Abstract
Summary
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive inherited syndrome caused by mutations in autoimmune regulator (AIRE) gene. The three clinical components of this syndrome are mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. In addition to these frequent symptoms, many other components have been reported including gastrointestinal manifestations.We report a case of a 17-year-old Caucasian female patient diagnosed with APECED who presented with acute abdominal pain. Her medical history revealed chronic digestive discomfort without bowel movement disorders. The patient needed a significant increase in doses of calcium supplementation and hydrocortisone which appeared to be partially inefficient. Investigation with esophagogastroduodenoscopy and biopsy showed autoimmune atrophic gastritis. The patient eventually needed increasing doses of treatment received in order to achieve desired clinical and biological therapeutic goals.
Learning points
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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive inherited syndrome caused by mutations in the autoimmune regulator (AIRE) gene.
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The three clinical components of this syndrome that appear in early childhood are mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency.
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In addition to these frequent symptoms, many other components have been reported including gastrointestinal manifestations like atrophic gastritis. They can be caused by many abnormalities including atrophic gastritis and the modification of intestinal biofilm and microbiota.
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Early diagnosis and treatment of gastrointestinal manifestations associated with APECED prevent multiple life-threatening consequences like acute adrenal crisis and severe symptomatic hypocalcemia.
Background
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is also referred to as autoimmune polyendocrine syndrome type 1 (1). It is a rare autosomal recessive inherited syndrome caused by mutations in the autoimmune regulator (AIRE) gene (1). The three first clinical components of this syndrome that appear in early childhood are mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. In addition to these symptoms, many other components have been reported including gastrointestinal manifestations like atrophic gastritis, dermatologic conditions like alopecia and endocrine disorders like type 1 diabetes (1, 2).
These manifestations that usually appear later in life can sometimes be responsible for life-threatening adverse events and are therefore important to keep in mind, especially in case of suggestive clinical or biological symptoms. For instance, gastrointestinal conditions can lead to malabsorption and alter the drug absorption process (3). This could negate the therapeutic efficacy of hydrocortisone and calcium supplements.
However, current studies do not highlight the importance of interactions between manifestations of APECED and the treatment received by these patients.
Herein, we report a case of a 17-year-old female patient diagnosed with APECED who presented with chronic abdominal discomfort and a significant increase in drug doses leading to the diagnosis of an autoimmune atrophic gastritis.
Case presentation
A 17-year-old Caucasian female patient diagnosed with APECED presented with chronic abdominal pain. She was the second child of consanguineous parents. Her older brother was diagnosed with APECED and treated for hypoparathyroidism and primary adrenal insufficiency. Our patient presented with the classic triad of clinical features made up of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency.
The onset of the manifestations began at the age of 4, when the patient was first diagnosed with adrenal insufficiency. It was discovered when the patient presented progressive melanodermia and then severe asthenia. Given the family history of an older brother diagnosed with APECED, the patient was therefore screened for it and the genetic study confirmed the AIRE R257X mutation. Later on, during the regular check-ups, the biology showed asymptomatic hypocalcemia and hypoparathyroidism were diagnosed at the age of 8 years. At the same year, the patient began to present onychodystrophy in her fingernails. The nail biopsy showed colonization by Candida albicans.
At 17 years of age, the patient began to present gastrointestinal manifestations from which she did not complain in earlier visits. The patient first complained of intermittent stomach pain with chronic discomfort in the upper abdomen. She had normal bowel movements. These complaints synchronized with progressive augmentation in calcium and alfacalcidol treatment doses in order to obtain calcium level targets. She was then admitted for acute adrenal insufficiency. Physical examination showed hyperpigmentation of skin and mucosae (Fig. 1), alopecia universalis (Fig. 2), and thickened nails, and in oral examination, enamel hypoplasia (Fig. 3). Abdominal examination showed mild intestinal distension without any other abnormalities. Her growth was normal. She has a height of 165 cm and a normal BMI of 19.83 kg/m². The menarche was at the age of 12 with regular menstrual cycles. The Tanner Staging in our patient was rated 4.
