A Novel Homozygous Pathogenic Variant in SCN9A Gene Causing Hereditary Sensory and Autonomic Neuropathy Type ID: A Case Report

A Novel Homozygous Pathogenic Variant in SCN9A Gene Causing Hereditary Sensory and Autonomic Neuropathy Type ID: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Novel Homozygous Pathogenic Variant in SCN9A Gene Causing Hereditary Sensory and Autonomic Neuropathy Type ID: A Case Report Roba Alzuhoor, Mahmoud A. Abu Mayaleh, Abdallah A. Najjar, Ghaida Atawneh, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7180980/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hereditary Sensory and Autonomic Neuropathy type ID (HSAN ID), caused by mutations in the SCN9A gene, is an exceptionally rare inherited disorder characterized by a profound absence of pain perception and varying degrees of autonomic dysfunction. We present the case of a female patient, currently in her early school-age years, born to consanguineous parents, who exhibited congenital insensitivity to pain and severe anhidrosis since infancy. Clinical presentation included recurrent unexplained injuries, oral self-mutilation, and frequent, unnoticed infections, leading to severe complications like left lung empyema requiring Video-Assisted Thoracoscopic Surgery (VATS) Decortication. Genetic testing via Whole Exome Sequencing identified a novel homozygous nonsense variant (c.901A > T, p.K301*) in the SCN9A gene, confirming the diagnosis and classifying it as pathogenic according to ACMG guidelines. This variant leads to a truncated, non-functional Nav1.7 channel protein, explaining the sensory deficits. This case highlights the challenges in diagnosing and managing such rare conditions, emphasizing the critical role of early genetic identification and a proactive multidisciplinary approach to prevent severe morbidity and improve long-term outcomes. Furthermore, the severe anhidrosis observed in this SCN9A-related case suggests a potentially broader involvement of Nav1.7 in autonomic functions than traditionally recognized. Hereditary Sensory and Autonomic Neuropathy SCN9A gene Congenital Insensitivity to Pain Anhidrosis Case Report Introduction Hereditary Sensory and Autonomic Neuropathies (HSANs) encompass several inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotension, excessive sweating ( 1 ). As epidemiology, HSAN is a very rare condition, with an estimated incidence of approximately 1 in 25,000 individuals worldwide. Although the overall prevalence remains extremely low, several genes have been identified and linked to specific HSAN subtypes.( 1 )( 2 )The presentation varies by subtype, with various autonomic dysfunctions and analgesia of varying degrees common to all disorders; they are phenotypically distinct, as they can be differentiated clinically and neuropathologically, and there is evidence of genotypic differences. ( 3 ) They have been categorized into types HSAN I–VI, although some children do not fit well into this classification due to overlapping or atypical phenotypes.( 4 ) The case described in this report is classified as HSAN type II, with the underlying genetic cause identified as a mutation in the SCN9A gene. This gene determines the formation of the sodium channels, which help in the conduction of action potential across excitable cells. Genetic polymorphism has been identified in the expression of the SCN9A gene, leading to several pain phenotypes from hypersensitivity to complete insensitivity ( 5 ). The management approach depends on the specific HSAN subtype, the underlying genetic mutation, and the severity of clinical manifestations. Supportive care may include non-invasive and occasionally invasive aiming to minimize morbidity and prevent early childhood mortality.( 6 ) Despite advances in understanding the genetic basis of HSAN subtypes, cases confirmed with SCN9A mutations related specifically to HSAN II remain rare, especially in the Middle East region. There is limited documentation of genetically confirmed HSAN II cases from Palestine, and this scarcity underlines the need for further genetic and clinical characterization of such patients. Reporting new cases contributes to expanding knowledge about phenotypic variability and can aid in improving early diagnosis and tailored management strategies. Case Presentation A female patient, born on October 5, 2018, was approximately 5 years and 9 months old at the time of her most recent hospital admission in late June 2024. This case adheres to strict de-identification protocols to protect privacy. The primary concerns presented by the parents were a history of recurrent unexplained injuries and the complete absence of pain perception since infancy. This was first noted at two weeks of age during routine BCG vaccination and heel prick testing, where healthcare providers observed the infant did not cry or respond to painful stimuli. By four months of age, the mother noticed oral self-mutilation during teething, specifically biting of her finger and tongue, which resulted in bleeding without any signs of distress or pain. Her birth was full-term and uneventful, with no dysmorphic features or perinatal complications. Growth parameters were within normal limits. The patient was born to consanguineous parents (mother and her maternal cousin). Her past medical history includes recurrent high-grade fevers (up to 40∘C at six months of age) and urinary tract infections (UTIs) since the age of 10 months, reported approximately twice a month. She also experienced repeated episodes of acute bronchitis. All these episodes occurred without any reported discomfort, suggesting impaired thermoregulation and a lack of typical infection symptoms. Dermatologic follow-up confirmed skin damage consistent with impaired thermoregulation and anhidrosis, with recurrent blisters and burns on her hands and feet. A detailed chronological overview of the patient's clinical course and significant events is provided in Table 1 . Table 1 Patient's Clinical Timeline This table provides a chronological summary of the key clinical events, diagnostic milestones, and interventions in the patient's medical history, from birth to the most recent follow-up. Age/Date Event Clinical Details / Key Findings Birth (Oct 5, 2018) Full-term, uneventful birth. Normal growth parameters. 2 Weeks First concern: No cry or response to BCG vaccination and heel prick. Absence of pain perception noted by healthcare providers. 4 Months Oral self-mutilation during teething. Biting of finger and tongue, resulting in bleeding without distress/pain. 6 Months First high-grade fever (40°C) and hospital admission. No pain response despite invasive procedures. < 10 Months Referral to pediatric neurologist. Neurological exam: normal motor, deficits in pain/temp sensation, preserved vibration/proprioception. By 10 Months Recurrent febrile episodes, UTIs, acute bronchitis begin. Occur without reported discomfort. Prior to 2019 Recurrent blisters and burns, dry skin suggestive of anhidrosis. Dermatologic follow-up confirms skin damage & impaired thermoregulation. 12-Oct-19 Abdominal & Pelvic Ultrasound (initial). Mild hepatosplenomegaly, diffuse bladder wall thickening suggestive of cystitis. 16-Nov-19 M.C.U.G.. Normal capacity/outline of urinary bladder, no vesico-ureteric reflux, no residual contrast. 08-Apr-20 Whole Exome Sequencing (WES) performed. Requested due to sensory neuropathy. Oct-20 Abdominal & Pelvic Ultrasound (follow-up). Distended colon with constipation signs, multiple small mesenteric lymph nodes. Normal liver, gallbladder, pancreas, kidneys. Mild splenomegaly. Around 5.5 Years Genetic testing results confirm HSAN ID. Homozygous pathogenic variant in SCN9A gene (c.901A > T p.