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. 2022 Sep 16;10(10):e2026. doi: 10.1002/mgg3.2026

Pain triangle phenomenon in possible association with SCN9A: A case report

Maurice Sopacua 1,2,✉, Janneke G J Hoeijmakers 1, Anneke J van der Kooi 3, Ingemar S J Merkies 1,4, Catharina G Faber 1
PMCID: PMC9544215  PMID: 36114697

Abstract

Background

Voltage‐gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Nav1.7, encoded by the SCN9A‐gene, has been of special interest in the last decades because missense gain‐of‐function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).

Methods

In this case report, we present a 61‐year‐old woman who was referred to our tertiary referral center in a standard day care setting with suspicion of SFN. We performed additional investigations: skin biopsy to determine the intra‐epidermal nerve fiber density (IENFD), quantitative sensory testing (QST), and blood examination (including DNA analysis) for possible underlying conditions.

Results

The patient showed a clinical picture that fulfilled the criteria of IEM, PEPD, and SFN. DNA analysis revealed the heterozygous variant c.554G > A in the SCN9A‐gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions. Because its pathogenicity has never been functionally confirmed, the variant is classified as a variance of unknown significance (VUS)/risk factor. This suggests that another genetic and/or environmental substrate plays a role in the development of neuropathic conditions like described.

Conclusion

We have described this as the SCN9A‐pain triangle phenomenon. Treatment should focus on pain management, genetic counseling, and improving/maintaining quality of life by treating symptoms and, if indicated, starting a rehabilitation program.

Keywords: genotype–phenotype relationships, neurogenetics, SCN9A variant

The clinical report showed a clinical picture that fulfilled criteria of IEM, PEPD, and SFN. DNA‐analysis revealed the heterozygous variant c.554G>A in the SCN9A‐gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions.

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1. INTRODUCTION

Previous research showed that changes in the expression of voltage‐gated sodium channels (VGSC) play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic (de Greef et al., 2016). These channels are found in the peripheral dorsal root ganglion (DRG), trigeminal ganglion, and sympathetic ganglion neurons.

Gain‐of‐function mutations in VGSC Nav1.7, that promote neuronal hyperexcitability, can cause human pain conditions. These pain syndromes are inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). IEM is a rare disorder characterized by recurrent attacks of red, warm and painful hands, and/or feet, with the onset of symptoms during the first decade (Arthur et al., 2019; Cheng et al., 2008; Dib‐Hajj et al., 2005; Drenth et al., 2005; Estacion et al., 2013; Harty et al., 2006). PEPD is known for its severe pain episodes and skin flushing starting in infancy and induced by perianal probing or bowel movement. The pain progresses to ocular and mandibular areas with age (Dib‐Hajj et al., 2008; Jarecki et al., 2009; Meglič et al., 2014; Suter et al., 2015; Yiangou et al., 2007). SFN patients typically manifest neuropathic pain in distal extremities, as well as autonomic dysfunction (Eijkenboom et al., 2019; Sopacua et al., 2019). All these conditions are linked to SCN9A missense variants. Pathogenic mutations in SCN9A, which encodes the VGSC Nav1.7, have been found. IEM is usually caused by enhanced Nav1.7 channel activation, whereas mutations that alter steady‐state fast inactivation often lead to PEPD. In SFN, functional variants of Nav1.7 impair channel slow inactivation and produce DRG neuron hyperexcitability that contributes to pain. Characteristics of SCN9A variants differ between and within the mentioned pain syndromes. Moreover, the same clinical phenotype may be associated with multiple different variants, and a single Nav1.7 variant can be associated with a range of clinical phenotypes (Sopacua et al., 2019). In this case report, the patient had a variant of uncertain significance in SCN9A, c.554G > A (OMIM 603415), which has been previously reported as a possible cause of pain syndromes.

2. CASE REPORT

The patient gave informed consent to share her clinical story for educational and/or scientific purposes. The study was conducted according to the ethical policies of Maastricht University Medical Center+ (MUMC+).

