Clinical Guidance

Disease severity varies within families. In one family, an infant with SCN9A-PEPD had a father with only ocular attacks . Although SCN9A variants resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with onset of manifestations at younger ages (P=.016), unknown inter-individual differences also influence age of onset: in two families in which individuals with erythromelalgia had the same variant (p.Ser241Thr), the age of onset was in the first decade in one family and the second decade in the other .

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Penetrance

The penetrance in families with SCN9A erythromelalgia and paroxysmal extreme pain disorder reported to date is 100%; individuals with SCN9A small fiber neuropathy show incomplete penetrance. Of note, in 2008 the Erythromelalgia Association conducted a survey of its members regarding diagnosis, symptoms, and response to medications (see www.erythromelalgia.org). In this heterogeneous group of 427 participants (of which an unknown subset has SCN9A-EM), only 5% reported a relative with a diagnosis of erythromelalgia – fewer than would be expected for an autosomal dominant disorder with high penetrance; however, a pattern of autosomal dominant inheritance with 100% penetrance was always observed in multi-generation families with SCN9A-EM.

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Diagnostic Criteria

Suggestive Findings

An SCN9A neuropathic pain syndrome (SCN9A-NPS) should be suspected in individuals with one of the following three neuropathic pain disorders. Erythromelalgia (EM), characterized by:

• Recurrent episodes of bilateral intense, burning pain;

• Redness, warmth, and occasionally swelling of the distal extremities;

• Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved.

Note: If manifestations are intermittent, photographs of the affected extremities during a flare can help with diagnosis . Paroxysmal extreme pain disorder (PEPD), characterized by:

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Differential Diagnosis

Erythromelalgia The differential diagnosis of SCN9A erythromelalgia (SCN9A-EM) includes secondary EM resulting from an underlying organic disease, medication, or toxin; neuropathies; other conditions with some overlapping features; and inherited erythromelalgia in which no SCN9A pathogenic variant is identified See . Table 3. Differential Diagnosis of SCN9A Erythromelalgia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an SCN9A neuropathic pain syndrome (SCN9A-NPS), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic examination, including a quantitative sensory test and pain assessment

• Clinical assessment of SCN9A-NPS that may include questionnaires such as the Small Fibre Neuropathy and Symptoms Inventory Questionnaire or the Neuropathic Pain Scale

• Assessment of the pain management strategies used

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Most affected individuals are treated in dermatology, neurology, or pain clinics; or by anesthesiologists specializing in the management of chronic pain.

SCN9A Erythromelalgia (SCN9A-EM)

The pain is often refractory to treatment. Cooling the extremities reduces pain in a symptomatic person. Cooling with a fan is generally safer than immersion in water; complications from prolonged immersion in ice baths include skin maceration, infection, and gangrene. Amputation has occasionally been necessary to treat these complications. Medications. The individual's treating physician should determine treatment based on factors including other medical conditions, known medication allergies, and potential for drug-drug interactions.

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Clinical Guidance

SCN9A erythromelalgia. Symptoms are triggered by warmth and standing and, in some individuals, by alcohol and spicy foods including chili peppers or garlic. In some individuals, exercise can trigger symptoms. However, for many individuals, the benefits of mild exercise outweigh the disadvantages. Swimming is a preferred exercise because the extremities remain cool. SCN9A paroxysmal extreme pain disorder is often triggered by defecation, cold wind, eating, and emotion. SCN9A small fiber neuropathy. Avoid additional risk factors for small fiber neuropathy such as diabetes mellitus, alcohol, and chemotherapy.

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"

Surveillance Guidelines

There are no published guidelines for surveillance for SCN9A-NPS. Follow up with a neurologist or neuromuscular specialist to assess for progression of the disease. It is important to monitor for known side effects of treatment of medications (e.g., Stevens-Johnson syndrome, liver toxicity, and neutropenia – associated with carbamazepine treatment).

Source: GeneReviews — "SCN9A Neuropathic Pain Syndromes"