(K301*)) identified. Both parents identified as heterozygous carriers. Diagnosis confirmed via Sanger sequencing, classified pathogenic (ACMG). 28-Jun-24 Hospital Admission for Left Lung Empyema. High CRP (360.8 mg/dL), Leukocytosis (WBC 14.5x10^3). Managed with IV Rocephin, then Tazocin. 29-Jun-24 Left VATS Decortication performed. Identification of extensive adhesions involving almost the whole lung. Pus and fluid collected. Multiple pleural peels sent for pathology/culture. Operation smooth, no complications. 07-Jul-24 Anterior chest tube removed. 08-Jul-24 Patient discharged. Stable vital signs, good general condition, off complaints. Ongoing Regular monitoring by specialists. Neurology, dermatology, genetics follow-up. Injury prevention, temperature regulation, early infection treatment. No major complications or new injuries reported during follow-up. Upon referral to a pediatric neurologist, neurological examination revealed normal motor function but distinct deficits in pain and temperature sensation, while vibration and proprioception were preserved. Physical examination showed part of her tongue was missing and one fingertip was deformed, attributed to chronic self-biting. Laboratory investigations during admissions for febrile episodes showed varying degrees of inflammation, with significantly elevated C-Reactive Protein (CRP) and White Blood Cell (WBC) count during her June 2024 admission. Initial abdominal and pelvic ultrasounds indicated mild hepatosplenomegaly and diffuse bladder wall thickening, while a Micturating Cystourethrogram (MCUG) was normal. The definitive diagnosis of Hereditary Sensory and Autonomic Neuropathy type ID (HSAN ID) was confirmed through Whole Exome Sequencing (WES), which identified a homozygous pathogenic variant in the SCN9A gene (c.901A > T p.(K301*)). The patient's management involved a multidisciplinary approach focusing on injury prevention, meticulous temperature regulation, and prompt, aggressive treatment of infections. Pharmacologic interventions during acute episodes included empirical antibiotics such as intravenous Rocephin (Ceftriaxone) followed by Tazocin (Piperacillin/Tazobactam). Surgical intervention was notably required for a severe complication, specifically left lung empyema, for which Left Video-Assisted Thoracoscopic Surgery (VATS) Decortication was performed on June 29, 2024. This procedure involved identifying and dissecting extensive adhesions, collecting pus and fluid, and removing pleural peels, representing a critical escalation from conservative medical management. Post-operatively, two chest tubes were inserted, which were removed on July 7, 2024. Following the surgery and empyema management, the patient's condition improved significantly, and she was discharged on July 8, 2024, in good general condition with stable vital signs. Post-operative follow-up included serial daily chest X-rays and laboratory tests (CBC, CRP), which showed improvement. Regular monitoring by specialists (neurology, dermatology, genetics) continues to track disease progression and prevent new complications. Intervention adherence, particularly for injury prevention and temperature regulation, is primarily assessed through consistent parental supervision and adherence to counseling. Adherence to prescribed oral medications (e.g., Augmentin) is assessed through parental report and clinical response, with good tolerability observed. The development of left lung empyema was a significant and serious unanticipated event. Other recurrent adverse events include repeated episodes of high-grade fever, urinary tract infections, and acute bronchitis, as well as chronic self-mutilation leading to loss of part of the tongue and deformed fingertips, directly attributable to the congenital insensitivity to pain. Discussion This case report presents a rare and severe manifestation of Hereditary Sensory and Autonomic Neuropathy type ID (HSAN ID) in a young Palestinian female, characterized by profound congenital pain insensitivity and severe anhidrosis. This unique presentation is linked to a novel homozygous nonsense variant (c.901A > T, p.K301*) in the SCN9A gene, a finding confirmed by Whole Exome Sequencing (WES) and Sanger sequencing, with both parents identified as heterozygous carriers, consistent with an autosomal recessive inheritance pattern ( 7 ). The report's strength lies in its definitive molecular diagnosis and a detailed longitudinal account of the patient's complex clinical course, from initial pain insensitivity at two weeks of age to a life-threatening left lung empyema requiring surgical intervention at nearly six years old. This comprehensive overview highlights the escalating complications due to the absence of the body's primary warning system, emphasizing the critical need for proactive, interdisciplinary care. While the individual case report has inherent limitations in generalizability and long-term outcome assessment, it significantly enriches the understanding of SCN9A -related channelopathies. Hereditary Sensory and Autonomic Neuropathies (HSANs) are a diverse group of rare genetic disorders characterized by significant sensory deficits, particularly affecting pain and temperature sensation, often accompanied by varying degrees of autonomic dysfunction ( 8 ). The SCN9A gene encodes Nav1.7, a voltage-gated sodium channel alpha subunit predominantly expressed in peripheral sensory (nociceptor) and autonomic neurons, playing a critical role in the initiation and propagation of action potentials for pain signal transmission and influencing autonomic functions ( 7 , 8 ). Loss-of-function mutations in SCN9A , like the protein-truncating variant in this case, lead to congenital insensitivity to pain (CIP) by preventing pain signal transmission, while gain-of-function mutations cause painful channelopathies ( 8 , 9 ). HSAN ID ( SCN9A -related CIP) is an exceptionally rare condition globally. Precise global prevalence figures or comprehensive registries of reported cases are not readily available in the medical literature, reflecting its extreme rarity ( 1 ). For instance, while HSAN III has an incidence of 1 per 3600 live births in specific populations, and several hundred cases of HSAN IV have been documented, SCN9A -related CIP remains significantly less common ( 9 ). Specific data on the number of reported cases of HSAN ID or SCN9A -related neuropathies within Palestine is also limited. Historically, studies in Palestine and neighboring regions have indicated that many CIP cases are predominantly caused by mutations in the NTRK1 gene, suggesting a founder effect ( 10 ). However, the present case is particularly significant as it identifies a novel homozygous mutation in the SCN9A gene (c.901A > T) in a Palestinian family. This finding is supported by another recent study from Palestine that also reported a novel SCN9A mutation in a family with CIP without anhidrosis, highlighting an emerging recognition of SCN9A -related CIP within the region ( 10 ). The identified homozygous nonsense variant c.901A > T (p.K301*) in the SCN9A gene introduces a premature stop codon at amino acid position 301, leading to the production of a severely truncated Nav1.7 channel protein ( 5 )( 9 ). Such truncated proteins are inherently unstable and are often targeted for degradation, resulting in a complete or near-complete