Case Report: Severe Hypocalcemic Episodes Due to Autoimmune Enteropathy

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease—Hashimoto’s thyroiditis, Addison’s disease, diabetes mellitus type 1 and primary ovarian insufficiency—developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.

Gastrointestinal manifestations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patient: major effect on treatment and prognosis

“…The pathological background of the gastrointestinal symptoms remains incompletely understood, but they have been attributed to multiple factors with autoimmunity being the most common underlying cause ( 11 ). About half of the patients with APECED have autoimmunity against gut neuroendocrine cells associated with antibodies against tryptophan hydroxylase ( 2 ).…”

“…It has also been found that APECED patients suffer from loss of epithelial enteroendocrine cells in the duodenal and small bowel mucosa ( 11 , 12 ).…”

New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden

“…Candidiasis is part of APS1, also called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), a rare monogenetic condition underlying autoimmune regulator ( AIRE ) gene mutation on chromosome 21q22.3 [ 53 , 54 , 55 ]. The AIRE protein is responsible for immune self-tolerance which causes immune dysregulation and autoimmune conditions in APS1, typically involving the classical triad: AD, hypoparathyroidism, and chronic cutaneomucosal candidiasis [ 53 , 54 , 55 ].…”

“…Candidiasis is part of APS1, also called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), a rare monogenetic condition underlying autoimmune regulator ( AIRE ) gene mutation on chromosome 21q22.3 [ 53 , 54 , 55 ]. The AIRE protein is responsible for immune self-tolerance which causes immune dysregulation and autoimmune conditions in APS1, typically involving the classical triad: AD, hypoparathyroidism, and chronic cutaneomucosal candidiasis [ 53 , 54 , 55 ]. Hypoparathyroidism is usually the first endocrine manifestation and the most common condition; moreover, APS1 includes type 1 diabetes mellitus (DM), autoimmune hypothyroidism, premature ovarian failure, and other nonendocrine disorders [ 56 , 57 ].…”

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

“…The deficit of vitamin D has been described in several patients with APS1 who also showed severe hypocalcemia [ 65 ]. The authors suggest that the loss of EECs in the gut epithelium contributed to vitamin D malabsorption, making useless the oral administration of calcitriol, while suggesting a better efficacy of parental vitamin D analogs in controlling hypoparathyroidism in these patients [ 65 , 66 ]. In light of the role of vitamin D in autoimmunity and its effects on microbiota, it is conceivable that its deficit in APS1 patients might be also involved in the pathogenesis of the disease or correlated with the severity of the clinical manifestations.…”