan Nagar, Srinagar, Kashmir - 190 010
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2319-7250.143676

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Hereditary sensory autonomic neuropathy (HSAN) is the term used to describe a group of inherited disorders that are associated with sensory dysfunction (reduced reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastro-esophageal reflux, postural hypotension, excessive sweating). Five different entities have been described under HSAN (types I-V) we report a case of HSAN IV in a one and a half year old female child, with the classical features of this disorder - insensitivity to pain, self mutilating behaviour, recurrent episodic fevers and anhidrosis.

Keywords: Anhidrosis, autonomic dysfunction, electroneuromyography, hereditary neuropathy, hereditary sensory autonomic neuropathy

How to cite this article:
Majid I, Yaseen A. The child who felt no pain: A case of hereditary sensory autonomic neuropathy (HSAN) type IV. Indian J Paediatr Dermatol 2014;15:140-3

How to cite this URL:
Majid I, Yaseen A. The child who felt no pain: A case of hereditary sensory autonomic neuropathy (HSAN) type IV. Indian J Paediatr Dermatol [serial online] 2014 [cited 2020 Nov 25];15:140-3. Available from: https://www.ijpd.in/text.asp?2014/15/3/140/143676

  Introduction Top

Hereditary sensory and autonomic neuropathies (HSANs) are clinically and genetically a heterogeneous group of inherited peripheral neuropathies, primarily affecting the peripheral sensory and autonomic neurons. [1] Patients usually exhibit prominent distal sensory loss frequently leading to chronic ulcerations in feet and hands. Autonomic dysfunction, such as anhidrosis, fever, blood pressure fluctuations, and gastrointestinal disturbances, are present in some patients. Electrophysiologically, axonal nerve damage of the sensory neurons is often found, but additional demyelination may also be present. [2] A classification of the hereditary sensory neuropathies into types HSAN I-V was made by Dyck (1993) based on age at onset, inheritance pattern, and several other features. Each HSAN disorder is likely caused by genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. [3] HSAN can be transmitted as an autosomal dominant (AD) (HSAN I) or autosomal recessive (AR) (HSAN II-V) trait. [4] We report herein a case of a female child with classical features of HSAN-IV (congenital insensitivity to pain with anhidrosis or CIPA or Nishida syndrome).

  Case report Top

A 1½-year-old female child, first and only product of a second-degree consanguineous marriage, was referred to us from the psychiatry department for evaluation for cause of self-mutilation. At the time of presentation, the child had a painless ulceration on the right hip of 2 months duration. There was history of similar painless ulcers in the past as well. There was also a history of multiple episodes of fever, especially during summer months, which were unresponsive to antipyretics. In addition, there was a history suggestive of absence of sweating since the child was 4 months old. Even during the episodes of fever, the child used to have no sweating. According to the mother, the child started biting her tongue, lips, and fingers after her teeth erupted at the age of 7 months. This used to lead to injuries on accessible sites and, as a result, the child had scarring at multiple sites on the body. The patient's mother also gave history of absence of crying in the child in response to painful stimuli, such as on receiving injections or even after self-inflicted injuries. There was a history of recurrent respiratory tract infections in the child since the last 1 year. The motor milestones of the child were delayed, though her mental and physical development was appropriate for age. At the time of presentation, the child was able to walk only with support. There was no history of feeding problems or seizures in the child. There was no significant family or drug history.

The patient was born at full term by normal vaginal delivery, with uneventful antenatal, intranatal, and postnatal periods.

On examination, the child was conscious, hyperactive, and not too cooperative for examination. There was mild pallor. She was afebrile. Patient had synophrys and long and curly eyelashes. Systemic examination of the respiratory, cardiovascular, and gastrointestinal systems revealed no abnormality. Neurologic examination documented normal muscle strength, muscle bulk, and deep tendon reflexes, and there were no abnormal involuntary body movements and no cranial nerve deficit. Plantar responses were normal. The child responded to touch, but there was complete generalized absence of pain and temperature perceptions. There was no peripheral nerve thickening. There was clinical evidence of mutilation of the lower lip, the tip of the tongue, and acromutilation involving the distal phalanx of the right index finger [Figure 1]. The patient had a generalized dry, coarse, and thick skin. There was a slow-healing, painless ulcer on the lateral aspect of the right hip joint [Figure 2]. Multiple scars and superficial erosions were present over the legs and dorsa of both hands [Figure 3] and [Figure 4]. The skin over palms and soles was mildly hyperkeratotic. Her hairs and nails were normal and no joint deformities were present. Ophthalmic and auditory examinations were normal.
Figure 1: Mutilation of lower lip

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Figure 2: Painless ulcer on the right hip

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Figure 3: Mutilation of the distal phalanx of right index finger

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Figure 4: Scarring seen on the dorsum of hand

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Laboratory investigations like complete hemogram, blood chemistry, liver and renal function tests, and urine and stool examinations were unremarkable in the patient. Serum uric acid levels were normal. Ultrasonography of the abdomen was also normal. Tests for autonomic function were normal. Anhidrosis was documented by the starch-iodine test.