absence of functional Nav1.7 channels in the patient's sensory neurons, which is entirely consistent with the observed severe loss-of-function phenotype ( 9 ). Functional Nav1.7 channels are indispensable for the generation and propagation of action potentials in nociceptors ( 8 ). The complete absence or severe dysfunction of these channels, due to the homozygous nonsense mutation, directly impairs the excitability of these neurons, preventing them from effectively transmitting noxious signals to the central nervous system and resulting in profound congenital insensitivity to pain. This fundamental lack of protective pain signals precipitates a cascade of severe and complex clinical issues. As vividly demonstrated by the patient's oral self-mutilation, deformed fingertips, and recurrent blisters and burns, the absence of pain prevents the individual from recognizing and reacting appropriately to harmful stimuli, leading to repeated self-inflicted injuries and unnoticed external trauma ( 8 ). Furthermore, without pain serving as an early warning sign, infections—such as recurrent urinary tract infections, acute bronchitis, and critically, the left lung empyema—can progress silently and severely before clinical detection and intervention. This patient's complex clinical course vividly illustrates how a single, profound molecular defect cascades into a multi-systemic array of complications. A striking and unusual feature of the present case is the profound pain insensitivity coupled with severe anhidrosis, which manifested as impaired thermoregulation and recurrent high-grade fevers. While Nav1.7 is most extensively characterized for its role in nociception, its expression has also been documented in autonomic neurons, including sympathetic neurons that innervate sweat glands ( 8 ). The severe anhidrosis observed in this patient, and its presence in other recently reported SCN9A cases with nonsense or frameshift mutations ( 11 ), strongly indicates that complete loss of Nav1.7 function may extend its impact beyond pain pathways to significantly affect sudomotor function. This unexpected co-occurrence challenges the long-held, traditional gene-phenotype correlations and suggests either a direct, previously underestimated role of Nav1.7 in sudomotor function or a more complex, indirect interplay where complete loss of Nav1.7 function leads to secondary effects on the development or maintenance of autonomic nerve fibers ( 11 ). The patient's birth to consanguineous parents (mother and her maternal cousin) is highly relevant in the context of this autosomal recessive disorder. Consanguineous marriages, which are particularly prevalent in many regions of the Middle East, including Palestine ( 12 ),( 13 ), significantly increase the probability of offspring inheriting two copies of the same recessive genetic mutation, directly leading to a higher incidence of autosomal recessive disorders within these populations ( 14 ). The patient's clinical history of recurrent high-grade fevers, urinary tract infections, acute bronchitis, and, critically, the development of left lung empyema, all occurring without reported discomfort, profoundly underscores the diagnostic and management challenges posed by congenital pain insensitivity. Pain serves as an indispensable biological warning system, prompting individuals to recognize and seek medical attention for injuries and infections ( 8 ). In the absence of this crucial protective signal, injuries can go unnoticed, wounds may heal poorly, and infections can progress silently to severe, life-threatening stages before clinical detection, as starkly exemplified by the empyema requiring Video-Assisted Thoracoscopic Surgery (VATS) Decortication. This progression from unnoticed minor infections to a severe, life-threatening condition highlights the "silent killer" aspect of CIP. The profound clinical implication is that healthcare providers managing these patients must adopt an exceptionally proactive and low-threshold approach to investigating any subtle signs of illness, as the typical "red flags" (pain, discomfort) are conspicuously absent. Comparison of Present Case with Selected Published Cases of HSAN ID/SCN9A-related Neuropathy Case ID SCN9A Variant(s) (Type, Zygosity) Key Phenotype (CIP, Anhidrosis, Recurrent Infections, Self-Mutilation, etc.) Onset Age Origin/Ethnicity Unique Features/Notable Outcome Present Case c.901A > T (p.K301*), Homozygous nonsense Profound CIP, severe anhidrosis, recurrent severe infections (empyema), oral self-mutilation, deformed fingertips. 2 weeks Palestinian, consanguineous parents Novel homozygous nonsense variant, severe anhidrosis, left lung empyema requiring VATS decortication. Case 1 ( 11 ) c.901A > T (p.Lys301*), Homozygous probable pathogenic (nonsense) Insensitivity to pain, recurrent febrile joint swelling, mouth ulcers, tongue biting, anhidrosis, Charcot joints, muscle atrophy. 2 years Not specified (consanguineous parents) Exact same novel homozygous nonsense variant, presence of anhidrosis, Charcot joints, osteomyelitis. Case 2 ( 8 ) W897X, Homozygous nonsense Congenital insensitivity to pain (classic CIP). Early childhood (implied) Not specified Classic CIP phenotype, often characterized by normal sweating and intelligence. Case 3 ( 15 ) c.5118delA (p.Val1709Phefs*33), Homozygous single base pair deletion (frameshift) Congenital insensitivity to pain, anhidrosis (hypohidrosis), recurrent bullous lesions, self-injuries (auto-amputation of finger), septic arthritis, corneal ulcerations, mild cognitive impairment. Few months after birth Egyptian, consanguineous parents (first-degree cousins) Novel homozygous frameshift variant, anhidrosis, mild cognitive impairment, septic arthritis. Conclusion Unexplained pain insensitivity, especially in infants and consanguineous populations, should trigger urgent genetic testing. Early diagnosis of HSAN ID is crucial for timely prevention and multidisciplinary care, impacting outcomes and avoiding severe complications. Management requires a proactive, tailored approach focusing on injury prevention, temperature control, and prompt infection treatment, even without pain symptoms. Regular monitoring by neurology, dermatology, orthopedics, pulmonology, and infectious disease specialists is vital. This case highlights that SCN9A-related disorders can show broader, atypical symptoms, including severe autonomic issues like anhidrosis, beyond classic insensitivity to pain. Clinicians should consider comprehensive genetic testing in patients with sensory neuropathies. Abbreviations ACMG : American College of Medical Genetics and Genomics BCG : Bacillus Calmette–Guérin CBC : Complete Blood Count CIP : Congenital Insensitivity to Pain CRP : C-Reactive Protein HSAN : Hereditary Sensory and Autonomic Neuropathy HSAN ID : Hereditary Sensory and Autonomic Neuropathy Type ID MCUG : Micturating Cystourethrogram Nav1.7 : Voltage-gated sodium channel subtype encoded by SCN9A SCN9A : Sodium Voltage-Gated Channel Alpha Subunit 9 UTI : Urinary Tract Infection VATS : Video-Assisted Thoracoscopic Surgery WBC : White Blood Cell WES : Whole Exome Sequencing Declarations Ethics approval and consent to participate Not applicable. As this is a case report of a single patient, formal ethics committee approval was not required. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Consent for publication Written informed consent was obtained from the patient's parents for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. Authors' contributions RA : Conceptualization, Data Curation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. MAAM : Conceptualization, Data Curation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. AAN : Conceptualization, Data Curation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. GA : Data Curation, Investigation, Writing – Review & Editing. AK : Data Curation, Investigation, Writing – Review & Editing. YB : Data Curation, Investigation, Writing – Review & Editing. MZ : Supervision, Clinical Management, Conceptualization, Final Review. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank the patient and her family for their willingness to participate in this case report. References Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2(1):39. King R. Hereditary sensory and autonomic neuropathy. Peripher nerve Disord. 2014;119–25. Axelrod FB. Hereditary sensory and autonomic neuropathies. Clin Auton Res. 2002;12:I2. Eichler FS, Kothari M, Firth H V, Shefner FmJM. Hereditary sensory and autonomic neuropathies. Waltham, MA UpToDate. 2007; Drenth JPH, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest. 2007;117(12):3603–9. Khalaf‐Nazzal R, Dweikat I, Ubeyratna N, Fasham J, Alawneh M, Leslie J, et al. TECPR2‐related hereditary sensory and autonomic neuropathy in two siblings from Palestine. Am J Med Genet Part A. 2024;194(7):e63579. NM_001365536.1(SCN9A):c.901A>T (p.Lys301Ter) AND Channelopathy-associated congenital insensitivity to pain, autosomal recessive - ClinVar - NCBI [Internet]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/RCV003448394/ Staud R, Price DD, Janicke D, Andrade E, Hadjipanayis AG, Eaton WT, et al. Two novel mutations of SCN9A (Nav1. 7) are associated with partial congenital insensitivity to pain. Eur J pain. 2011;15(3):223–30. Cox JJ, Sheynin J, Shorer Z, Reimann F, Nicholas AK, Zubovic L, et al. Congenital insensitivity to pain: novel SCN9A missense and in‐frame deletion mutations. Hum Mutat. 2010;31(9):E1670–86. Khaled B, Alzahayqa M, Jaffal A, Sallam H, Thawabta R, Mansour M, et al. Identification of founder and novel mutations that cause congenital insensitivity to pain (CIP) in palestinian patients. BMC Med Genomics. 2023;16(1):120. Al-Hroub NN, Ala’a A, Taamreh MA, Abunejma FM, Dukmak ON, Al-Salahat A, et al. Congenital Insensitivity to Pain: A Case Study of a Rare Genetic Disorder. Cureus. 2024;16(9). Khayat AM, Alshareef BG, Alharbi SF, AlZahrani MM, Alshangity BA, Tashkandi NF, et al. Consanguineous marriage and its association with genetic disorders in Saudi Arabia: a review. Cureus. 2024;16(2). Cousin - Wikipedia [Internet]. Available from: https://en.wikipedia.org/wiki/Cousin Congenital Insensitivity to Pain: Diagnosis, Treatment, and More [Internet]. Available from: https://www.webmd.com/children/what-is-congenital-insensitivity-pain Romagnuolo M, Moltrasio C, Cavalli R, Brena M, Tadini G. A novel mutation in the SCN9A gene associated with congenital insensitivity to pain, anhidrosis, and mild cognitive impairment. Pediatr Dermatol. 2024;41(1):80–3. 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17:08:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":637923,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7180980/v1/a32af893-a0f8-4363-b69a-84247f73b0c3.pdf"},{"id":92078125,"identity":"fb0f5e74-b779-436f-851f-8419f25ac1d1","added_by":"auto","created_at":"2025-09-24 11:20:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":330511,"visible":true,"origin":"","legend":"","description":"","filename":"CARE.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7180980/v1/ad2abd1de4033c0e990eafdf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Homozygous Pathogenic Variant in SCN9A Gene Causing Hereditary Sensory and Autonomic Neuropathy Type ID: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHereditary Sensory and Autonomic Neuropathies (HSANs) encompass several inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotension, excessive sweating (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAs epidemiology, HSAN is a very rare condition, with an estimated incidence of approximately 1 in 25,000 individuals worldwide. Although the overall prevalence remains extremely low, several genes have been identified and linked to specific HSAN subtypes.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)The presentation varies by subtype, with various autonomic dysfunctions and analgesia of varying degrees common to all disorders; they are phenotypically distinct, as they can be differentiated clinically and neuropathologically, and there is evidence of genotypic differences. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThey have been categorized into types HSAN I\u0026ndash;VI, although some children do not fit well into this classification due to overlapping or atypical phenotypes.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe case described in this report is classified as HSAN type II, with the underlying genetic cause identified as a mutation in the SCN9A gene. This gene determines the formation of the sodium channels, which help in the conduction of action potential across excitable cells. Genetic polymorphism has been identified in the expression of the SCN9A gene, leading to several pain phenotypes from hypersensitivity to complete insensitivity (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe management approach depends on the specific HSAN subtype, the underlying genetic mutation, and the severity of clinical manifestations. Supportive care may include non-invasive and occasionally invasive aiming to minimize morbidity and prevent early childhood mortality.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eDespite advances in understanding the genetic basis of HSAN subtypes, cases confirmed with SCN9A mutations related specifically to HSAN II remain rare, especially in the Middle East region. There is limited documentation of genetically confirmed HSAN II cases from Palestine, and this scarcity underlines the need for further genetic and clinical characterization of such patients. Reporting new cases contributes to expanding knowledge about phenotypic variability and can aid in improving early diagnosis and tailored management strategies.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA female patient, born on October 5, 2018, was approximately 5 years and 9 months old at the time of her most recent hospital admission in late June 2024. This case adheres to strict de-identification protocols to protect privacy.\u003c/p\u003e\u003cp\u003e The primary concerns presented by the parents were a history of recurrent unexplained injuries and the complete absence of pain perception since infancy. This was first noted at two weeks of age during routine BCG vaccination and heel prick testing, where healthcare providers observed the infant did not cry or respond to painful stimuli. By four months of age, the mother noticed oral self-mutilation during teething, specifically biting of her finger and tongue, which resulted in bleeding without any signs of distress or pain.