A 61‐year‐old woman was referred to the neurological outpatient clinic because she experienced neuropathic pain in her feet, which started four years ago. The pain in her feet became worse during walking. She described the pain as a burning and tingling sensation. A couple of months after initiation, the complaints extended to her legs. Furthermore, she developed complaints of itching all over her body, especially in her lower back and lower legs. Dysautonomic symptoms were present, such as hyperhidrosis during the night, hot flashes, and palpitations. Sometimes she had complaints of obstipation.

Furthermore, she described attacks of dull rectal pain, particularly during the nights and after defecation. Sometimes, she has attacks of allodynia in her legs and feet, only present on the left side of her body.

She preferred cold circumstances and walking barefoot at home. She sleeps with air‐conditioning on the footboard of her bed; even more, she daily brings cold packs to her working place to put occasionally on her legs in order to reduce the burning sensation. Pressure on her feet during lying or walking with shoes is painful for her. She is not able to use a conventional bike because of the pressure on the pedals and rides more comfortably with an e‐bike.

Three years ago, the patient experienced painful feet with attacks of redness. Attacks last for 90 min and disappear with rest. Situational factors such as warm weather and/or exercise worsened these pain attacks. She was diagnosed with primary erythromelalgia. Clonidine was started to reduce the pain; however, it had no effect. Subsequently, amitriptyline was started, up to 25 mg ante noctem. She experienced side effects such as nausea and vertigo. The dosage was lowered to 15 mg which resulted in some pain relief during the night. Yet, she was not able to sleep more than 3–4 h because pain intensity remained relatively high.

The patient has a daughter and three sisters, without similar complaints. Her grandmother had diabetes mellitus type II without neuropathic pain symptoms.

2.1. Level of daily functioning

The patient works for more than 40 years in a factory where she has been exposed to toxic fluids and gases. She still works despite her pain. She is not able to walk longer than 12 min due to painful feet. Driving a car is possible but may lead to dangerous situations if she gets into a pain attack. She and her husband adjusted their lives to the pain by avoiding activities that aggravate the pain, such as long walks, dining out, and city trips. However, they do everything to maintain their Quality of Life.

2.2. Clinical assessment and additional investigations

During the neurological examination, there was no indication of a central nervous system problem or involvement of large nerve fiber pathology. During the examination, red feet and dry skin on the lower legs were noticed.

Besides a high Vitamin B12 (>1000 pmol/L), other laboratory abnormalities that could be associated with SFN‐like symptoms were not found (de Greef et al., 2018).

Nerve conduction studies to test large nerve fibers were normal. Quantitative sensory testing (QST), according to the Levels method, showed an abnormal warmth sensation in both feet. Furthermore, the IENFD was 5.6/mm, which was normal according to the reported normative values (5th percentile: 3.2/mm; median: 8.7/mm) (Lauria et al., 2010).

DNA analysis of the SCN9A, SCN10A, and SCN11A, by means of the molecular inversion Probes‐next‐generation sequencing (MIPs‐NGS) (Almomani et al., 2020), showed the following variant: c.554G > A (version number AB839087.1) in the SCN9A gene, which is a gain‐of‐function variant which enhanced resurgent currents within the DRG neurons and renders DRG neurons hyperexcitable (Faber et al., 2012; Han, Hoeijmakers, Liu, et al., 2012). The variant is classified as a variant of unknown significance(VUS)/risk factor (Eijkenboom et al., 2019), according to the Practice Guidelines by the Association for Clinical Genetic Science (ACGS) and recommendations by Waxman et al. (2014).

2.3. Diagnosis

The patient was diagnosed with the combination of IEM, PEPD, and SFN, based on clinical symptoms and an abnormal QST, and could be associated with the variant c.554G > A in the SCN9A‐gene.

