An Extraordinary Case of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) Syndrome Misdiagnosed as Juvenile Idiopathic Arthritis on Admission

Background APECED is a syndrome characterized by autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy. The most observed clinical findings are chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. Case Presentation. A three-year-old male patient was admitted with classical signs of juvenile idiopathic arthritis and treated with nonsteroidal anti-inflammatory drugs. During follow-up, signs of autoimmunity, candidiasis, nail dystrophy, and onychomycosis were observed. The parents were consanguineous, and targeted next-generation sequencing was performed. A homozygous mutation in the AIRE gene SAND domain (c.769C > T, p.Arg257Ter) was detected, and the patient was diagnosed with APECED syndrome. Conclusion Inflammatory arthritis is rarely described in association with APECED and is often misdiagnosed as juvenile idiopathic arthritis. In APECED cases, nonclassical symptoms such as arthritis may occur before developing classical symptoms and considering the diagnosis of APECED in patients with CMC and arthritis is useful for early diagnosis before development of complications and management of disease.


Background
APECED (autoimmune polyendocrinopathy-candidiasisectodermal dystrophy) is a syndrome characterized by multiple signs of autoimmunity [1]. Autoimmune polyglandular syndrome type 1 (APS-1) is the other name of APECED syndrome. It is a rare inherited disease that affects multiple organs and is characterized by three main symptoms caused by mutations in the autoimmune regulatory gene (AIRE) [2]. Te total number of APECED patients worldwide is estimated to be approximately 1000 individuals [2]. Individuals afected as a result of AIRE gene mutation show endocrine and autoimmune manifestations characterized by autoantibody production. Te classic triad of symptoms is chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and autoimmune adrenal insufciency [1]. A few more organ-specifc manifestations occur, including premature ovarian failure, autoimmune thyroid disease, type 1 diabetes, autoimmune gastritis and enteropathy, autoimmune hepatitis, alopecia, vitiligo, and keratitis [3]. More than 80-90% of APECED cases have chronic mucocutaneous candidiasis as the frst symptom [4].
We present a case presenting with a nonclassical symptom of APECED, arthritis, and misdiagnosed as systemic juvenile idiopathic on admission who lately developed signs of autoimmunity and candidiasis. Our aim is to emphasize to think about possible APECED diagnosis when the clinicians encounter arthritis, rash, fever, and history of moniliasis.

Case Presentation
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 fndings, 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 signifcant swelling especially in the right knee.
Te patient was the second child of consanguineous parents. Tere was a third-degree cousin marriage without any other parental comorbidities. Te other two children of the family were doing well and did not have any health problems.
No pathological fndings were detected in the chest Xray. 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 antiinfammatory 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. Te lymphocyte subset analysis by fow cytometry and T/B cell proliferation tests resulted normal. However, without genetic analysis, we could not exclude innate immune system defciency, 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 defciencies.
Ten, genetic examination could be performed to exclude primary immunodefciency 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). Ten, the patient was diagnosed with APECED syndrome. Te 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, difuse 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 T17-mediated disorder, and T cell assistance was not sufcient.
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 fuconazole and trimethoprim sulfamethoxazole prophylactic treatment. He also recovered from arthritis very well without any other medication. At the age of fve, 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, fuconazole prophylaxis, and IVIG, and he is doing well.

