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

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 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.

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.

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.

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.

Table 2: Comparison of Present Case with Selected Published Cases of HSAN ID/SCN9A-related Neuropathy.

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

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, MAAM, AAN: Conceptualization, Data Curation, Formal Analysis, Writing - Original Draft, Writing - Review & Editing. GA, AK, 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.