Immunology · Year 2 · from Immunology

Case 3: Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1/APECED)

Patient Demographics

• Age: 9 years old
• Sex: Female
• Ethnicity: Finnish descent

Chief Complaint

Muscle cramps and recurrent oral thrush

History of Present Illness

A 9-year-old girl of Finnish descent presents with hand and foot muscle cramping and tingling for 2 weeks. She has a history of chronic oral thrush since age 3 that has been difficult to control. Her parents note that she has also developed patchy hair loss over the past year.

Past Medical History

• Chronic mucocutaneous candidiasis since age 3 (oral, esophageal, nail involvement)
• Alopecia areata starting at age 8
• Dental enamel hypoplasia (noted by dentist)

Family History

• Parents are first cousins (consanguineous)
• No known family history of autoimmune disease

Physical Examination

• General: Well-appearing girl
• Vital Signs: Normal
• HEENT: White plaques on tongue and buccal mucosa (oral candidiasis); dental enamel defects
• Skin: Patches of alopecia on scalp (alopecia areata pattern)
• Nails: Thickened, dystrophic fingernails (onychomycosis)
• Neurological: Positive Chvostek sign (facial muscle twitch with tapping over facial nerve); positive Trousseau sign (carpopedal spasm with BP cuff inflation)

Laboratory Workup

Clinical Image

Image showing chronic oral candidiasis, one of the characteristic features of APECED/APS-1. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Oral_thrush_adult.jpg). Licensed under CC BY-SA 4.0.

Diagnosis

Autoimmune Polyendocrine Syndrome Type 1 (APS-1)/APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) due to AIRE gene mutation.

Discussion

APS-1/APECED is caused by autosomal recessive mutations in AIRE (Autoimmune Regulator), a transcription factor critical for central T cell tolerance:

AIRE's normal function:

• Expressed in medullary thymic epithelial cells
• Drives expression of tissue-restricted antigens (insulin, thyroglobulin, etc.) in the thymus
• Allows deletion of T cells reactive against these peripheral tissue antigens
• Without AIRE, autoreactive T cells escape to the periphery

Classic diagnostic triad (2 of 3 required):

1. Chronic mucocutaneous candidiasis (CMC) - usually first manifestation, often by age 5
2. Hypoparathyroidism - causes hypocalcemia (present in this case)
3. Adrenal insufficiency - often develops later

Additional manifestations:

• Ectodermal dystrophy: Dental enamel hypoplasia, nail dystrophy
• Alopecia areata or totalis
• Vitiligo
• Autoimmune hepatitis
• Type 1 diabetes
• Autoimmune thyroiditis
• Pernicious anemia
• Autoimmune ovarian/testicular failure

Why does AIRE deficiency cause candidiasis?

• Patients develop neutralizing autoantibodies against IL-17A, IL-17F, and IL-22
• These cytokines are essential for mucosal defense against Candida
• The autoantibodies functionally impair Th17-mediated immunity
• This case demonstrates positive anti-IL-17 and anti-IL-22 antibodies

Epidemiology:

• More common in Finnish, Iranian Jewish, and Sardinian populations
• Autosomal recessive inheritance (consanguinity is a risk factor)

Treatment

1. Hypoparathyroidism: Calcium and calcitriol (active vitamin D) supplementation
2. Chronic mucocutaneous candidiasis: Long-term antifungal therapy (fluconazole, itraconazole)
3. Surveillance for additional autoimmune manifestations:

• Annual screening for adrenal insufficiency (cortisol, ACTH)
• Monitor for diabetes, thyroid disease, hepatitis

1. Hormone replacement: As needed for each endocrinopathy
2. Genetic counseling: For autosomal recessive inheritance
3. No disease-modifying therapy available: Treatment is supportive and directed at individual manifestations

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