\u003c/p\u003e\u003cp\u003eHer birth was full-term and uneventful, with no dysmorphic features or perinatal complications. Growth parameters were within normal limits. The patient was born to consanguineous parents (mother and her maternal cousin). Her past medical history includes recurrent high-grade fevers (up to 40∘C at six months of age) and urinary tract infections (UTIs) since the age of 10 months, reported approximately twice a month. She also experienced repeated episodes of acute bronchitis. All these episodes occurred without any reported discomfort, suggesting impaired thermoregulation and a lack of typical infection symptoms. Dermatologic follow-up confirmed skin damage consistent with impaired thermoregulation and anhidrosis, with recurrent blisters and burns on her hands and feet. A detailed chronological overview of the patient's clinical course and significant events is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003ePatient's Clinical Timeline\u003c/b\u003e This table provides a chronological summary of the key clinical events, diagnostic milestones, and interventions in the patient's medical history, from birth to the most recent follow-up.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge/Date\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical Details / Key Findings\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBirth (Oct 5, 2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFull-term, uneventful birth. Normal growth parameters.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst concern: No cry or response to BCG vaccination and heel prick.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAbsence of pain perception noted by healthcare providers.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral self-mutilation during teething.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBiting of finger and tongue, resulting in bleeding without distress/pain.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst high-grade fever (40\u0026deg;C) and hospital admission.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo pain response despite invasive procedures.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;10 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReferral to pediatric neurologist.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNeurological exam: normal motor, deficits in pain/temp sensation, preserved vibration/proprioception.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBy 10 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecurrent febrile episodes, UTIs, acute bronchitis begin.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOccur without reported discomfort.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrior to 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecurrent blisters and burns, dry skin suggestive of anhidrosis.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDermatologic follow-up confirms skin damage \u0026amp; impaired thermoregulation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12-Oct-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbdominal \u0026amp; Pelvic Ultrasound (initial).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMild hepatosplenomegaly, diffuse bladder wall thickening suggestive of cystitis.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16-Nov-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM.C.U.G..\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal capacity/outline of urinary bladder, no vesico-ureteric reflux, no residual contrast.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e08-Apr-20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWhole Exome Sequencing (WES) performed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRequested due to sensory neuropathy.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOct-20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbdominal \u0026amp; Pelvic Ultrasound (follow-up).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDistended colon with constipation signs, multiple small mesenteric lymph nodes. Normal liver, gallbladder, pancreas, kidneys. Mild splenomegaly.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAround 5.5 Years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGenetic testing results confirm HSAN ID.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHomozygous pathogenic variant in SCN9A gene (c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T p.(K301*)) identified. Both parents identified as heterozygous carriers. Diagnosis confirmed via Sanger sequencing, classified pathogenic (ACMG).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28-Jun-24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHospital Admission for Left Lung Empyema.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh CRP (360.8 mg/dL), Leukocytosis (WBC 14.5x10^3). Managed with IV Rocephin, then Tazocin.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e29-Jun-24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeft VATS Decortication performed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIdentification of extensive adhesions involving almost the whole lung. Pus and fluid collected. Multiple pleural peels sent for pathology/culture. Operation smooth, no complications.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e07-Jul-24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnterior chest tube removed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e08-Jul-24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient discharged.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStable vital signs, good general condition, off complaints.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOngoing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegular monitoring by specialists.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNeurology, dermatology, genetics follow-up. Injury prevention, temperature regulation, early infection treatment. No major complications or new injuries reported during follow-up.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eUpon referral to a pediatric neurologist, neurological examination revealed normal motor function but distinct deficits in pain and temperature sensation, while vibration and proprioception were preserved. Physical examination showed part of her tongue was missing and one fingertip was deformed, attributed to chronic self-biting. Laboratory investigations during admissions for febrile episodes showed varying degrees of inflammation, with significantly elevated C-Reactive Protein (CRP) and White Blood Cell (WBC) count during her June 2024 admission. Initial abdominal and pelvic ultrasounds indicated mild hepatosplenomegaly and diffuse bladder wall thickening, while a Micturating Cystourethrogram (MCUG) was normal.\u003c/p\u003e\u003cp\u003eThe definitive diagnosis of Hereditary Sensory and Autonomic Neuropathy type ID (HSAN ID) was confirmed through Whole Exome Sequencing (WES), which identified a homozygous pathogenic variant in the SCN9A gene (c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T p.(K301*)).\u003c/p\u003e\u003cp\u003eThe patient's management involved a multidisciplinary approach focusing on injury prevention, meticulous temperature regulation, and prompt, aggressive treatment of infections. Pharmacologic interventions during acute episodes included empirical antibiotics such as intravenous Rocephin (Ceftriaxone) followed by Tazocin (Piperacillin/Tazobactam). Surgical intervention was notably required for a severe complication, specifically left lung empyema, for which Left Video-Assisted Thoracoscopic Surgery (VATS) Decortication was performed on June 29, 2024. This procedure involved identifying and dissecting extensive adhesions, collecting pus and fluid, and removing pleural peels, representing a critical escalation from conservative medical management. Post-operatively, two chest tubes were inserted, which were removed on July 7, 2024.