3. DISCUSSION

In literature, the SCN9A‐variant c.554G > A is known to cause several pain syndromes, namely IEM (Goldberg et al., 2012), PEPD (Meglič et al., 2014) and SFN (Han, Hoeijmakers, Ahn, et al., 2012). This patient presented an unusual combination of signs and symptoms of three pain syndromes, IEM, PEPD, and SFN. Situational factors such as warm weather and/or exercise worsened the total package of her complaints. Therefore, this concept could be described as a “pain triangle phenomenon” (see Figure 1).

FIGURE 1.

FIGURE 1

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The SCN9A‐pain triangle phenomena

Interestingly, the patient was found to carry an SCN9A missense variant, c.554G > A. This variant has been previously reported to cause all three pain syndromes in different case reports. However, some doubt about its pathogenicity could be raised due to its relatively high frequency in the general population (0.3% in the total population, 0.24% in the European‐non Finnish population, and 1.4% in the African/African‐American population in GnomADv2.1.1) and in healthy heterozygous carriers. Moreover, it is still an open question how the same genetic variant could cause early‐onset diseases, like EM and PEPD, as well as a late‐onset condition, like SFN.

The late onset of IEM and PEPD is rare. Both conditions have been linked to symptoms that start in childhood (Arthur et al., 2019; Fertleman et al., 2007). In this case, symptoms started with the clinical picture of SFN (burning feet after walking) and probably triggered the IEM and PEPD symptoms. Interestingly, no family members were known with identical clinical symptoms. For this reason, co‐segregation research has not been conducted. However, it would be interesting to investigate whether other genetic factors (by whole exome sequencing) could be involved in the possible missing hereditability in healthy carriers of this SCN9A variant and provide novelty in the explanation of genotype–phenotype correlation.

Nevertheless, it is important as a consultant to recognize (parts of) this triangle in order to put in the appropriate additional investigations and discuss treatment options. Genetic counseling is important to find out the underlying cause and/or get informed about the future perspective and inheritance pattern of patients and their families with a pathogenic SCN9A mutation. Furthermore, clinical studies with Nav1.7‐selective blockers have started to test pain relief (de Greef et al., 2016), but its clinical use is still scarce. Nowadays, the treatment of neuropathic pain should follow an algorithm not focusing on the physical aspects but also psychological and social aspects (Brouwer et al., 2015).

3.1. Patients' perspective

Our patient was complimented and encouraged to keep her lifestyle as active as possible. She accepted the illness as it is. Another pain medication such as pregabalin and carbamazepine was offered, but she was reluctant in taking pain medication due to its side effects. She tries to focus on activities that give her relaxation and energy such as playing the piano, reading books, and working in the garden. She was informed to contact a rehabilitation consultant when she experienced significant limitations in her daily activities within her household and/or on a society level.

4. MAIN CONCLUSION AND RELEVANCE

This is the first case that describes a combination of signs and symptoms of IEM, PEPD, and SFN. With genetic diagnostic screening, a missense variant in the SCN9A gene was found, which is classified as VUS/risk factor. This means that other genetic factors might play a role in this genotype–phenotype correlation. Previously, these three pain conditions have been linked separately to the same variant. In complicated pain conditions, it is evident to focus on the sound and loudness that the triangle produces. Perhaps more importantly, attention to factors that determine its tone and volume and its position in the societal orchestra is important.

AUTHOR CONTRIBUTIONS

All authors contributed equally to this article, from case description to discussion.

CONFLICT OF INTEREST

There are no conflicts of interest.

ETHICS STATEMENT

Our patient signed informed consent for the publication of her clinical picture in an international scientific journal.

Sopacua, M. , Hoeijmakers, J. G. J. , van der Kooi, A. J. , Merkies, I. S. J. , & Faber, C. G. (2022). Pain triangle phenomenon in possible association with SCN9A: A case report. Molecular Genetics & Genomic Medicine, 10, e2026. 10.1002/mgg3.2026

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