AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 1: A RARE CASE REPORT AND REVIEW OF THE LITERATURE

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1 Case Report AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 1: A RARE CASE REPORT AND REVIEW OF THE LITERATURE Imran Sarker, MD 1 ; Mohammad Bahadur Ali Miah, MD 1 ; Mohammad Abdul Hannan, MD 1 ; Nusrat Sultana, MD 2 ; Mohammed Fariduddin, MD 2 ABSTRACT Objective: The objective of this article is to present a case report of autoimmune polyendocrine syndrome type 1 (APS-1) diagnosed at a tertiary level hospital. Methods: This report summarizes the clinical presentations, laboratory values, treatments, and follow-up of a patient with APS-1. The diagnosis of APS-1 was based on clinical features and laboratory criteria. Results: The study patient with APS-1 was a 9-yearold girl that presented with recurrent seizure as a consequence of hypocalcemia due to primary hypoparathyroidism; an important component of this syndrome. A computerized tomography scan showed diffuse calcification of both basal ganglia and subcortical structures of the brain. Biochemical study showed features of primary hypothyroidism (free thyroxine = 0.31 ng/dl, free triiodothyronine = 1.0 pg/ml, thyroid-stimulating hormone >150 µiu/ ml), primary hypoparathyroidism (serum calcium = 6.2 mg/dl, serum magnesium = 1.8 mg/dl, serum inorganic phosphate = 7.9 mg/dl, serum parathyroid hormone <3 pg/ ml), partial adrenal insufficiency (serum cortisol = nmol/l, adrenocorticotropic hormone = pg/ml), and fasting blood glucose of 3.9 mmol/l. Estimation of thyroid antibody activities revealed elevated anti-thyroglobulin Submitted for publication April 21, 2016 Accepted for publication June 9, 2016 From the 1 Department of Neurology and 2 Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka-1000, Bangladesh. Address correspondence to Dr. Imran Sarker, Department of Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka-1000, Bangladesh. imran37mmc@gmail.com. DOI: /EP CR To purchase reprints of this article, please visit: antibody (207 IU/mL) and anti-thyroid peroxidase antibody (>1,000 IU/mL), which was highly suggestive of autoimmune hypothyroidism. The patient was managed with supplemental calcium, activated vitamin D, glucocorticoid, levothyroxine, antifungal medications, and anticonvulsants. Conclusion: Physician awareness of this rare autoimmune polyendocrine disorder can increase its early recognition and treatment, potentially preventing associated fatalities. (AACE Clinical Case Rep. 2017;3:e96-e100) Abbreviations: APS-1 = autoimmune polyendocrine syndrome type 1; AIRE = autoimmune regulator gene INTRODUCTION Autoimmune polyendocrine syndrome type 1 (APS- 1) (Online Mendelian Inheritance in Man [OMIM] number ) is a rare autosomal recessive disorder that develops in early childhood and results in tissue-specific multiorgan autoimmunity, leading to the hypofunction of multiple glands (1). Endocrine organs such as the adrenal cortex, ovaries, and parathyroid glands are typically affected, resulting in a variety of clinical diseases, including hypocortisolism, hypoaldosteronism, delayed puberty, premature ovarian failure, and hypoparathyroidism with life-threatening hypocalcemia (2). APS-1 is clinically defined as the presence of at least two components of the classic triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis (3). Additionally, nonendocrine immune diseases may be present. According to Neufeld and Blizzard (4), there are 4 main types of APS: type 1 (the presence of at least 2 of chronic candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency), type 2 (autoimmune adrenal insufficiency with autoimmune thyroid disease and/or type 1 diabetes mellitus), e96 AACE CLINICAL CASE REPORTS Vol 3 No. 2 Spring 2017