\u003c/p\u003e\u003cp\u003eFollowing the surgery and empyema management, the patient's condition improved significantly, and she was discharged on July 8, 2024, in good general condition with stable vital signs. Post-operative follow-up included serial daily chest X-rays and laboratory tests (CBC, CRP), which showed improvement. Regular monitoring by specialists (neurology, dermatology, genetics) continues to track disease progression and prevent new complications. Intervention adherence, particularly for injury prevention and temperature regulation, is primarily assessed through consistent parental supervision and adherence to counseling. Adherence to prescribed oral medications (e.g., Augmentin) is assessed through parental report and clinical response, with good tolerability observed. The development of left lung empyema was a significant and serious unanticipated event. Other recurrent adverse events include repeated episodes of high-grade fever, urinary tract infections, and acute bronchitis, as well as chronic self-mutilation leading to loss of part of the tongue and deformed fingertips, directly attributable to the congenital insensitivity to pain.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case report presents a rare and severe manifestation of Hereditary Sensory and Autonomic Neuropathy type ID (HSAN ID) in a young Palestinian female, characterized by profound congenital pain insensitivity and severe anhidrosis. This unique presentation is linked to a novel homozygous nonsense variant (c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T, p.K301*) in the \u003cem\u003eSCN9A\u003c/em\u003e gene, a finding confirmed by Whole Exome Sequencing (WES) and Sanger sequencing, with both parents identified as heterozygous carriers, consistent with an autosomal recessive inheritance pattern (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The report's strength lies in its definitive molecular diagnosis and a detailed longitudinal account of the patient's complex clinical course, from initial pain insensitivity at two weeks of age to a life-threatening left lung empyema requiring surgical intervention at nearly six years old. This comprehensive overview highlights the escalating complications due to the absence of the body's primary warning system, emphasizing the critical need for proactive, interdisciplinary care. While the individual case report has inherent limitations in generalizability and long-term outcome assessment, it significantly enriches the understanding of \u003cem\u003eSCN9A\u003c/em\u003e-related channelopathies.\u003c/p\u003e\u003cp\u003eHereditary Sensory and Autonomic Neuropathies (HSANs) are a diverse group of rare genetic disorders characterized by significant sensory deficits, particularly affecting pain and temperature sensation, often accompanied by varying degrees of autonomic dysfunction (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The \u003cem\u003eSCN9A\u003c/em\u003e gene encodes Nav1.7, a voltage-gated sodium channel alpha subunit predominantly expressed in peripheral sensory (nociceptor) and autonomic neurons, playing a critical role in the initiation and propagation of action potentials for pain signal transmission and influencing autonomic functions (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Loss-of-function mutations in \u003cem\u003eSCN9A\u003c/em\u003e, like the protein-truncating variant in this case, lead to congenital insensitivity to pain (CIP) by preventing pain signal transmission, while gain-of-function mutations cause painful channelopathies (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). HSAN ID (\u003cem\u003eSCN9A\u003c/em\u003e-related CIP) is an exceptionally rare condition globally. Precise global prevalence figures or comprehensive registries of reported cases are not readily available in the medical literature, reflecting its extreme rarity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). For instance, while HSAN III has an incidence of 1 per 3600 live births in specific populations, and several hundred cases of HSAN IV have been documented, \u003cem\u003eSCN9A\u003c/em\u003e-related CIP remains significantly less common (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Specific data on the number of reported cases of HSAN ID or \u003cem\u003eSCN9A\u003c/em\u003e-related neuropathies within Palestine is also limited. Historically, studies in Palestine and neighboring regions have indicated that many CIP cases are predominantly caused by mutations in the \u003cem\u003eNTRK1\u003c/em\u003e gene, suggesting a founder effect (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, the present case is particularly significant as it identifies a novel homozygous mutation in the \u003cem\u003eSCN9A\u003c/em\u003e gene (c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T) in a Palestinian family. This finding is supported by another recent study from Palestine that also reported a novel \u003cem\u003eSCN9A\u003c/em\u003e mutation in a family with CIP without anhidrosis, highlighting an emerging recognition of \u003cem\u003eSCN9A\u003c/em\u003e-related CIP within the region (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe identified homozygous nonsense variant c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.K301*) in the \u003cem\u003eSCN9A\u003c/em\u003e gene introduces a premature stop codon at amino acid position 301, leading to the production of a severely truncated Nav1.7 channel protein (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Such truncated proteins are inherently unstable and are often targeted for degradation, resulting in a complete or near-complete absence of functional Nav1.7 channels in the patient's sensory neurons, which is entirely consistent with the observed severe loss-of-function phenotype (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Functional Nav1.7 channels are indispensable for the generation and propagation of action potentials in nociceptors (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The complete absence or severe dysfunction of these channels, due to the homozygous nonsense mutation, directly impairs the excitability of these neurons, preventing them from effectively transmitting noxious signals to the central nervous system and resulting in profound congenital insensitivity to pain. This fundamental lack of protective pain signals precipitates a cascade of severe and complex clinical issues. As vividly demonstrated by the patient's oral self-mutilation, deformed fingertips, and recurrent blisters and burns, the absence of pain prevents the individual from recognizing and reacting appropriately to harmful stimuli, leading to repeated self-inflicted injuries and unnoticed external trauma (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Furthermore, without pain serving as an early warning sign, infections\u0026mdash;such as recurrent urinary tract infections, acute bronchitis, and critically, the left lung empyema\u0026mdash;can progress silently and severely before clinical detection and intervention. This patient's complex clinical course vividly illustrates how a single, profound molecular defect cascades into a multi-systemic array of complications.