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Year : 2020  |  Volume : 65  |  Issue : 4  |  Page : 299-303
Sisters with no pain, no tears: A report of a new variant of hereditary sensory and autonomic neuropathy (Type IX) Caused by a novel SCN11A mutation

Department of Dermatology, Venereology and Leprology, K. J. Somaiya Medical College, Mumbai, Maharashtra, India

Date of Web Publication11-Jun-2020

Correspondence Address:
Shital Poojary
OPD 26, 6th Floor, Department of Dermatology, Venereology and Leprology, K. J. Somaiya Medical College, Everard Nagar, Sion Chunnabhatti, Mumbai - 400 022, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijd.IJD_416_18

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Lack of pain sensation in children involves a rare group of heritable disorders; hereditary sensory and autonomic neuropathy (HSAN). Till date, eight types of HSAN have been described depending on the clinical phenotype and the underlying gene mutation. We report a new variant of HSAN (Type IX) in two siblings (of Indian origin) with a novel mutation of SCN11Agene and a distinct clinical phenotype.

Keywords: Anhidrosis, hereditary sensory and autonomic neuropathy Type IX, insensitivity to pain, SCN11A gene

How to cite this article:
Poojary S, Jaiswal S, Shah KS, Bhalala KB. Sisters with no pain, no tears: A report of a new variant of hereditary sensory and autonomic neuropathy (Type IX) Caused by a novel SCN11A mutation. Indian J Dermatol 2020;65:299-303

How to cite this URL:
Poojary S, Jaiswal S, Shah KS, Bhalala KB. Sisters with no pain, no tears: A report of a new variant of hereditary sensory and autonomic neuropathy (Type IX) Caused by a novel SCN11A mutation. Indian J Dermatol [serial online] 2020 [cited 2022 Dec 2];65:299-303. Available from:

   Introduction Top

Hereditary sensory and autonomic neuropathy (HSAN) is a genetic disorder of sensory and autonomic dysfunction. Till date, eight types of HSAN have been described depending on the clinical phenotype and the underlying gene mutation.[1],[2] We report a new variant of HSAN in two siblings (of Indian origin) with a novel mutation of SCN11A gene and a distinct clinical phenotype.

   Case Report Top

Two sisters (aged 6 and 3 years) born of a nonconsanguineous marriage presented with absence of pain sensation and sweating since birth along with redness over the body on heat exposure, recurrent febrile episodes, dry mouth, and decreased tears. The elder child complained of recurrent episodes of mild abdominal pain. History of celiac disease and hypothyroidism was present in the paternal cousin sister. There was no evidence of mental retardation, self-mutilating behavior, developmental delay, or history of recurrent infections. Superficial and deep pain sensations were absent over the entire body, while touch, temperature, pressure, and vibration sensations were normal. Tendon reflexes and muscle power in both the upper and lower limbs were normal. Erythema was present on the bilateral malar areas in both children [Figure 1]a. On oral examination, overcrowded, dysplastic teeth, and malocclusion with dental caries were present [Figure 1]b. Xerophthalmia was evident with positive Schirmer's test. Electromyography (EMG) and nerve conduction velocity (NCV) studies of both sisters showed impaired sympathetic skin responses from both the hands and feet, suggestive of small fiber neuropathy or autonomic dysfunction. Biopsies from the palms of both sisters showed sweat ducts but mostly absent secretory portion of eccrine glands. Intelligence quotient of both girls was normal. Anti-Ro and anti-La antibodies and transglutaminase antibodies were negative.
Figure 1: (a) Marked erythema on malar area of the face, (b) dysplastic teeth with malocclusion and dental caries in proband 2

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Based on the clinical features and preliminary investigations, the diagnosis of HSAN with idiopathic non-Sjögren Sicca Syndrome-like symptoms was considered. Targeted gene sequencing in elder sister detected a heterozygous missense variation (c.4064G>G/T [p. Cys1355Phe]) in exon 25 of SCN11A (chromosome 3:38892235; C>C/A; Depth: 41x) with autosomal dominant inheritance, resulting in substitution of phenylalanine for cysteine at codon 1355 (p. Cys1355Phe; ENST00000302328). Younger sibling and father also showed the same heterozygous missense variation in exon 25 of SCN11A. However, the father was asymptomatic with normal EMG and NCV studies. Genetic analysis of mother was normal. Parents were counseled to prevent both sisters from high-impact activities and extreme temperatures. Soft-sole footwear for the prevention of trophic changes, lubricant eye drops, and professional dental care were advised.

   Discussion Top

In 1993, Dyck provided a detailed classification of HSAN based on the clinical features.[1] The classification has been modified subsequently based on causative genes and identification of new types. The types of HSAN with their clinical features, genetic defect, and mode of inheritance are described in [Table 1]. This heterogeneous group of disorders can arise through (i) congenital absence or a progressive degeneration of sensory and/or autonomic neurons (neuropathy) or (ii) altered function of voltage-gated sodium channels (Nav1.7 and Nav1.9) within normal sensory neurons (channelopathy).
Table 1: Classification of HSAN based on age of onset, mode of inheritance, clinical presentation and their genetic background

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The neuropathies are caused by a variety of genes affecting neurotrophic functions (neurotrophic receptor tyrosine kinase-1 and nerve growth factor), sphingolipid metabolism (SPTLC1and SPTLC2), structural integrity of the endoplasmic reticulum (ATL1) and Golgi apparatus (FAM134B), vesicular trafficking (KIF1A), and epigenetic regulator expressed in nociceptors (PRDM12).[2],[3]

