A three-year-old male patient was admitted with complaints of pain and swelling in both ankles and wrists and rash with fever for more than 6 weeks. In addition to these clinical findings, he was referred to our hospital for the evaluation of increased acute phase reactants and examination of splenomegaly and abdominal distension. In the physical examination, the patient had fever and significant swelling especially in the right knee.
The patient was the second child of consanguineous parents. There was a third-degree cousin marriage without any other parental comorbidities. The other two children of the family were doing well and did not have any health problems.
A preliminary diagnosis of systemic juvenile idiopathic arthritis (JIA) was considered because of complaints of fever, splenomegaly, rash, and arthritis lasting more than 10 days. Laboratory findings revealed an increase in acute phase reactants as C-reactive protein (CRP): 13.4 mg/dl (normal: 0-0.5), ferritin: 143.5 ng/ml (normal: 7-140), erythrocyte sedimentation rate (ESR): 26 mm/h (normal: <15 mm/h), and serum amyloid A (SAA): 209 mg/l (normal: <6.4). Hypergammaglobulinemia (IgG : 3810 mg/dl, IgA : 165 mg/dl, and IgM : 161 mg/dl) and positive antinuclear antibody (ANA) (1/160 cytoplasmic) were detected. Anti-double-stranded DNA antibody (Anti-DsDNA) was negative. His antistreptolysin O titer (ASO), rheumatoid factor (RF), and antineutrophil cytoplasmic antibody tests were all negative. PPD (purified protein derivative) intradermal test for tuberculosis examination resulted as anergic. Brucellosis and toxoplasmosis laboratory tests were both negative. Ophthalmologic examination for uveitis was found to be normal.
No pathological findings were detected in the chest X-ray. Since the patient had splenomegaly, bone marrow aspiration was performed for possible malignancies and macrophage activation syndrome. In the bone marrow examination, no signs of hemophagocytosis, atypical cells, and blasts were found while a few hypersegmented neutrophils were observed. Treatment of nonsteroidal anti-inflammatory drugs (NSAIDs) was started.
Arthritis, fever, and rash began to recover after two weeks of treatment. However, moniliasis was observed on the oral mucous membranes and tongue in the oropharyngeal examination. Additionally, nail dystrophy and onychomycosis in the right thumb were observed. Nail dystrophy was secondary to onychomycosis and occurred after 4-5 months after onychomycosis. The lymphocyte subset analysis by flow cytometry and T/B cell proliferation tests resulted normal. However, without genetic analysis, we could not exclude innate immune system deficiency, and intravenous immunoglobulin (IVIG) treatment (in a dose of 0.5 gm/kg, once in four weeks) was started as it was used both in systemic juvenile idiopathic arthritis and in innate immune deficiencies.
Then, genetic examination could be performed to exclude primary immunodeficiency in this case with chronic onychomycosis. STAT-1 GOF mutation was considered due to moniliasis, onychomycosis, arthritis, hypergammaglobulinemia, and consanguineous marriage. In targeted next-generation sequencing (TNGS), A homozygous mutation in the AIRE gene SAND domain (c.769C > T, p.Arg257Ter) was detected (Figure 1). Then, the patient was diagnosed with APECED syndrome. The parents were heterozygous for the same mutation.
After a short while, he had cough and fatigue and was hospitalized with the diagnosis of pneumonia. In the lung examination, diffuse crepitant rales were present, more prominent on the left. Acute phase reactants were found to be high. Community-acquired pneumonia was considered, with no sequelae. Coronavirus 229E/NL6 was detected in the respiratory virus panel. IVIG treatment was given to prevent chronic infections and for immunomodulation purposes, as it is a Th17-mediated disorder, and T cell assistance was not sufficient.
Dental caries developed in the follow-up of our patient. No other clinical problems were encountered in the next two years with IVIG treatment and fluconazole and trimethoprim sulfamethoxazole prophylactic treatment. He also recovered from arthritis very well without any other medication. At the age of five, hypoparathyroidism developed with low calcium, high phosphorus, low parathormone, and high 25OHD vitamin levels. He is still on treatment with calcium lactate, calcitriol, trimethoprim sulfamethoxazole, fluconazole prophylaxis, and IVIG, and he is doing well.