ESPE Abstracts

Introduction: Autoimmune polyendocrinopathy type 1 (APECED) is an autosomal recessive disease caused by loss of function mutations of autoimmune regulatory (AIRE) gene. Characteristically, early onset ectodermal dysplasia, mucocutaneus candidiasis is followed by hypoparathyroidism and primary adrenal insufficiency usually within the first two decades. Although clinical features may be variable, recently, it is suggested that population characteristics and natural course and clinical features of the disease are associated. Herein a case of APECED referred with growth retardation, arthritis, diarrhea and pneumonia, followed by type 1 diabetes and adrenal insufficiency is presented.

Case: The patient presented with chronic diarrhea when he was 9 years old. At the age of 10, he was referred with swelling, pain and limited movements of the left knee and was diagnosed with arthritis. At the age of 13.5, he was admitted for necrotizing pneumonia, had severe short stature. He was started on intravenous antibiotics and immunoglobulin. Family history revealed that the patient was the third child of a consanguineous couple, and had two healthy siblings. His mother and aunt also had short stature. On physical examination he had severe short stature (117.6 cm, -7.66 SDS) and malnutrition (17.7 kg, -5.22 SDS); immature facial features, high-pitched voice, dry, hyperpigmented skin. Pubertal stage was Tanner 1. He had normochromic normocytic anemia, and lipid soluble vitamin deficiency, liver transaminases were elevated. Baseline immunologic examination and sweat chlorine levels were within the normal range. Bone age was 8 years, IGF-1 and IGFBP3 levels were very low (<-3SD).

Colonoscopic ileum biopsy revealed eosinophilic ileitis. During follow-up, hyperglycemia was detected, simultaneous serum insulin and c-peptide levels were low, HbA1c was normal, anti-GAD autoantibodies were elevated (72,37 U/L). A preliminary diagnosis of IPEX Syndrome was ruled out with FOXP3 gene sequencing. The patient was examined for other autoimmune endocrinopathies however he did not have hypoparathyroidism or hypothyroidism. Primary adrenal insufficiency was suspected and peak cortisol of 14 mcg/dl during ACTH test established the diagnosis; hydrocortison replacement was initiated. Next-generation sequencing(NGS) revealed an insertion leading to a frameshift mutation in the AIRE (autoimmune regulator) gene (c.208_209insCAGG-p.Asp70fs). Immunosuppressive therapy was started.

Conclusion: Chronic diarrhea causing resistant metabolic acidosis, malnutrition and type 1 diabetes in the first decade is uncommon in APECED's. This case is important as it emphasizes its phenotypic variability. The molecular alteration caused by frameshift mutation may explain the severity of the phenotypical features of the patient that would be expected in IPEX.