Autoimmune polyglandular syndromes (APS) are a group of rare disorders characterized by the coexistence of at least two endocrine gland insufficiencies of autoimmune origin, often accompanied by non-endocrine autoimmune manifestations. Among these, Autoimmune Polyglandular Syndrome Type I (APS I), also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is the rarest and most well-characterized form, with a prevalence of 1:90,000 to 1:200,000 in most populations. APS I typically manifests during childhood or adolescence, classically defined by the triad of Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis.[1] The syndrome results from mutations in the AIRE (autoimmune regulator) gene, leading to impaired central immune tolerance and failure to eliminate autoreactive T lymphocytes. These T cells subsequently target multiple endocrine organs, culminating in glandular failure. The onset of Addison’s disease in APS I is considered one of the most severe and life-threatening presentations because adrenal cortical failure, if undiagnosed, can precipitate adrenal crisis with catastrophic consequences.[2] Addison’s disease, or primary adrenal insufficiency (PAI), occurs when the adrenal cortex is destroyed or dysfunctional, resulting in deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens. Clinical features include hyperpigmentation, fatigue, weight loss, hypotension, and electrolyte disturbances, but the disease often presents insidiously with nonspecific symptoms that delay diagnosis. Autoimmune adrenalitis is the leading cause in developed nations, accounting for approximately 70-90% of cases, whereas infectious causes, particularly tuberculosis, remain important in developing countries. In APS I, Addison’s disease is part of a broader systemic autoimmune process that may simultaneously or sequentially involve the parathyroid glands, gonads, thyroid, and other tissues.[3] APS I most commonly manifests in childhood, and reports of its onset in adulthood are scarce, highlighting the uniqueness and clinical importance of such cases. Adult-onset APS I poses diagnostic challenges because clinicians often consider more common etiologies of adrenal insufficiency such as tuberculosis, metastatic infiltration, hemorrhage, or isolated autoimmune Addison’s disease rather than syndromic autoimmunity. Furthermore, hypoparathyroidism and candidiasis may not always be clinically apparent at presentation, resulting in incomplete recognition of the syndrome. Delayed diagnosis may expose patients to recurrent adrenal crises, hypocalcemic seizures, and complications of untreated autoimmune endocrinopathies. This underlines the critical importance of maintaining clinical suspicion even when APS I presents in atypical demographics.[4] The literature suggests that APS I is associated with significant morbidity but, with early recognition and appropriate replacement therapy, affected individuals can achieve near-normal life expectancy. The rarity of APS I in adult males makes each documented case a valuable contribution to the clinical spectrum and academic understanding of this disease. Case reports remain an essential tool to broaden awareness among clinicians, particularly in resource-limited settings where autoimmune etiologies are often overlooked in favor of infectious causes.[5] In this report, we present the case of a 30-year-old male who developed Addison’s disease as part of APS I, manifesting with hyperpigmentation, fatigue, and biochemical evidence of adrenal and parathyroid insufficiency. The uniqueness of this case lies in its adult onset, absence of candidiasis at presentation, and the diagnostic challenge posed by overlapping clinical features with more prevalent conditions in his geographic region. Through this report, we aim to underscore the importance of considering APS I as a differential diagnosis in adults presenting with Addison’s disease, to highlight the role of comprehensive autoimmune screening, and to emphasize long-term multidisciplinary follow-up in ensuring favorable outcomes.