  Discussion Top

A group of rare disorders characterized by inherited sensory and autonomic dysfunction and described as HSAN can be classified into five different types. [3] HSAN I is perhaps the most common of these hereditary disorders. It is AD with onset of symptoms in the second through fourth decades with sensory loss and subsequent tissue injury. [5] This late onset of symptoms distinguishes HSAN I from other types of HSAN, which typically have an early onset. Insensitivity to pain is more prominent than decreased touch sensation. HSAN II is recessively inherited and begins at birth or in infancy. There is generalized pan-sensory loss. Autonomic disturbances include bladder dysfunction, impotence, and anhidrosis of hands and feet. Motor function is preserved, but tendon reflexes are usually lost. HSAN types III-V are also AR, and type III is associated with prominent autonomic involvement. Clinical manifestations of HSAN V include mutilating acropathy and bilateral neurotrophic keratitis. Motor functions and tendon reflexes are normal. [6]

HSAN IV or Nishida syndrome [7] is the second most common HSAN, and like the other recessively transmitted HSANs, its onset is in infancy. [8] HSAN IV is a rare disorder with less than 50 cases reported up to 2006. [9] HSAN IV is caused by mutations in the NTRK1 (TRKA) gene that is located on chromosome 1 (1q21-q22). This gene encodes for neurotrophic tyrosine kinase receptor type 1 that is autophosphorylated in response to nerve growth factor (NGF). As a result of loss of function mutations, signal transduction at the NGF receptor is impeded and NGF-dependent neurons, the small sensory and sympathetic neurons, fail to survive. [2],[8],[10] There does not seem to be a particular ethnic distribution for this recessive disorder, but one-half of the reported cases have occurred in consanguineous marriages. [10],[11] Although many mutations have been described, commercial molecular genetic diagnostic testing is not yet feasible.

HSAN IV is characterized by anhidrosis, i.e. absent or markedly decreased sweating. [10],[11],[12],[13] It is the anhidrosis that causes episodic fevers and extreme hyperpyrexia that is usually the earliest sign of the disorder and can cause recurrent febrile convulsions secondary to high environmental temperature. [1],[10] The anhidrosis is probably secondary to impaired thoracolumbar sympathetic outflow. It is present on the trunk and upper extremities in 100% of cases, whereas other areas of the body are variably affected. It causes the skin to become thick and callused with lichenification of palms and dystrophic nails. [10],[11],[12]

Although there is no immunological problem, individuals with HSAN IV have definite problems in healing of ectodermal structures - skin and bone. Fractures are slow to heal and large weight-bearing joints appear particularly susceptible to repeated trauma and frequently go on to develop Charcot's joints and osteomyelitis. Speech is usually clear. Although hypotonia and delayed developmental milestones are frequent in the early years, strength and tone normalize with age. However, there can be severe learning problems. Hyperactivity and emotional lability are common. [1],[10],[12] Postural hypotension with compensatory tachycardia may be present, but not episodic hypertension, suggesting that the blood pressure problems are secondary to disuse atrophy rather than sympathetic dysfunction. There is none to minimal gastrointestinal dysmotility; vomiting is not a feature of the disease and cyclical crises do not occur. Insensitivity to hypoxia and hypercapnia has not been noted.