\u003c/p\u003e\u003cp\u003eA striking and unusual feature of the present case is the profound pain insensitivity coupled with severe anhidrosis, which manifested as impaired thermoregulation and recurrent high-grade fevers. While Nav1.7 is most extensively characterized for its role in nociception, its expression has also been documented in autonomic neurons, including sympathetic neurons that innervate sweat glands (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The severe anhidrosis observed in this patient, and its presence in other recently reported \u003cem\u003eSCN9A\u003c/em\u003e cases with nonsense or frameshift mutations (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), strongly indicates that complete loss of Nav1.7 function may extend its impact beyond pain pathways to significantly affect sudomotor function. This unexpected co-occurrence challenges the long-held, traditional gene-phenotype correlations and suggests either a direct, previously underestimated role of Nav1.7 in sudomotor function or a more complex, indirect interplay where complete loss of Nav1.7 function leads to secondary effects on the development or maintenance of autonomic nerve fibers (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The patient's birth to consanguineous parents (mother and her maternal cousin) is highly relevant in the context of this autosomal recessive disorder. Consanguineous marriages, which are particularly prevalent in many regions of the Middle East, including Palestine (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e),(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), significantly increase the probability of offspring inheriting two copies of the same recessive genetic mutation, directly leading to a higher incidence of autosomal recessive disorders within these populations (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe patient's clinical history of recurrent high-grade fevers, urinary tract infections, acute bronchitis, and, critically, the development of left lung empyema, all occurring without reported discomfort, profoundly underscores the diagnostic and management challenges posed by congenital pain insensitivity. Pain serves as an indispensable biological warning system, prompting individuals to recognize and seek medical attention for injuries and infections (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In the absence of this crucial protective signal, injuries can go unnoticed, wounds may heal poorly, and infections can progress silently to severe, life-threatening stages before clinical detection, as starkly exemplified by the empyema requiring Video-Assisted Thoracoscopic Surgery (VATS) Decortication. This progression from unnoticed minor infections to a severe, life-threatening condition highlights the \"silent killer\" aspect of CIP. The profound clinical implication is that healthcare providers managing these patients must adopt an exceptionally proactive and low-threshold approach to investigating any subtle signs of illness, as the typical \"red flags\" (pain, discomfort) are conspicuously absent.\u003c/p\u003e\n\u003ch3\u003eComparison of Present Case with Selected Published Cases of HSAN ID/SCN9A-related Neuropathy\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSCN9A Variant(s) (Type, Zygosity)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKey Phenotype (CIP, Anhidrosis, Recurrent Infections, Self-Mutilation, etc.)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOnset Age\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOrigin/Ethnicity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnique Features/Notable Outcome\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent Case\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.901A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.K301*), Homozygous nonsense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProfound CIP, severe anhidrosis, recurrent severe infections (empyema), oral self-mutilation, deformed fingertips.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePalestinian, consanguineous parents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNovel homozygous nonsense variant, severe anhidrosis, left lung empyema requiring VATS decortication.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 1 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.901A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Lys301*), Homozygous probable pathogenic (nonsense)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInsensitivity to pain, recurrent febrile joint swelling, mouth ulcers, tongue biting, anhidrosis, Charcot joints, muscle atrophy.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNot specified (consanguineous parents)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eExact same novel homozygous nonsense variant, presence of anhidrosis, Charcot joints, osteomyelitis.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 2 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eW897X, Homozygous nonsense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital insensitivity to pain (classic CIP).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEarly childhood (implied)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNot specified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eClassic CIP phenotype, often characterized by normal sweating and intelligence.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 3 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.5118delA (p.Val1709Phefs*33), Homozygous single base pair deletion (frameshift)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital insensitivity to pain, anhidrosis (hypohidrosis), recurrent bullous lesions, self-injuries (auto-amputation of finger), septic arthritis, corneal ulcerations, mild cognitive impairment.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFew months after birth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEgyptian, consanguineous parents (first-degree cousins)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNovel homozygous frameshift variant, anhidrosis, mild cognitive impairment, septic arthritis.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUnexplained pain insensitivity, especially in infants and consanguineous populations, should trigger urgent genetic testing. Early diagnosis of HSAN ID is crucial for timely prevention and multidisciplinary care, impacting outcomes and avoiding severe complications. Management requires a proactive, tailored approach focusing on injury prevention, temperature control, and prompt infection treatment, even without pain symptoms. Regular monitoring by neurology, dermatology, orthopedics, pulmonology, and infectious disease specialists is vital. This case highlights that SCN9A-related disorders can show broader, atypical symptoms, including severe autonomic issues like anhidrosis, beyond classic insensitivity to pain. Clinicians should consider comprehensive genetic testing in patients with sensory neuropathies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eACMG\u003c/strong\u003e: American College of Medical Genetics and Genomics\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBCG\u003c/strong\u003e: Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCBC\u003c/strong\u003e: Complete Blood Count\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCIP\u003c/strong\u003e: Congenital Insensitivity to Pain\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCRP\u003c/strong\u003e: C-Reactive Protein\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHSAN\u003c/strong\u003e: Hereditary Sensory and Autonomic Neuropathy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHSAN ID\u003c/strong\u003e: Hereditary Sensory and Autonomic Neuropathy Type ID\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMCUG\u003c/strong\u003e: Micturating Cystourethrogram\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNav1.7\u003c/strong\u003e: Voltage-gated sodium channel subtype encoded by SCN9A\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSCN9A\u003c/strong\u003e: Sodium Voltage-Gated Channel Alpha Subunit 9\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eUTI\u003c/strong\u003e: Urinary Tract Infection\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eVATS\u003c/strong\u003e: Video-Assisted Thoracoscopic Surgery\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWBC\u003c/strong\u003e: White Blood Cell\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWES\u003c/strong\u003e: Whole Exome Sequencing\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e Not applicable. As this is a case report of a single patient, formal ethics committee approval was not required. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Written informed consent was obtained from the patient\u0026apos;s parents for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e No funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eRA\u003c/strong\u003e: Conceptualization, Data Curation, Formal Analysis, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMAAM\u003c/strong\u003e: Conceptualization, Data Curation, Formal Analysis, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAAN\u003c/strong\u003e: Conceptualization, Data Curation, Formal Analysis, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGA\u003c/strong\u003e: Data Curation, Investigation, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAK\u003c/strong\u003e: Data Curation, Investigation, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eYB\u003c/strong\u003e: Data Curation, Investigation, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMZ\u003c/strong\u003e: Supervision, Clinical Management, Conceptualization, Final Review. All authors read and approved the final manuscript.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e The authors would like to thank the patient and her family for their willingness to participate in this case report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAxelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2(1):39. \u003c/li\u003e\n\u003cli\u003eKing R. Hereditary sensory and autonomic neuropathy. Peripher nerve Disord. 2014;119\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eAxelrod FB. Hereditary sensory and autonomic neuropathies. Clin Auton Res. 2002;12:I2. \u003c/li\u003e\n\u003cli\u003eEichler FS, Kothari M, Firth H V, Shefner FmJM. Hereditary sensory and autonomic neuropathies. Waltham, MA UpToDate. 2007; \u003c/li\u003e\n\u003cli\u003eDrenth JPH, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest. 2007;117(12):3603\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eKhalaf‐Nazzal R, Dweikat I, Ubeyratna N, Fasham J, Alawneh M, Leslie J, et al. TECPR2‐related hereditary sensory and autonomic neuropathy in two siblings from Palestine. Am J Med Genet Part A. 2024;194(7):e63579. \u003c/li\u003e\n\u003cli\u003eNM_001365536.1(SCN9A):c.901A\u0026gt;T (p.Lys301Ter) AND Channelopathy-associated congenital insensitivity to pain, autosomal recessive - ClinVar - NCBI [Internet]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/RCV003448394/\u003c/li\u003e\n\u003cli\u003eStaud R, Price DD, Janicke D, Andrade E, Hadjipanayis AG, Eaton WT, et al. Two novel mutations of SCN9A (Nav1. 7) are associated with partial congenital insensitivity to pain. Eur J pain. 2011;15(3):223\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eCox JJ, Sheynin J, Shorer Z, Reimann F, Nicholas AK, Zubovic L, et al. Congenital insensitivity to pain: novel SCN9A missense and in‐frame deletion mutations. Hum Mutat. 2010;31(9):E1670\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eKhaled B, Alzahayqa M, Jaffal A, Sallam H, Thawabta R, Mansour M, et al. Identification of founder and novel mutations that cause congenital insensitivity to pain (CIP) in palestinian patients. BMC Med Genomics. 2023;16(1):120. \u003c/li\u003e\n\u003cli\u003eAl-Hroub NN, Ala\u0026rsquo;a A, Taamreh MA, Abunejma FM, Dukmak ON, Al-Salahat A, et al. Congenital Insensitivity to Pain: A Case Study of a Rare Genetic Disorder. Cureus. 2024;16(9). \u003c/li\u003e\n\u003cli\u003eKhayat AM, Alshareef BG, Alharbi SF, AlZahrani MM, Alshangity BA, Tashkandi NF, et al. Consanguineous marriage and its association with genetic disorders in Saudi Arabia: a review. Cureus. 2024;16(2). \u003c/li\u003e\n\u003cli\u003eCousin - Wikipedia [Internet]. Available from: https://en.wikipedia.org/wiki/Cousin\u003c/li\u003e\n\u003cli\u003eCongenital Insensitivity to Pain: Diagnosis, Treatment, and More [Internet]. Available from: https://www.webmd.com/children/what-is-congenital-insensitivity-pain\u003c/li\u003e\n\u003cli\u003eRomagnuolo M, Moltrasio C, Cavalli R, Brena M, Tadini G. A novel mutation in the SCN9A gene associated with congenital insensitivity to pain, anhidrosis, and mild cognitive impairment. Pediatr Dermatol. 2024;41(1):80\u0026ndash;3. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hereditary Sensory and Autonomic Neuropathy, SCN9A gene, Congenital Insensitivity to Pain, Anhidrosis, Case Report","lastPublishedDoi":"10.21203/rs.3.rs-7180980/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7180980/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHereditary Sensory and Autonomic Neuropathy type ID (HSAN ID), caused by mutations in the SCN9A gene, is an exceptionally rare inherited disorder characterized by a profound absence of pain perception and varying degrees of autonomic dysfunction. We present the case of a female patient, currently in her early school-age years, born to consanguineous parents, who exhibited congenital insensitivity to pain and severe anhidrosis since infancy. Clinical presentation included recurrent unexplained injuries, oral self-mutilation, and frequent, unnoticed infections, leading to severe complications like left lung empyema requiring Video-Assisted Thoracoscopic Surgery (VATS) Decortication. Genetic testing via Whole Exome Sequencing identified a novel homozygous nonsense variant (c.901A\u0026thinsp;\u0026gt;\u0026thinsp;T, p.K301*) in the SCN9A gene, confirming the diagnosis and classifying it as pathogenic according to ACMG guidelines. This variant leads to a truncated, non-functional Nav1.7 channel protein, explaining the sensory deficits. This case highlights the challenges in diagnosing and managing such rare conditions, emphasizing the critical role of early genetic identification and a proactive multidisciplinary approach to prevent severe morbidity and improve long-term outcomes. Furthermore, the severe anhidrosis observed in this SCN9A-related case suggests a potentially broader involvement of Nav1.7 in autonomic functions than traditionally recognized.\u003c/p\u003e","manuscriptTitle":"A Novel Homozygous Pathogenic Variant in SCN9A Gene Causing Hereditary Sensory and Autonomic Neuropathy Type ID: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-24 11:16:03","doi":"10.21203/rs.3.rs-7180980/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dd40aea1-f903-4af4-8a71-f98aa3a217e3","owner":[],"postedDate":"September 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-18T07:40:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-24 11:16:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7180980","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7180980","identity":"rs-7180980","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}