The patient, a 30-year-old male, resident of a rural village and employed as a computer operator, presented with a one-year history of progressive hyperpigmentation and persistent fatigue. Over the preceding six months, he reported an unintentional weight loss of 5 kilograms despite no changes in dietary habits. His symptoms were insidious in onset and gradually progressive. There was no history of fever, night sweats, cough, or myalgias, ruling out common infectious or constitutional syndromes. He denied episodes of dizziness, syncope, chest pain, palpitations, vomiting, or diarrhea. Importantly, there was a positive family history of tuberculosis, as his father had succumbed to complications of pulmonary Koch’s disease one year earlier. The patient denied tobacco, alcohol, or illicit drug use and had no prior medical comorbidities or history of chronic illnesses. On general physical examination, the patient appeared alert but visibly hyperpigmented. The pigmentation was diffuse, more prominent over sun-exposed and friction-prone areas such as the knuckles, elbows, and palmar creases, and extended to the oral mucosa, a hallmark feature of chronic primary adrenal insufficiency. There was no pallor, icterus, cyanosis, lymphadenopathy, or pedal edema. Examination of the external genitalia was normal. His vital signs revealed blood pressure of 90/70 mmHg without postural drop, pulse of 80 beats per minute, respiratory rate of 14 per minute, and afebrile status. Cardiovascular, respiratory, abdominal, and neurological examinations were unremarkable, and no stigmata of tuberculosis, malignancy, or systemic autoimmune diseases were evident. Laboratory investigations revealed striking abnormalities. Early morning serum cortisol (7-9 AM) measured 0.5 μg/dL (reference range 4.82-19.5 μg/dL), confirming adrenal insufficiency. Plasma ACTH was markedly elevated at 1328.13 pg/mL (reference range 4.7-48.8 pg/mL), establishing the diagnosis of primary adrenal insufficiency. Serum electrolytes were not significantly deranged, but further endocrine evaluation revealed a low intact parathyroid hormone (iPTH) level of 15.6 pg/mL (reference 18.5-88 pg/mL), consistent with hypoparathyroidism. Screening for systemic autoimmune disorders via an ANA blot profile (22 parameters) was negative, and anti-thyroid peroxidase antibodies were absent. Thyroid function tests were within normal limits. Hematological parameters, blood glucose, and renal and liver function tests were unremarkable. Imaging with plain CT chest and abdomen excluded tuberculosis and adrenal hemorrhage. Both adrenal glands were mildly bulky, with a small calcific focus in the left adrenal gland, consistent with chronic autoimmune adrenalitis rather than infection or malignancy. Given the clinical context of Addison’s disease with concomitant hypoparathyroidism, and absence of infectious, neoplastic, or secondary autoimmune causes, the diagnosis of Autoimmune Polyglandular Syndrome Type I was established. The differential diagnosis initially considered included isolated Addison’s disease, tubercular adrenalitis, and secondary adrenal insufficiency due to pituitary disease. However, the presence of hyperpigmentation and elevated ACTH clearly indicated primary adrenal pathology. Tuberculosis was excluded by imaging and absence of constitutional symptoms. Secondary adrenal insufficiency was unlikely given the biochemical profile of elevated ACTH and preserved mineralocorticoid function. The patient was initiated on lifelong oral glucocorticoid replacement with Prednisone 20 mg daily, titrated to clinical response. Mineralocorticoid supplementation was deemed unnecessary as serum sodium and potassium were stable. He was counseled extensively about the chronic nature of his illness, the importance of adherence to therapy, and the need for stress-dose steroids during intercurrent illness or surgery to prevent adrenal crisis. For hypoparathyroidism, calcium and vitamin D supplementation were advised. A multidisciplinary team involving endocrinology, internal medicine, and nutrition was engaged for long-term management. Unfortunately, the patient was irregular in follow-up, highlighting the challenges of compliance in resource-limited rural settings. At his last documented follow-up, the patient reported symptomatic improvement in fatigue and stabilization of weight, though hyperpigmentation persisted. He was counseled on the potential evolution of additional autoimmune manifestations such as chronic mucocutaneous candidiasis, primary hypogonadism, pernicious anemia, and alopecia, warranting periodic screening. Prognosis was explained as favorable with consistent therapy but with high risk of morbidity if treatment was interrupted.

Autoimmune Polyglandular Syndrome Type I (APS I), also referred to as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), is a rare inherited multisystem autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. Classically, it manifests in childhood or adolescence with the triad of Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis as described by Ahonen et al.[6] in a large Finnish cohort. The current case is unusual because it involves a 30-year-old adult male presenting with Addison’s disease and hypoparathyroidism, but without candidiasis. This atypical presentation emphasizes the heterogeneity of APS I and the diagnostic complexity when classical features are incomplete. Interpretation of the Case. Our patient’s symptoms of fatigue, weight loss, diffuse hyperpigmentation, and hypotension, together with biochemical evidence of low morning cortisol and elevated ACTH, confirmed primary adrenal insufficiency (Addison’s disease). Hyperpigmentation, resulting from ACTH overstimulation of melanocortin-1 receptors, is nearly always present in long-standing Addison’s as noted by Ten et al.