Sural nerve biopsies show that myelinated nerve fibers are present but unmyelinated fibers are absent. [14] Skin biopsy morphology of HSAN IV patients reveals deficient C and Aδ fibers in the epidermis and absent or hypoplastic dermal sweat glands without innervations, [15] which accounts for the clinical manifestation of severe anhidrosis. Although central neuropathology has not been demonstrated for HSAN type IV, the affected individuals have clinical features suggesting central involvement as the patients frequently exhibit hypotonia and delayed developmental milestones in the early years and there can be severe learning problems, often associated with hyperactivity. [1],[10] It has been suggested that diagnosis of this disorder requires three clinical criteria, i.e. anhidrosis, decreased pain perception, and mental retardation. [10] However, the degree of expression of the three clinical features, especially intellectual ability, can be extremely varied. HSAN IV is the only HSAN that is associated with widespread anhidrosis. Though no disorder exactly mimics HSAN type IV, impairment of pain sensation and oral mutilation have been reported in some syndromes such as Lesch-Nyhan syndrome, Tourette syndrome, and de Lange syndrome. [16] Absence of nail and hair abnormalities and presence of normal sweat glands on skin biopsy exclude the anhidrotic ectodermal dysplasia. Keeping all the clinical features in view, a diagnosis of HSAN IV was made based on the hallmark features of complete insensitivity to pain and temperature, anhidrosis, self-mutilating behavior, hyperactivity, and episodic fevers.

Medical management is supportive and oriented to control of hyperthermia, prevention of self-mutilation, and treatment of orthopedic problems that potentially can cause severe and debilitating deformities. Febrile spikes will respond to use of acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket. Chlorpromazine or chloral hydrate is effective in relaxing the children and allowing them to cool. [8] Careful daily inspection for unrecognized injury is important. Braces may be required on the ankles to prevent injury to these weight-bearing joints. Some children will require smoothing of teeth or extraction to prevent self-mutilation of the tongue and lips.

  References Top

1.Axelrod FB. Autonomic and Sensory Disorders. In: Principles and Practice of Medical Genetics. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, editors. 5 th ed., Vol 3. Edinburgh: Churchill Livingstone; 2007. p. 2802-16.  Back to cited text no. 1
2.Rotthier A, Baets J, De Vriendt E, Jacobs A, Auer-Grumbach M, Lévy N, et al. Genes for hereditary sensory and autonomic neuropathies: A genotype-phenotype correlation. Brain 2009;132:2699-711.  Back to cited text no. 2
3.Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral neuropathy. 3 rd ed. Philadelphia: WB Saunders; 1993. p. 1065-93.  Back to cited text no. 3
4.Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, et al. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: A review. Arch Neurol 2003;60:329-34.  Back to cited text no. 4
5.Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown RH Jr, et al. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyl transferase, critical for sphingolipid synthesis. J Clin Invest 2002;110:1301-8.  Back to cited text no. 5
6.Axelrod FB, Pearson J. Congenital sensory neuropathies: Diagnostic distinction from familial dysautonomia. Am J Dis Child 1984;138:947-54.  Back to cited text no. 6
7.Ishikiriyama S. Congenital insensitivity to pain with anhidrosis, Nishida syndrome. Ryoikibetsu Shokogun Shirizu 2000;30:288-90.  Back to cited text no. 7
8.Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: Types II, III, and IV. Orphanet J Rare Dis 2007;2:39.  Back to cited text no. 8
9.Marik I, Kuklik M, Kuklikova D, Kozlowsk K. Hereditary sensory and autonomic neuropathy type IV orthopaedic complications. J Pediar Orthop B 2009;18:138-40.  Back to cited text no. 9
10.Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 1996;13:485-8.  Back to cited text no. 10
11.Toscano E, Andria G. Congenital insensitivity to pain with anhidrosis: An NGF/TrkA-related disorder. Am J Med Genet 2001;99:164-5.  Back to cited text no. 11
12.Rosenberg S, Marie SK, Kliemann S. Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomc neuropathy type IV). Pediatr Neurol 1994;11:50-6.  Back to cited text no. 12
13.Vassella F, Emrich HM, Kraus-Ruppert R, Aufdermaur F, Tönz O. Congenital sensory neuropathy with anhidrosis. Arch Dis Child 1968;43:124-30.  Back to cited text no. 13
14.Dyck P, Ohta M. Neuronal atrophy and degeneration predominantly affecting peripheral sensory neurons. In: Peripheral Neuropathy. Dyck PJ, Thomas PK, Lambert EH, editors. Vol. 2. Philadelphia: WB Saunders; 1975. p. 791.  Back to cited text no. 14
15.Nolano M, Crisci C, Santoro L, Barbieri F, Casale R, Kennedy WR, et al. Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clin Neurophysiol 2000;111:1596-601.  Back to cited text no. 15
16.Dua T, Sharma J, Singhal T, Arya VB. Hereditary sensory autonomic neuropathy type IV. Indian Pediatr 2005;42:281-4.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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