Hyperpigmentation of skin and mucosae and alopecia universalis.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0352
Thickened nails.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0352
Enamel hypoplasia.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0352
No precipitating factor for the acute adrenal insufficiency was found, and after reanimation, the patient needed to stay on bigger doses of oral hydrocortisone reaching 40 mg to maintain hemodynamic stability and normal plasma sodium and potassium levels.
Malabsorption was suspected since the laboratory findings showed normochromic normocytic anemia, and the patient needed higher treatment dosing.
Investigation
Laboratory findings showed normochromic normocytic anemia, with low calcemia levels. Other biological assessments were normal including normal lipase, C-reactive protein, albumin, and ferritin levels (Table 1). Anti-endomysium and anti-transglutaminase antibodies were negative ruling out coeliac disease. A urinary tract infection was excluded. Vitamin B12 levels were low (122 pg/mL). The sampling was conducted at the age of 17 years. Abdominal ultrasound ruled out signs of appendicitis and cholecystitis.
Biological characteristics of the patient.
| Result | Reference range | |
|---|---|---|
| Hemoglobin (g/dL) | 11.7 | 12–15 |
| MCV (fL) | 89 | 80–100 |
| MCHC (g/dL) | 30 | 36–44% |
| WBC count (cells/mm3) | 5800 | 4500–11,000 |
| Calcium (mmol/L) | 1.82 | 2.25–2.65 |
| Magnesium (mmol/L) | 0.7 | 0.8–1.1 |
| Phosphorus (mmol/L) | 2.6 | 0.9–1.45 |
| C-reactive protein (mg/L) | 3 | <10 |
| Albumin (g/L) | 31 | 40–54 |
| Ferritin (µg/L) | 20 | 10–120 |
| Lipase (UI/L) | 8 | <160 |
| Vitamin B12 (pg/mL) | 122 | 190–950 |
| Folate (ng/mL) | 7.3 | 2.7–17 |
MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume
Esophagogastroduodenoscopy with endoscopic biopsies showed signs of atrophic gastritis and calcifications in some segments of the duodenal epithelium. Antibodies targeting intrinsic factors were positive. The diagnosis of autoimmune atrophic gastritis was therefore held.
Treatment
As the patient was diagnosed with autoimmune atrophic gastritis, she was prescribed vitamin B12 injections. As for the other treatments, the patient needed higher doses of hydrocortisone and fludrocortisone to maintain hemodynamic stability. Hydrocortisone doses were increased based on clinical examination of the patient (blood pressure and pulse). The patient was put on the minimal doses at which hemodynamic stability was guaranteed which was 20 mg/m²/day. Fludrocortisone was increased based on plasma sodium and potassium levels and reached 100 µg.
In order to reach calcemic targets, she needed 6000 mg of calcium carbonate with 5 µg of alfacalcidol and 1200 mg of magnesium. Other treatment options for hypoparathyroidism in this case could include subcutaneous daily injection of PTH analogs, but this treatment is not available in our country. We therefore chose to continue oral vitamin D and calcium supplements. The biological and clinical evaluations following these high doses were normal.
Discussion
In this paper, we reported a case of autoimmune atrophic gastritis associated with APECED and which resulted in significantly increased doses of treatment with calcium and hydrocortisone.
APECED is a rare disorder affecting one in every two to three million newborns (1). The diagnostic criteria include the presence of at least two of the first components including chronic mucocutaneous candidiasis, hypoparathyroidism, or adrenal insufficiency. The diagnostic could be retained also with one of the components if a sibling has definite APECED disease-causing mutations in both AIRE genes (3). There is a high heterogeneity of mutations of the AIRE gene, which can vary between different regions within the same country. The R257X mutation of the AIRE gene is the most common mutation in the population of eastern and central Europe (4).