2 APS type 1 in a Young Girl, AACE Clinical Case Rep. 2017;3(No. 2) e97 type 3 (autoimmune thyroid disease with other autoimmune diseases, excluding chronic candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency), and type 4 (2 or more organ-specific autoimmune diseases that do not fall into types 1, 2, or 3). APS-1, also known as APECED (autoimmune-polyendocrinopathy-candidiasisectodermal-dystrophy), MEDAC (multiple endocrine deficiency autoimmune candidiasis syndrome), juvenile autoimmune polyendocrinopathy, or Whitaker syndrome (OMIM ), is classically defined by the association of at least 2 of 3 major component diseases: chronic mucocutaneous candidiasis, primary hypoparathyroidism, and autoimmune adrenal insufficiency (4-6). When relatives of a patient are analyzed, only one condition is required for APS-1 diagnosis (7). CASE REPORT We report a typical case of APS-1 that displayed several features described in the literature. The 9-year-old girl, a child from a consanguineous marriage, presented with recurrent generalized tonic-clonic seizures. In addition, she also had history of recurrent oral ulceration, dental problems, delayed growth, and prolonged diarrhea that was unresponsive to medications since the age of 5 years. Cognitive function was normal. On general examination, we found her growth to be stunted for her age, with proptosis in both eyes, pigmentation in the lips and tongue, a healing oral ulcer, and hypoplastic dental enamel in the left upper jaw. Fingernails of the right hand showed a yellowish lesion, suggestive of early nail dystrophy (Fig. 1). For evaluation of seizure, a computerized tomography scan was performed which showed diffuse calcification of both the basal ganglia and subcortical structures of the brain (Fig. 2). Figure 3 displays pigmentation on the lips along with dental enamel hypoplasia. The patient s hematology parameters were as follows: hemoglobin = 10.3 g/dl, erythrocyte sedimentation rate = 20 mm/hour, total count = 10,500 cells/ml, differential count: neutrophils = 65%, lymphocytes = 26%, monocytes = 6%, and eosinophils = 3%, fasting blood glucose = 3.9 mmol/l, serum alanine aminotransferase = 25 U/L, and serum creatinine = 1.1 mg/dl. For further evaluation of intracranial calcification, a metabolic panel was explored which revealed autoimmune hypothyroidism (free thyroxine = 0.31 ng/dl, free triiodothyronine = 1.0 pg/ml, thyroid-stimulating hormone >150 µiu/ml, antithyroglobulin antibody = IU/mL, anti-thyroid peroxidase antibody >1,000 IU/mL), primary hypoparathyroidism (serum calcium = 6.2 mg/dl, serum magnesium = 1.8 mg/dl, serum inorganic phosphate = 7.9 mg/dl, serum parathyroid hormone <3 pg/ml), and partial adrenal insufficiency (basal cortisol = nmol/l, plasma adrenocorticotropic hormone = pg/ml). The presence of 3 major endocrine organ abnormalities, along with mucocutaneous candidiasis and nail dystrophy, led to the diagnosis of APS-1. She also had dental enamel hypoplasia, which is observed in 12 to 60% of APS-1 patients. In addition to this, ectodermal dysplasia was also evident in her fingernails. Interestingly, despite multiple endocrine problems, she was not seriously ill to the point of seeking a doctor. The development of recurrent seizures prompted her parents to see a local physician who referred her to our institute. The patient is currently under treatment with supplemental calcium, activated vitamin D, glucocorticoid, levothyroxine, antifungal medications, and anticonvulsants. Fig. 1. Nail dystrophy.

3 e98 APS type 1 in a Young Girl, AACE Clinical Case Rep. 2017;3(No. 2) Fig. 2. Computerized tomography scan showing intracranial calcification. Fig. 3. Lip pigmentation and dental enamel hypoplasia. DISCUSSION APS-1 APECED is generally seen in infants and diagnosis is made when a child has 2 or 3 of the following components: mucocutaneous candidiasis, hypoparathyroidism, and Addison disease. Mucocutaneous candidiasis involving the mouth and nails is usually the first disease to present, followed by the development of hypotension or fatigue from Addison disease or hypocalcemia from hypoparathyroidism. Our patient also had oral ulcers and onychomycosis, suggestive of mucocutaneous candidiasis. Other autoimmune diseases associated with APS-1 include type 1A diabetes, vitiligo, alopecia, hepatitis, pernicious anemia, primary hypothyroidism, hypergonadotropic hypogonadism, malabsorption syndrome with steatorrhea, and pure red cell aplasia (8). In this case, we found all of the common components, although type 1A diabetes was absent. APS-1 is one of the best-understood disorders leading to more common diseases such as Addison disease and type 1A diabetes (immune mediated diabetes). The importance of APS-1 relates to the discovery of the genetic abnormality underlying the syndrome: mutations in the autoimmune regulator (AIRE) gene. Once the association of autoimmune diseases was appreciated, the pathogenesis of their association was investigated. Two genes were identified that contribute to the APS syndrome: human leukocyte antigen (HLA), encoding the major histocompatability complex needed for antigen presentation to T lympho-

