|Year : 2021 | Volume
| Issue : 3 | Page : 260-263
Congenital insensitivity to pain with anhidrosis and compensatory hyperhidrosis
Aradhana Rout1, Sandeep Arora1, Shamsher Singh Dalal2, Sudeep Kumar2
1 Department of Dermatology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Pediatrics, Command Hospital Air Force, Bengaluru, Karnataka, India
|Date of Submission||27-Jun-2020|
|Date of Decision||03-Jul-2020|
|Date of Acceptance||30-Mar-2021|
|Date of Web Publication||30-Jun-2021|
Department of Dermatology, Command Hospital Air Force, Bengaluru - 560 007, Karnataka
Source of Support: None, Conflict of Interest: None
Hereditary sensory and autonomic neuropathy is a rare syndrome characterized by congenital insensitivity to pain, temperature changes, and an autonomic nerve formation disorder. We report an 8-year-old boy who presented with late-onset of self-mutilating behavior, insensitivity to pain, temperature, and anhidrosis with compensatory hyperhidrosis. Exome sequencing revealed a mutation of the SCN9A gene at chromosome 2 with nucleotide change c. G554A/p. Arg185His at exon 5 along with HSPB1 mutation at chromosome 5.
Keywords: Anhidrosis, compensatory hyperhidrosis, congenital insensitivity to pain, hereditary sensory and autonomic neuropathy, self-mutilation
|How to cite this article:|
Rout A, Arora S, Dalal SS, Kumar S. Congenital insensitivity to pain with anhidrosis and compensatory hyperhidrosis. Indian J Paediatr Dermatol 2021;22:260-3
|How to cite this URL:|
Rout A, Arora S, Dalal SS, Kumar S. Congenital insensitivity to pain with anhidrosis and compensatory hyperhidrosis. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Oct 22];22:260-3. Available from: https://www.ijpd.in/text.asp?2021/22/3/260/319937
| Introduction|| |
Hereditary sensory and autonomic neuropathy (HSAN) is a rare syndrome characterized by congenital insensitivity to pain, temperature changes, and an autonomic nerve formation disorder. Of its four types, type IV results from lack of maturation of small myelinated and unmyelinated fibers of the peripheral nerves, which convey sensations of pain and temperature. Type IV HSAN is also known as Congenital Insensitivity to Pain and Anhidrosis (CIPA). Loss-of-function mutations in the NTRK1 gene-encoding TrkA (tropomyosin-related kinase A), a receptor tyrosine kinase for nerve growth factor (NGF), defects in NGF itself, channelopathy due to loss-of-function mutations in the SCN9A gene and rarely nonMendelian inheritance characterized by uniparental disomy of chromosome 1 have all been associated with this disorder.
We recently reviewed a case that presented with late-onset of self-mutilating behavior, insensitivity to pain and temperature, and anhidrosis with compensatory hyperhidrosis.
| Case Report|| |
An 8-year-old male child born of a nonconsanguineous marriage, with normal birth history presented with complaints of generalized absence of sweating with isolated patch of excessive sweating, insensitivity to pain and temperature sensation, extreme heat intolerance, and poor scholastic performance. Parents gave a history of recurrent febrile episodes since the age of 6 months, needing repeated hospital admissions. There was no history of febrile seizures in early childhood or convulsions later in life. Recently, he had started exhibiting anger outbursts, extreme irritability and would often pour water over himself even at school to stay comfortable. Self-mutilating behavior in the form of purposely touching hot objects, head banging against hard objects, and jumping from heights in an attempt to feel pain had resulted in multiple bruises and burns over his body.
Examination revealed stunted growth (weight and height <2 SD) with normal vitals.
Musculoskeletal examination showed microcephaly with depressed calvaria, depressed sternum [Figure 1], and mild scoliosis and lordosis [Figure 2] and [Figure 3]. Intellectual impairment (IQ-45) was present.
|Figure 3: Starch iodide test revealing generalized anhidrosis with compensatory hyperhidrosis; with obvious lordosis|
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Dermatological examination revealed multiple healed scars. Sweat mapping with starch iodide showed generalized anhidrosis with a patch of compensatory hyperhidrosis in the axillary and lateral thoracic wall [Figure 3] and [Figure 4]. Histamine flare response was absent in anhidrotic skin. Marked xerosis over the distal third of all four limbs with hyper linearity of the palms and soles was noted. Nails showed leukonychia and grade 2 clubbing. Hair was dry, lustreless and oral mucosa was normal.
|Figure 4: Starch iodide test of the entire trunk revealing anhidrosis with patchy hyperhidrosis on the lateral thoracic wall|
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Neurological examination revealed loss of pain sensation at peripheries, reduced temperature, and touch sensation however with the ability to distinguish between hot and cold. Vibration, proprioception was intact, cranial nerves and deep tendon jerks were normal. Reduced conduction velocity and amplitude with increased latency were observed on nerve conduction study of all four limbs. Ophthalmological examination showed reduced corneal sensation in both eyes with Schirmer's test suggestive of dry eyes (<5 mm) while dental examination showed dental development normal for age with dental caries of upper incisors and upper and lower canines. He had no postural fall in blood pressure.