The most frequent symptom is mucocutaneous candidiasis affecting mainly the mouth cavity and the nails. It is seen in about 80–90% of the patient (2). The second most frequent clinical feature is hypoparathyroidism observed in about 79% of the patients (5).
In contrast to the organ-specific autoimmune symptoms of APECED, other manifestations have been reported including in around 25% of the patient’s gastrointestinal manifestations, which are mainly autoimmune-related diseases like atrophic gastritis, autoimmune enteropathy, and intestinal infections mainly candida esophagitis (6). Chronic diarrhea is the first manifestation in 5% of patients and severe constipation in 2%, whereas malabsorption varies from 9 to 26%, according to the series (7).
Candida infection in APECED patients can affect the oral and the oesophageal mucosa. Chronic gastritis seen in APECED is of the A type, which, according to the Strickland classification, is based on an autoimmune response to the gastric mucosa (7). Systemic dissemination with potential lethal outcomes is possible but quite rare and mostly because of additional iatrogenic factors such as immunosuppressive therapies (7). Autoimmune atrophic gastritis affects the gastric parietal cells and intrinsic factor which leads to gastric atrophy, vitamin B12 deficiency, and pernicious anemia (8). Delayed onset of abdominal manifestations was related to the absence of correlation between biopsy proven gastritis and macroscopic features. Although histologically proven gastritis has been found in almost half of the patients, it was not commonly symptomatic (9).
In the study published by Ferre et al. including 35 APECED patients, biopsy-proven gastritis was seen in 17 patients (48.6%) and 10 patients (28.6%) had B12 deficiency associated with positive intrinsic-factor antibody (10).
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). The loss of neuroendocrine cells leads to decreased serum serotonin levels, which in turn is associated with symptoms of obstipation (5). In addition, around a quarter of the patients exhibit autoimmunity against defensins, culminating in a loss of Paneth cells. Anti-defensin antibodies are linked to gut microbiota dysbiosis in AIRE −/− mice and diarrhea in humans (5). This gastritis can be responsible for hypocalcemia and severe cases of intractable hypocalcemia have been described following gastrointestinal manifestations.
It has also been found that APECED patients suffer from loss of epithelial enteroendocrine cells in the duodenal and small bowel mucosa (11, 12).
The small intestine and mainly the duodenum are primarily responsible for calcium absorption, through active transport stimulated by 1.25-dihydroxyvitamin D. Loss of epithelial enteroendocrine cells leads to malabsorptive diarrhea which causes aggravation of hypocalcemia in these patients (11).
Another plausible cause for gastrointestinal manifestations is the modified intestinal biofilm (8). Analysis of gut microbiota indicated that both alpha- and beta-diversity were altered in patients with APECED compared to healthy controls and is enriched with predominantly gram-negative bacterial taxa (12). There are a number of similarities between the microbiomes of patients with APECED and those with inflammatory bowel disease: The fraction of Faecalibacterium was reduced in patients with APECED while that of Atopobiumspp. and several gram-negative genera previously implicated in biofilm formation, for example, Veillonella, Prevotella, Megasphaera, and Haemophilus, were increased (12). Moreover, the probiotic Lactobacillus acidophilus was notably depleted in APECED patients (13). The identification of gut microbiota dysregulation allowed promising treatment solutions for the gastrointestinal manifestations and their possibly mortal consequences like severe hypocalcemia.
In conclusion, gastrointestinal manifestations in APECED patients can be caused by many abnormalities including atrophic gastritis, loss of EE cells, and the modification of intestinal biofilm and microbiota. Treatment options include probiotics to help improve the microbiota. Early diagnosis and treatment of gastrointestinal manifestations associated with APECED prevent multiple life-threatening consequences like acute adrenal crisis and severe symptomatic hypocalcemia.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed and written consent has been obtained from the patient after full explanation of the purpose and nature of all procedures used.
Author contribution statement
The main writers of the manuscript are B Y Hadami and T Ach. All the authors participated in the revision of the review and helped in the patient’s care.
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