4 APS type 1 in a Young Girl, AACE Clinical Case Rep. 2017;3(No. 2) e99 cytes, and the AIRE gene. HLA alleles affect tolerance at multiple levels, being essential for antigen presentation (9). Asplenism is associated with APS-1 as Friedman and colleagues (10) reported 4 of 9 patients with APS-1 were asplenic. A recent paper by Meager and co-workers (11) indicates that 100% of patients with APS-1 have autoantibodies reacting with interferon omega, and assays for such autoantibodies may aid in rapid diagnosis. APS-1 is almost always autosomal recessive, however, a family with an autosomal dominant mutation in AIRE has been described (primarily thyroid autoimmunity) and this mutation has recently been modeled in mice (12). In the current case, no other family members have demonstrated any symptoms or signs of APS-1. Genetic studies for APS-1 are not available in our country. The patient s family was advised to undergo genetic testing abroad, but this was not performed due to financial constraints. Diagnosis, Screening, and Treatment The actual diagnosis of APS involves serological measurement of organ-specific antibodies and subsequent functional testing (13-16). These special diagnostic approaches, and the management of patients with APS and their relatives, are best performed in centers with special expertise in autoimmune endocrine diseases. The mainstream treatment of this syndrome is to supply the various deficiencies, which, at first, may seem a simple procedure. However, tricky situations are likely to arise, requiring the utmost attention as detailed below. Patients suffering from hypoparathyroidism must receive calcium and vitamin D derivatives in doses sufficient to maintain plasma calcium in the lower half or slightly below the normal range and urinary calcium in the normal range. As a life-threatening condition, adrenal insufficiency should be diagnosed before it becomes symptomatic. Glucocorticoid replacement must be initiated immediately and doses have to be increased during periods of acute stress, such as infection and surgery. It is important to be aware of the likelihood of hypocalcemia whenever glucocorticoid replacement is increased, and to adjust hypoparathyroidism treatment accordingly. Mineralocorticoid deficiency is managed with fludrocortisone acetate. L-thyroxine supplementation is administered in cases of hypothyroidism, always after ruling out or treating adrenal insufficiency. Thyroid hormone increases hepatic clearance of cortisol, which may precipitate adrenal crisis in undiagnosed adrenal insufficiency. In addition, patients with untreated adrenal insufficiency may display a reversible increase in thyrotropin levels, since glucocorticoids inhibit thyrotropin secretion. Estrogen or androgen replacement should be started at pubertal age in hypogonadal children. Doses should be gradually increased and treatment should be maintained during adulthood. Vitamin B12 replacement therapy should be given whenever necessary. The patient in the current report is being treated with regular doses of vitamins. We believe that high-dose vitamins will not improve her growth as APS-1 is an immunologically mediated metabolic/endocrine disorder. It is noteworthy that intestinal dysfunction may lead to inadequate and erratic absorption of medications. Maintaining appropriate levels of hormones and other substances may be very challenging in some cases. Malabsorption may be improved with oral replacement of pancreatic enzymes and by decreasing fat intake or replacing common fats with medium-chain triglycerides (17). Again, it must be emphasized that hypocalcemia may worsen malabsorption and, therefore, must be prevented. Chronic mucocutaneous candidiasis should be controlled with antifungal medication. Azole agents like miconazole, ketoconazole, itraconazole, and fluconazole are often effective, although long-term use may lead to drug resistance (18). Another important issue to consider is that azoles may interfere with steroidogenesis, worsening or causing adrenal insufficiency. Amphotericin B and nystatin, polyene class antifungals, should be preferred. Oral and esophageal candidiasis must be strictly controlled to prevent development of squamous cell carcinoma (19). Keratitis may be ameliorated with local glucocorticoids, and topical vitamin A may prevent corneal ulcerations. Patients with asplenia are recommended to be vaccinated against pneumococcus, however, some authors suggest that every APS-1 patient should be vaccinated, as asplenia is commonly asymptomatic (17). The role of immunosuppressive therapy has been reported in several publications with different drugs. Immunosuppressive therapy seems to control malabsorption and pancreatic insufficiency, hepatitis, keratitis, alopecia, and other symptoms, but with variable results (2). It is important to remember that immunosuppressive therapy predisposes the patient to the spreading of superficial candidiasis to a generalized and severe form (2,7). CONCLUSION APS-1 is a complex syndrome characterized by multiple organ damage. Although rare, it must be diagnosed at an early stage, given its high morbidity and mortality. Treatment and follow-up are demanding and require a multidisciplinary approach. The main objective of treatment is to preserve the patient s quality of life. Psychosocial support is essential for most patients. DISCLOSURE The authors have no multiplicity of interest to disclose.

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