Hematological and biochemical parameters showed reduced Vitamin D levels of 14.6 ng/ml (normal: 30–100 ng/ml) and serum calcium of 8 mg/dl (normal: 9.2–11 mg/dl). Magnetic resonance imaging of the brain, electrocardiogram, and echocardiography was normal.
Skin biopsy revealed mild perivascular lymphocytic dermal infiltrate with an essentially normal skin.
Gene sequencing (Exome sequencing report) showed a heterozygous missense mutation of SCN9A gene at chromosome 2 with nucleotide change c. G554A/p. Arg185His at exon 5 along with HSPB1 mutation at chromosome 5.
Based on his clinical presentation and investigations, he was diagnosed as a case of CIPA.
Patient's parents were counseled regarding the complications of this condition and the child was placed on emollients, saline eye drops, calcium carbonate 500 mg, and cholecalciferol supplements 60,000 units with advice for monthly follow-up. He was advised to be managed in a cooler environment in school and at home.
| Discussion|| |
CIPA an autosomal recessive condition with an incidence of 1 in 125 million newborns is an extremely rare disorder. First described by Dearborn in the early 1900s, and published in 1963 by Swanson in twin siblings. it is characterized by three clinical findings: Insensitivity to pain, inability to sweat, and mental retardation and structurally by the absence of afferent nociceptive neurons and loss of sympathetic innervation of the eccrine sweat glands. Nociceptive sensory neurons that respond to tissue damage are NGF-dependent for development, survival, and maintenance.
The NGF gene is responsible for the formation and survival of embryonic neuritic outgrowths and for phosphorylation of the receptor tyrosine kinase (which is encoded by TrkA/NTRK1 gene on chromosome 1) which effects intracellular signal transduction.
The NTRK1 mutation causes deficient development of the central nervous system and disruption of immune and nervous system interaction. In addition, the SCN9A gene provides instructions for making one part of the sodium channel (alpha subunit) called NaV1.7 found on nociceptors, and mutations in this gene are described in relation to CIPA, erythromelalgia, paroxysmal extreme pain disorder, related to or identical with some forms of hereditary sensory autonomic neuropathy. HSPB1 gene mutations have been associated with hereditary motor neuropathies such as Charcot-Marie-Tooth disease More Details.
The differential diagnosis includes radicular hereditary sensory neuropathy I, HSAN II, familial dysautonomia or Riley–Day syndrome (HSAN III), congenital indifference to pain (HSAN V), and Lesch–Nyhan syndrome. Among all these diagnostic possibilities CIPA must be the first diagnostic hypothesis when assessing a patient who has the three manifestations: Insensitivity to pain, anhidrosis, and self-mutilation. Self-mutilation starts in childhood possibly accidentally and is later perpetuated by pain insensitivity, attention-seeking, and mental retardation. Hyperthermia due to impaired thermoregulation has been described to kill 20% before the age of 3 years.
Clinical evaluation reveals absent sweating and histopathologic evaluation shows absent innervation of sweat glands and normal/hypoplastic sweat glands. Nerve conduction tests provide additional information in the form of prolongation of the central conduction time, reduced amplitude, and short-latency somatosensory evoked potentials. Microneurography is suggestive of abnormal activity of somatic A-delta and C fibers in the dermal nerves.
Proposed therapeutic interventions include counseling parents and school authorities about the risk of severe self-mutilation and the importance of protected environment, especially temperature. Early management of malignant hyperthermia and hypothermia, orthopedic, dental, and ophthalmic problems are essential.
Our patient had features of CIPA and had compensatory hyperhidrosis. Interestingly, congenital absence of pain with generalized paroxysmal hyperhidrosis was reported where cutaneous vascular afferents were proposed to play an important role in pathogenesis. Hyperhidrosis in our case was possibly on account of excitability of thoracic sympathetic ganglions. There were no features of motor involvement. Mutations in such cases with variations of sensitivity to pain are a complex subject where possibly one single mutation is unable to explain the entire syndrome and their association; a difficulty typically faced in analysis of these extremely rare syndromes. Significance of HSPB1 mutation, in this case, is not clinically evident. Further genetic analysis of similar rare cases to this case may help corroborate our genetic findings.
| Conclusion|| |
The extreme rarity of this condition along with failure to recognise it early in age increases its morbidity. The varied clinical presentations and genetic defects reported in literature confirm our knowledge of HSAN is lacking. These cases may present with compensatory hyperhidrosis or abnormal behaviour while pain insensitivty may need to be enquired into specifically.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]