Autoimmune polyglandular syndrome type 1 (APS-1) is caused by mutations in the AIRE gene, which is located on chromosome 21 (21q22.3) and encodes the AIRE protein. Here, we report an APS-1 patient who harboured heterozygous mutations in AIRE, including c.371C > T (p.Pro124Leu) and c.623G > T (p.Gly208Val). These two mutations are novel and likely pathogenic according to the ClinVar database and function-prediction software. AIRE functions as a transcription factor and regulates the transcription of peripheral tissue antigens in thymic medullary epithelial cells. It plays a key role in shaping central and peripheral immunological tolerance by facilitating negative selection of autoreactive T cells in the thymus and inducing a specific subset of regulatory T cells [6, 7].
In the absence of AIRE, autoimmunity develops from two failed tolerance mechanisms targeting more than one endocrine organ and a nonendocrine organ. APS-1 can be diagnosed clinically based on the appearance of at least two of the three conditions: candidiasis, hypoparathyroidism and adrenocortical failure [4, 5]. In this patient, hypoparathyroidism was the first manifestation of APS-1 and occurred at the age of seven years old. She also had adrenal insufficiency and other endocrinological symptoms, such as premature ovarian and osteoporosis. Mucocutaneous candidiasis was not observed. Moreover, she had chronic diarrhoea and recurrent pneumonia with bronchiectasis.
Haematological abnormalities have also been identified in APS-1. In the largest cohort study of APS-1, consisting of 112 patients in Russia, pernicious anaemia was seen in 8% (10/112) [8]. Pernicious anaemia is the most common cause of anaemia as a result of autoimmune gastritis with vitamin B12 deficiency [3]. In the above study, PRCA was only found in 1% of the patients [8], with coexistence with large granular lymphocyte leukaemia in some. Autoimmune haemolytic anaemia is very rare [9, 10].
Eight cases of PRCA associated with APS-1 have been reported [11,12,13,14,15,16,17], of which only four had coexisting LGLL [15,16,17]. All four patients were female, and their first manifestations of APS-1 were during childhood. PRCA and T-LGLL were diagnosed simultaneously. Three patients were in their 20 s, and one was 46 years old. In the current case, APS-1 preceded PRCA and T-LGLL by 24 years. This may not be a coincidence, as APS-1, PRCA and T-LGLL are all rare diseases, and PRCA and LGLL can even develop in siblings with the same AIRE mutation [18]. To date, some mechanisms for patients diagnosed with LGLL with PRCA have been explored [19]. Regarding molecular mechanisms, STAT3 mutations have been found in some PRCA patients with LGLL [20], though it remains uncertain whether STAT3-mutated T cells have an inhibitory effect on erythroid cell production. Furthermore, STAT5b mutations have essential roles in the survival and proliferation of haematopoietic cells. Nonetheless, the present patient did not carry STAT3 or STAT5b mutations. Regarding the immune mechanism, Handgretinger et al. [21] reported that in a patient with γδT-LGLL-associated PRCA, γδT-LGLs inhibited erythroid precursors by KIRs. It is possible that autoimmunity of APS-1 may predispose an individual to the development of clonal proliferation of LGLs. The T-LGLL clone might recognize a self-antigen and expand due to AIRE regulatory failure and lack of deletion of that T cell clone. The LGLL clone targets an erythroid antigen, resulting in PRCA.
Treatment responses to glucocorticoid and immunosuppressive drugs such as cyclophosphamide [12, 15] or mycophenolate-mofetil [13] vary among cases. In our case, glucocorticoids resulted in remission of PRCA, though lymphocytosis persisted. Sirolimus and tacrolimus failed to maintain normal haemoglobin levels.
In conclusion, we report a rare case of APS1 caused by AIRE mutations presented with PRCA and LGLL. With further literature review, AIRE is thought to be causally related to the development of LGLL and consequent PRCA due to some immunological mechanisms which need further investigation.