[7] The additional finding of low intact parathyroid hormone indicated concurrent hypoparathyroidism, thereby meeting the criteria for APS I despite the absence of candidiasis. This case supports the growing evidence that APS I has variable phenotypic expression. Michels and Gottlieb et al.[8] note that not all patients develop the complete triad, and the timing of endocrinopathies may vary significantly. In adults, partial or atypical presentations are possible, leading to underdiagnosis. The fact that our patient was male and presented in adulthood makes this case particularly noteworthy, as APS I more commonly affects females and is typically diagnosed earlier. Comparison with Literature The prevalence of Addison’s disease in APS I ranges from 60-100% of cases, often occurring after hypoparathyroidism and candidiasis, as shown in the series by Betterle et al.[9] However, isolated Addison’s as the initial adult presentation of APS I is rarely described. Reports from Scandinavian populations, such as those by Perheentupa et al.[10], have highlighted the phenotypic variability, with some patients presenting as late as the fourth decade. This aligns with our patient’s onset, supporting the need to suspect APS I in adults with Addison’s and an additional autoimmune endocrinopathy. Importantly, the absence of systemic autoantibodies such as ANA or thyroid peroxidase antibodies does not rule out APS I. Alimohammadi et al.[11] demonstrated that APS I is associated with organ-specific autoantigens, including NALP5 in the parathyroid gland. Our patient’s negative autoantibody profile but positive dual endocrinopathy reinforces that clinical suspicion must outweigh negative serology. The distinction from isolated autoimmune Addison’s disease is critical. Addison’s alone typically affects women in the third to fifth decades and does not involve parathyroid insufficiency. The co-existence of hypoparathyroidism in this male patient confirms a syndromic diagnosis rather than isolated disease, consistent with the observations of Husebye et al.[12] Diagnostic Challenges Diagnosis was complicated by several factors. The family history of tuberculosis initially suggested tubercular adrenalitis, a prevalent cause of Addison’s in developing countries. However, imaging revealed bulky adrenal glands with calcifications typical of autoimmune adrenalitis rather than infection. Moreover, the absence of candidiasis or ectodermal features made clinicians reluctant to consider APS I. Finally, the non-specific symptoms of fatigue and weight loss could easily have been misattributed to malnutrition or psychosocial causes. This underscores the need for systematic endocrine evaluation in patients with Addison’s, especially when other glandular abnormalities are suspected. Clinical Reasoning in Management Following biochemical confirmation, the patient was started on prednisone 20 mg daily, sufficient for glucocorticoid replacement. Mineralocorticoid replacement was not required due to preserved electrolyte levels. Hypoparathyroidism was managed with calcium and vitamin D supplementation. As highlighted by Husebye et al.[13], lifelong replacement therapy and education on adrenal crisis prevention are essential. Unfortunately, our patient did not return for follow-up, illustrating the risk of poor compliance, which significantly increases morbidity and mortality in APS I. Implications for Clinical Practice This case has several implications: 1. Age Consideration - APS I can present in adults; absence of candidiasis should not exclude the diagnosis. 2. Comprehensive Screening - All Addison’s patients should be evaluated for other autoimmune endocrinopathies. 3. Adherence and Education - Lifelong hormone replacement requires ongoing counseling, and innovative community-based strategies may improve compliance. 4. Crisis Prevention - Families must be educated about stress dosing, recognition of crisis, and when to seek emergency care. Alternative Explanations and Limitations Although tuberculosis is a common etiology, it was excluded through imaging and absence of systemic signs. Other causes, such as adrenal metastases or drug-induced suppression, were excluded clinically. A limitation is the absence of AIRE gene testing, which would have definitively confirmed APS I. Additionally, lack of follow-up limits the documentation of future syndrome components such as candidiasis, hypogonadism, or alopecia. Future Directions This case highlights the need for more research into late-onset APS I phenotypes, which may be underdiagnosed. Longitudinal registries of Addison’s patients would help clarify natural history and improve recognition. Furthermore, strategies such as digital health monitoring, structured education, and peer support groups may address the problem of treatment non-adherence in resource-limited settings. In summary, this case challenges the notion of APS I as a purely pediatric disease, demonstrating adult-onset Addison’s disease with hypoparathyroidism. It reinforces the need for comprehensive evaluation, multidisciplinary management, and vigilance regarding patient compliance.

This case illustrates the diagnostic and management challenges of Autoimmune Polyglandular Syndrome Type I presenting in an adult male with Addison’s disease and hypoparathyroidism. Key learning points include the need for heightened suspicion of APS I even in adults, the critical role of biochemical and imaging studies in differentiating autoimmune from infectious etiologies, and the necessity of lifelong hormone replacement therapy. The case emphasizes the importance of patient education and adherence, as non-compliance significantly increases the risk of adrenal crisis and mortality. Academically, the case broadens the clinical spectrum of APS I and supports the inclusion of adult-onset presentations in future diagnostic criteria. For clinical practice, it reinforces the imperative of multidisciplinary management, regular follow-up, and proactive screening for associated endocrinopathies to improve patient outcomes.

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