Voltage-gated sodium channels in cell membranes are essential for initiation and propagation of action potentials in neurons. Ten such channels (Nav1.1–1.9 and Nav2.x) which are encoded by genes SCN1A-SCN5A and SCN7A-SCN11A have been discovered till date. Defects in Nav1.7, Nav1.8, and Nav1.9 encoded by SCN9A, SCN10A, and SCN11A,, respectively, have been reported to cause pain disorders.[4],[5],[6],[7],[8],[9],[10]

Nav1.9 is expressed in peripheral sensory, trigeminal and dorsal root ganglia, and enteric plexus. The main function of Nav1.9 is to transmit pain signals from the periphery to the central nervous system. It consists of a 260-kDa α-subunit and an auxiliary β-subunit. Each α-subunit consists of six α-helical transmembrane-spanning segments (S1–S6). S1–S4 segments form the voltage-sensing domain that controls voltage-dependent gating while S5–S6 segments form the pore domain which conducts selective sodium filtering.

SCN11Agene (chromosome 3), which encodes Nav1.9, has 26 exons that annotate 31 domains. Gain-of-function mutations in SCN11A have been reported to cause loss of pain sensation (HSAN VII) as well as the severe paroxysmal pain disorder (familial episodic pain syndrome 3).[6],[7] These seemingly contradictory consequences of similar mutations is explained by the impact on resting membrane potential (RMP), wherein large depolarizations of RMP caused by some mutations are associated with hypoexcitability (insensitivity to pain, HSAN VII), whereas lesser degrees of membrane depolarization caused by other Nav1.9 mutations are associated with hyperexitability (familial episodic pain disorder).[8]

Till date, HSAN VII has been reported to be caused by two heterozygous missense mutations in SCN11A; (1) c.2432T>C (p. Leu811Pro) in exon 15 and (2) c.3904C>T (p. Leu1302Phe) in exon 23.[4],[9],[10] These gain-of-function mutations result in excess sodium influx, and subsequent cell depolarization at rest may cause progressive conduction block in other ion channels. Insufficient activation of calcium ion channels results in impaired neurotransmitter release at presynaptic nerve terminals resulting in nontransmission of pain signals to the spinal cord.[4]

Apart from congenital sensitivity to pain, Type VII HSAN clinical phenotype comprises severe self-mutilation, multiple painless fractures, delayed motor development, and hyperhidrosis. None of these were present in the present cases. Possibly, the novel mutation in SCN11A might have caused a different structural alteration in the Nav1.9 channel resulting in hypohidrosis, alacrimia, lack of salivary secretion, a much lesser severity of sensory dysfunction, and lack of any developmental delay. Thus, we propose this hitherto undescribed phenotype of HSAN with non-Sjögren sicca syndrome-like symptoms (alacrimia and dry mouth) and a novel mutation (p. Cys1355Phe) of SCN11A to be a new type of HSAN, i.e., HSAN Type IX. Another notable feature in this family is the incomplete penetrance of the mutation with the father having virtually no symptoms despite carrying the same mutation.

This case report highlights the variability of phenotypes and penetrance in HSAN, variability of phenotype in SCN11A mutations, and also the importance of the genetic mutation in designating appropriate classification of HSAN.

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.


The author would like to thank Dr. Anahita Hegde, Consultant Pediatric Neurologist, Breach Candy Hospital Trust, Mumbai, for her valuable inputs and assistance in genetic analysis of the patient.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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. 3rd ed. Philadelphia: W.B. Saunders Co.; 1993. p. 1065-93.  Back to cited text no. 1
Mroczek M, Kabzińska D, Kochański A. Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies. Acta Neurobiol Exp (Wars) 2015;75:126-43.  Back to cited text no. 2
Haga N, Kubota M, Miwa Z; Japanese Research Group on Congenital Insensitivity to Pain. Hereditary sensory and autonomic neuropathy types IV and V in Japan. Pediatr Int 2015;57:30-6.  Back to cited text no. 3
Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, et al.A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet 2013;45:1399-404.  Back to cited text no. 4
Huang W, Liu M, Yan SF, Yan N. Structure-based assessment of disease-related mutations in human voltage-gated sodium channels. Protein Cell 2017;8:401-38.  Back to cited text no. 5
Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JG, Gerrits MM, et al. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 2014;137:1627-42.  Back to cited text no. 6
Han C, Yang Y, Te Morsche RH, Drenth JP, Politei JM, Waxman SG, et al. Familial gain-of-function nav1.9 mutation in a painful channelopathy. J Neurol Neurosurg Psychiatry 2017;88:233-40.  Back to cited text no. 7
Huang J, Vanoye CG, Cutts A, Goldberg YP, Dib-Hajj SD, Cohen CJ, et al. Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J Clin Invest 2017;127:2805-14.  Back to cited text no. 8
Woods CG, Babiker MO, Horrocks I, Tolmie J, Kurth I. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur J Hum Genet 2015;23:1434.  Back to cited text no. 9
Phatarakijnirund V, Mumm S, McAlister WH, Novack DV, Wenkert D, Clements KL, et al. Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9. Bone 2016;84:289-98.  Back to cited text no. 10


  [Figure 1]

  [Table 1]

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