STAT1 Gain of Function Disease

STAT1 gain-of-function disease is an autosomal dominant immune dysregulation disorder from heterozygous activating variants in STAT1. It is the commonest genetic cause of chronic mucocutaneous candidiasis.

Pathophysiology. Excess STAT1 phosphorylation after interferon signalling amplifies interferon responses and suppresses development of IL-17-producing T helper cells. The result is poor defence against Candida, together with infection by other pathogens and autoimmunity.

Onset is usually in infancy or early childhood, but diagnosis can be delayed for years. Penetrance is high but incomplete, and severity varies within families.

Over 90% have chronic mucocutaneous candidiasis. Aneurysms and squamous cell carcinoma are the most serious late problems.

• Chronic or recurrent candidiasis of the mouth, oesophagus, nails and skin, often resistant to azoles
• Recurrent sinopulmonary bacterial infection and bronchiectasis
• Severe herpesvirus infection (herpes simplex, zoster, CMV, EBV)
• Disseminated endemic fungal disease (histoplasmosis, coccidioidomycosis) and mycobacterial infection
• Autoimmunity: hypothyroidism (about a quarter), type 1 diabetes, autoimmune cytopenias, enteropathy, lupus like disease, alopecia
• Intracranial and aortic aneurysm
• Oesophageal and skin squamous cell carcinoma
• Hypogammaglobulinaemia in some

• Th17 cell count: reduced IL-17A-producing CD4 T cells on flow cytometry.
• STAT1 phosphorylation assay: raised phosphorylated STAT1 after stimulation with interferon gamma or interferon alpha, with sequencing of STAT1 for confirmation.
• Immunoglobulins, lymphocyte subsets and specific antibody responses.
• Thyroid function, glucose and HbA1c, full blood count, direct antiglobulin test, autoantibodies.
• Fungal cultures with susceptibility testing of Candida isolates.
• Vascular imaging: MR or CT angiography of the brain, and of the aorta in adults.
• Upper gastrointestinal endoscopy for dysphagia, with biopsy.

Differential diagnosis.

• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (AIRE deficiency)
• CARD9, IL-17RA and IL-17F deficiency
• STAT3 loss-of-function (hyper IgE) syndrome
• Common variable immunodeficiency
• HIV infection, diabetes, corticosteroid or inhaled steroid use
• Mendelian susceptibility to mycobacterial disease

• Acute oropharyngeal or oesophageal candidiasis: fluconazole 200 to 400 mg orally on day 1 then 100 to 200 mg once daily for 7 to 14 days for the mouth and 14 to 21 days for the oesophagus (children 6 mg/kg on day 1 then 3 to 6 mg/kg daily). Maximum 400 mg daily. Halve the dose at creatinine clearance under 50 mL/min. Check liver enzymes and QTc and avoid QT-prolonging drugs.
• Long term suppression in most patients: fluconazole 100 to 200 mg orally once daily, which often breeds resistance.
• Azole resistant disease: itraconazole oral solution 200 mg once daily on an empty stomach, posaconazole modified release tablets 300 mg twice daily on day 1 then 300 mg once daily with food, or voriconazole 400 mg twice daily on day 1 then 200 mg twice daily (check trough levels). If these fail, micafungin 100 mg intravenously once daily, or liposomal amphotericin B 3 mg/kg intravenously daily.
• JAK inhibitor for refractory disease or severe autoimmunity: ruxolitinib 5 mg orally twice daily in adults, titrated every 2 to 4 weeks to response, up to 20 mg twice daily. Reduce the dose by half when fluconazole is used at a dose over 200 mg daily. Check full blood count every 2 weeks at first and then monthly, with lipids and liver enzymes. Screen for hepatitis B and tuberculosis before starting. Taper rather than stopping suddenly, because symptoms rebound.
• Immunoglobulin replacement for low IgG or poor specific antibody responses: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Prophylaxis: azithromycin 500 mg orally three times weekly in adults with bronchiectasis (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms. Aciclovir 400 mg orally twice daily for recurrent herpesvirus disease (reduce at creatinine clearance under 25 mL/min).
• Autoimmunity: replace thyroid hormone (levothyroxine 1.6 microgram/kg daily in adults, titrated to TSH), insulin for diabetes, and prednisolone 1 mg/kg daily (maximum 60 mg) with taper for cytopenias.
• Aneurysm and cancer control: control blood pressure, repeat vascular imaging every 1 to 2 years, endoscopy for new dysphagia, and yearly skin examination.
• Vaccines: avoid live vaccines.
• Haematopoietic stem cell transplantation has a high rate of graft failure and death and is limited to refractory, life threatening disease.

Special groups.

• Pregnancy: avoid high dose fluconazole in the first trimester, and stop ruxolitinib in pregnancy.

Monitoring. Candida cultures and azole susceptibility when treatment fails. Full blood count, liver enzymes and lipids every month on a JAK inhibitor. Trough IgG every 3 to 6 months on replacement. Thyroid function and HbA1c yearly. Vascular imaging every 1 to 2 years.

Referral and escalation. Refer to immunology. Urgent for severe headache or neurological deficit (aneurysm), dysphagia with weight loss, disseminated fungal or mycobacterial infection, or sepsis.