Polyglandular Autoimmune Syndrome Type I

Etiology

Autoimmune polyglandular syndrome type 1 is due to mutations in the autoimmune regulatory (AIRE) gene,  located in the short arm of chromosome 21. Inheritance of APS-1 is in an autosomal recessive manner.  The AIRE gene codes for a protein named autoimmune regulator. There are over ver 60 recognized different mutations in the AIRE gene, which might explain the variability in presentation and natural course of the disease. Over 95% of patients with APS-1 have one of the two most common mutations, which are arginine substitution at position 257 and 13 base pair deletion in exon 8.[2][3]

Epidemiology

Autoimmune polyglandular syndrome type 1 is a rare disorder affecting 1 in every 2 to 3 million newborns. The prevalence in Norway is 1 per 90000 and in Ireland is 1 per 130000, but it is more common in the Sardinians and Iranian Jews with a prevalence of 1 per 14000 and 1 per 9000, respectively. There is no discernable gender preponderance. The age of the first manifestation also differs widely ranging from 0.2 to 18 years.[4][5][1]

Pathophysiology

Autoimmune polyglandular syndrome type 1 is due to decreased central tolerance resulting in autoimmunity. Since the discovery of the AIRE gene, there have been considerable advances in the understanding of this disorder. AIRE is expressed in the thymic medullary cells and encodes for a DNA binding protein namely, autoimmune regulator. The hypothesis is that this protein helps in regulating the thymic expression of various tissue-specific antigens leading to the elimination of autoreactive T cells. In its absence, autoreactive cells escape the negative selection and get released into the circulation.[3]

History and Physical

The clinical properties of autoimmune polyglandular syndrome type 1 are variable, even between siblings who have the same mutation. The most common initial manifestation is chronic mucocutaneous candidiasis presenting at a median age of 1.7 to 3 years. Hypoparathyroidism is the second component of the triad to appear; it appears earlier in females as compared to males. Addison’s disease typically presents 5 years after hypoparathyroidism.[6]

Mucocutaneous candidiasis: It is the most prevalent manifestation of APS-1, mostly affecting the oral cavity; however, it may also affect the nails first. Clinically, oral candidiasis presents as redness and ulceration at the angle of the mouth. It may also manifest as white or gray plaques and hyperkeratosis. Rarely,  leukoplakic nodules or patches are present, which could be potentially precancerous. Esophageal candidiasis presents with chest pain and odynophagia. Recurrent infections can lead to esophageal strictures which may need dilation. Rarely, genital and intestinal candidiasis can occur. There are also reports of squamous cell cancers of the oral cavity and esophagus in association with APS-2 which could have been induced by chronic candidiasis.[6][7][8]

Hypoparathyroidism: It is the second most prevalent feature of APS-1 with about 33% presenting at age 5 years; it is more prevalent in females. Clinically, it presents as numbness or tingling in the perioral area and fingertips, muscle cramps and seizures. Chvostek and Trousseau signs are indicators of neuromuscular irritability and can be positive. Chvostek's sign is elicited by gently tapping the angle of the jaw which would cause twitching of the lips. Trousseau sign is elicited by inflating a blood pressure cuff around the shoulder to a pressure higher than systolic blood pressure for 3 minutes which should lead to flexion of the wrist and metacarpophalangeal joints and extension of the interphalangeal joints.[9][6]

Adrenal insufficiency: It is the last of the triad to appear and manifests between 5-15 years. It presents as fatigue, abdominal pain, dizziness, weight loss, and hyperpigmentation. The physical exam may show hyperpigmentation of knuckles, joints, oral mucosa and scars. In females, there may be an absence of axillary and pubic hair because of the lack of production of adrenal androgens.[10][11]

Other manifestations of APS-1 include:

Alopecia is the most common dermatological manifestation and typically appears around 40 years of age. The presentation varies widely from patchy alopecia to alopecia totalis. Alopecia correlates with the levels of anti-tyrosine hydroxylase antibodies.[12]

Keratitis presents in about a quarter of the patients with APS-1. It appears around the age of 20 years. Its characteristics include decreased lacrimation, photophobia, and blepharospasm. Treatment is with topical glucocorticoids and cyclosporine. Topical vitamin A may prevent corneal ulcerations.[9][13]

Gastritis and pernicious anemia may also present in association with APS-1. Anti-intrinsic factor antibodies are present which hinder the absorption of vitamin B12 leading to megaloblastic anemia. Management involves supplementation of vitamin B12.