Discussion
Te AIRE gene causing APECED syndrome was frst identifed in 1997 [3]. Tis gene encodes transcriptional regulators primarily expressed in medullary thymic epithelial cells and contributes to the development of central immune tolerance in the thymus [5]. APECED is typically characterized by autosomal recessive inheritance, but autosomal dominant inheritance has also been reported. Compound heterozygosity is also common [1]. More than 126 AIRE mutations have been identifed up to date. Tey are varying from single-nucleotide substitutions to large deletions spreading out across the coding sequence [3].
A cluster of missense mutations was detected in the CARD and PHD1 domains [6]. Te APECED protein contains two zinc fngers of the plant homeodomain type (PHD), a DNA-binding domain, dubbed "SAND" [7]. Te most common worldwide mutation is the FIN major mutation in the SAND domain in p.r257. It is dominant not only in Finland but also in many Eastern European countries. Te SAND domain is a conserved 80 amino acid sequence likely to mediate protein-protein interaction and DNA binding. A number of nonsense mutations were located in this domain [3]. Our patient also had a homozygous mutation in the SAND domain which was published before [8].
AIRE is a transcriptional regulator primarily expressed in medullary thymic epithelial cells (mTECs) and plays an important role in thymocyte training and negative selection by controlling the expression of peripheral antigens in the thymus [9]. AIRE defciency in the thymus impairs presentation of self-antigens that inhibit negative selection of autoreactive T cells [10]. In the absence of AIRE expression, autoreactive T cells undergo clonal deletion or transform into regulatory T cells, rushing to the periphery where they cause autoimmune destruction [5]. Faulty function in the AIRE gene may impair the clearance of autoreactive T cells and the development of Treg cells in the thymus. Patients with APECED show low expression of forkhead box protein P3 (FOXP3), which is critical for Treg cell activation and proliferation [10]. Tey are key mediators in peripheral tolerance and prevention of autoimmunity [4]. Our patient developed autoimmune manifestations such as hypoparathyroidism and arthritis.
Enamel hypoplasia, gastrointestinal dysfunction, and urticarial eruption may also occur [5]. Abnormalities such as ectodermal nail dystrophy and tympanic membrane calcifcation have been reported [1]. Our patient also developed dental problems, urticarial rash, and nail dystrophy.
Te disease may also present with pneumonia and autoimmune hepatitis [11]. Our presented case had a severe pneumonia before IVIG therapy. Te clinical spectrum of APECED may be highly variable even among siblings with the same AIRE genotype [3]. Te AIRE protein is found not only in immunologically important tissues such as thymic medullary epithelial cells but also in peripheral blood, monocytes, and dendritic cells. Tis widely and diferent expression explains the variability of heterogenous symptoms in APECED patients [12].
Infammatory arthritis, though very rare in APECED cases, may be an early manifestation [1]. Four patients with juvenile arthritis or misdiagnosed as JIA and lately diagnosed as APECED have been reported up to date ( Table 1).
As shown in Table 1, novel compound heterozygous mutations were defned in a female case, diagnosed with APECED at the age of 10, and clinical fndings of polyarticular JIA were observed at the age of 2 years (2nd patient). Carpopedal spasm and hypoparathyroidism were also observed in the follow-up of this patient [7]. Tird case in   Table 1 was a 2-year-old female patient who was diagnosed with systemic JIA with recurrent fever attacks, rash, and arthralgia. Tis case developed hypoparathyroidism at the age of 7 years, adrenal insufciency at the age of 8 years, and ovarian insufciency at the age of 12 years [12]. As in our patient, 4th case had dental problems that appeared in the early period and hypoparathyroidism developed at the age of fve. After three years, she developed chronic mucocutaneous candidiasis, type 1 diabetes mellitus, adrenal insufciency and ovarian insufciency, and alopecia totalis [13]. Recurrent fever attacks accompanied by rash, enteritis, and swelling in the hand were observed in the 5th case. Ten, she developed chronic mucocutaneous candidiasis, autoimmune hepatitis, nail mycosis, hypothyroidism, diarrhea, hypoparathyroidism, subclinical adrenal insufciency, candida esophagitis, and vitiligo [14]. Identifed cases are female, but our case is male. A single-nucleotide polymorphism (SNP) that was strongly associated with APECED was identifed in a largescale genome-wide cohort of patients with rheumatoid arthritis. Two SNPs in AIRE gene, rs2075876 and rs760426, showed strong association with rheumatoid arthritis risk suggesting that in addition to the key AIRE gene mutations and other genetic and environmental factors, SNPs may have an impact on the phenotypic expression of APECED [2]. In addition, it is important to emphasize that a delay in diagnosis in a patient with arthritis may lead to poor prognostic outcomes.
In conclusion, infammatory arthritis is rarely described in association with APECED and is misdiagnosed as juvenile idiopathic arthritis. In APECED cases, nonclassical symptoms such as arthritis may occur before developing classical symptoms and considering the diagnosis of APECED in patients with CMC and arthritis is very important for early diagnosis before development of complications and management of disease.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Ethical Approval
Tis study has been granted an exemption from requiring ethics approval by Ege University Medical Research Ethics Committee.

Consent
Written parental consent was obtained from the patient's parent for publication of this case report and any accompanying images.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
NK and GA designed and wrote the article. BG, NEK, and IA provided the patient's clinical information. ET, NEK, and GA performed clinical follow-up of the patient. NK and GA edited the fnal version. All authors have read and approved the manuscript.