There are reports of asplenia or absence of a spleen in patients with 20% of adults and 10% of children with APS-1. Howell-Jolly bodies are visible in the erythrocytes. Abdominal CT should be done to confirm the diagnosis of asplenia if Howell-Jolly bodies are detected. Asplenia makes the patient susceptible to infections by encapsulated organisms; therefore vaccinations against pneumococcus, meningococcus, and Hemophilus influenza are necessary.[9]

Type 1 diabetes mellitus may present in patients aged 30 to 50 years. Diagnosis is by detecting fasting blood sugars greater than 126, or hemoglobin A1c of >6.5, or a random blood sugar of greater than 200 with symptoms of polyuria, polydipsia, or weight loss. Insulin antibodies or IA-2 antibodies may be detected.[14]

Primary hypogonadism may be seen late in the disease in patients with anti-side-chain cleavage enzyme (SCC) antibodies. The clinical features include fatigue, muscle loss, and decreased libido. Diagnosis is by low measured testosterone in conjunction with a high luteinizing hormone (LH). Treatment includes testosterone supplementations. Occasionally, isolated azoospermia may also accompany the hypogonadism.[14]

Pituitary failure may be seen early in the course of the disease secondary to pituitary antibodies against tudor domain protein. Deficiencies of growth hormone, gonadotropin, or ACTH deficiency.[6]

Autoimmune hepatitis is present in 20% of patients with APS-1. It does not appear after the age of 20 years. It characteristically presents with elevated levels of AST and ALT. Treatment involves immunosuppression with the use of glucocorticoids.[15][16]

Autoimmune hypothyroidism or Hashimoto hypothyroidism, characterized by the presence of anti-thyroid peroxidase (TPO) antibodies anti-thyroglobulin antibodies may also be present. Clinical features include weight gain, loss of appetite, cold intolerance, and constipation. Diagnosis is by measuring thyroid-stimulating hormone (TSH) and thyroxine (T4) levels.

Enamel dysplasia is observable in 75% of Finnish patients. In milder forms, alternate bands of intact enamel and dysplastic enamel with observable pits and fissures present, while in more severe forms the entire enamel is involved. Prompt evaluation by a dentist is warranted, and in most instances extensive dental treatment is necessary. Due to the wearing of teeth and resulting malocclusion, temporomandibular joint pain can occur.[17][18]

Vitiligo may be the initial manifestation and is a clinical feature in 33% of patients with APS-1. The degree of skin involvement is variable, and it can manifest as isolated spots or involving the whole skin. It correlates with the antibodies against SOX9 and SOX10. Unfortunately, there is no effective therapy against vitiligo.[9]

Evaluation

The diagnosis of autoimmune polyglandular syndrome type 1 is made by diagnosing at least two of the three major components or having mutations in both the AIRE genes. However, it can be difficult because of the rarity and varied presentation of the disorder. However, it is essential to make the diagnosis as it helps anticipate or discover the presence of other associated disorders. Genetic testing may help families make informed decisions about family planning.

Diagnostic criteria for autoimmune polyglandular syndrome- 1 

Definite diagnosis:

1. Presence of two of the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison disease.
2. One of the above triad plus a sibling with proven APS-1
3. Known disease-causing mutations in the AIRE gene.

Probable diagnosis:

1. Presence of one of the triad (before 30 years) along with one of the following components chronic diarrhea, keratitis, periodic rash with fever, severe constipation, autoimmune hepatitis, vitiligo, alopecia, and enamel hypoplasia.
2. Any one of the above triad and anti-interferon antibodies
3. Any one of the above triad and antibodies against NALP5, aromatic L-amino acid decarboxylase (AADC), tryptophan hydroxylase (TPH), or tyrosine hydroxylase (TH)[6]

Treatment / Management

Treatment with APS-1 is multi-faceted and needs collaboration among different specialties.

Mucocutaneous candidiasis: Oral candidiasis treatment is with two topical polyene antifungals for 4-6 weeks. Recurrent oral candidiasis treatment is with weekly pulse prophylaxis with a polyene antifungal given every 3 weeks. Therapy for infection of the angle of the mouth is with natamycin or chlorhexidine gel. Vaginal candidiasis should have treatment with fluconazole. Nail infection can be challenging to treat and may require a referral to a podiatrist.

Hypoparathyroidism: The objective of treatment is to maintain normocalcemia. Acute hypocalcemia warrants intravenous supplementation of calcium gluconate or calcium chloride. In nonacute circumstances, oral calcium and vitamin D supplementation may suffice to maintain normocalcemia. The goal is to maintain calcium in the low normal range.  Recombinant PTH may be an option in cases where conventional treatment fails to normalize the calcium levels.

Adrenal insufficiency: The mainstay of treatment is glucocorticoid supplementation with hydrocortisone. The recommended dose is 10 mg in the morning and 5 mg around 3:00 to 4:00 PM. In cases of malabsorption, higher doses of hydrocortisone may be necessary.  Fludrocortisone (0.05 to 2 mg) may be used to replace mineralocorticoids; however, sensitivity varies among individuals. Dosing will require titration to maintain normokalemia and prevent pedal edema. All patients with adrenal insufficiency should wear an alert bracelet.[6]

Differential Diagnosis

• Chromosomal disorder

• Congenital rubella 

• Hemochromatosis

• Hypogonadism 

• Kearns-Sayre syndrome 

• Wolfram syndrome