Polyglandular Autoimmune Syndrome Type I

What is Polyglandular Autoimmune Syndrome Type I?

Autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a type of autoimmune disease where the body’s immune system mistakenly attacks its own cells and organs. APS-1 is specifically marked by three conditions happening together: hypoparathyroidism (where the parathyroid glands in the neck don’t produce enough parathyroid hormone), Addison disease (which affects the body’s ability to regulate blood sugar and salt), and chronic mucocutaneous candidiasis (a type of yeast infection affecting the skin, nails, and mucous membranes).

This syndrome results from mutations or changes in a gene called the autoimmune regulatory gene (AIRE). To date, about 60 different mutations have been identified. However, due to its rarity and the wide range of symptoms it presents, APS-1 might be underdiagnosed.

Besides the three conditions mentioned, APS-1 can be accompanied by several other autoimmune diseases. Diagnosis is typically done by looking for specific antibodies, substances produced by the body in response to allergens, viruses, or bacteria, against interferon-omega or interferon-alpha, or by identifying disease-causing mutations in the AIRE gene.

Treating this complex disorder requires a team approach that involves various medical specialties, given the multiple organs that can be affected.

What Causes Polyglandular Autoimmune Syndrome Type I?

Autoimmune polyglandular syndrome type 1 is caused by changes or mutations in a gene known as the autoimmune regulatory (AIRE) gene. This gene is located on the short arm (a term to describe a shorter section) of chromosome 21, which is one of the tiny structures that make up our DNA.

This syndrome is passed down in a way known as ‘autosomal recessive’, meaning you need to inherit a defective copy of the gene from both parents to get the disorder. The AIRE gene works by coding a protein called the autoimmune regulator, which helps manage our immune responses.

With over 60 known different mutations in this gene, the symptoms and progression of this disease may vary among patients. However, 95% of patients with this syndrome have one of two most common faults in their AIRE gene. These include a change in the amino acid arginine at a specific position (257) and a deletion of 13 base pairs (elements of DNA) in a particular area (exon 8).

Risk Factors and Frequency for Polyglandular Autoimmune Syndrome Type I

Autoimmune polyglandular syndrome type 1 is a rare condition that affects about 1 in 2 to 3 million newborns worldwide. In some regions, however, this condition is more common. For instance, it occurs in about 1 out of every 90,000 people in Norway, 1 out of 130,000 in Ireland, 1 out of 14,000 in Sardinia, and 1 out of 9,000 among Iranian Jews. Both males and females can be affected equally by this syndrome. The age at which the first symptoms appear can differ considerably, ranging from as young as 0.2 years to as old as 18 years.

Signs and Symptoms of Polyglandular Autoimmune Syndrome Type I

Autoimmune Polyglandular Syndrome Type 1 (APS-1) can present differently even among siblings with the same genetic mutation. Typically, the first sign is chronic mucocutaneous candidiasis, appearing at an age between 1.7 and 3 years. Hypoparathyroidism usually comes next, typically showing up earlier in females. The last element of the triad, Addison’s disease, typically occurs about 5 years after the onset of hypoparathyroidism.

Mucocutaneous candidiasis is the most common sign of APS-1. It mostly affects the mouth, but may also affect the nails first. Symptoms include redness and ulcers around the mouth, white or grey plaques, and sometimes even precancerous nodules or patches. The disease can cause chest pain and difficulty swallowing if it affects the esophagus. In rare cases, it may also lead to the development of oral or esophageal cancers.

Hypoparathyroidism is the second most common feature of APS-1, often presenting as numbness or tingling around the mouth and fingertips, muscle cramps, or seizures. Chvostek and Trousseau signs, which are indicators of neuromuscular irritability may also be present.

Adrenal insufficiency usually appears last, presenting as fatigue, abdominal pain, dizziness, weight loss, and skin darkening. The physical exam may show darker skin on the knuckles, joints, inside of the mouth, and scars.

Alopecia (hair loss), often around 40 years of age.
Keratitis (inflammation of the eye), often around 20 years of age, presenting as decreased tear production, sensitivity to light, and muscle spasms in the eyelid.
Gastritis and pernicious anemia due to the production of antibodies that reduce vitamin B12 absorption.
Asplenia, seen as the absence of a spleen in some cases, increasing susceptibility to certain infections.
Type 1 diabetes, usually in patients aged 30-50 years, diagnosed through fasting blood sugar tests, or hemoglobin A1c tests.
Primary hypogonadism, which may be seen in patients with specific antibodies, presenting as fatigue, muscle loss, and decreased sexual desire.
Pituitary failure may be seen early in the disease, due to antibodies against certain proteins leading to deficiencies.
Autoimmune hepatitis is present in 20% of patients with APS-1, characterised by elevated levels of certain liver enzymes.
Autoimmune hypothyroidism, or Hashimoto hypothyroidism, is characterised by weight gain, loss of appetite, cold intolerance, and constipation.
Enamel dysplasia, observable in some patients, warranting prompt dental examination, leading to extensive dental treatment.
Vitiligo, a skin condition that causes white patches on the skin, is seen in 33% of patients with APS-1.

Testing for Polyglandular Autoimmune Syndrome Type I

Autoimmune polyglandular syndrome type 1 is a rare condition that can be tricky to diagnose because the signs and symptoms can vary greatly. However, it’s important to diagnose this syndrome because it can help doctors look for other associated health problems. Genetic testing also allows families to make informed decisions about family planning.

To diagnose this condition, doctors look for at least two of the three main components of the syndrome or search for mutations in both AIRE genes. The three primary components include long-term skin and mucous membrane infections, hypoparathyroidism (underactive parathyroid glands) or Addison’s disease (adrenal insufficiency).

A definitive diagnosis exists if the individual has:

Two out of the three main components.
One of the three main components, plus a sibling with a proven diagnosis of the syndrome.
Identified mutations in the AIRE gene.

Sometimes, a probable diagnosis is given. This happens when:

One of the primary components exists (before 30 years of age) along with one other specific condition such as chronic diarrhea, keratitis (inflammation of the eye’s cornea), periodic rash with fever, severe constipation, autoimmune hepatitis, vitiligo (loss of skin color in patches), alopecia (hair loss), or enamel hypoplasia (underdeveloped tooth enamel).
Presence of one of the primary components and anti-interferon antibodies, which are antibodies that mistakenly attack proteins in our body needed for immune response.
One of the primary syndrome components is present along with antibodies that attack proteins such as NALP5, aromatic L-amino acid decarboxylase (AADC), tryptophan hydroxylase (TPH), or tyrosine hydroxylase (TH).

Treatment Options for Polyglandular Autoimmune Syndrome Type I

Treatment of APS-1, a type of autoimmune disorder, often requires a team of specialists due to its complex nature. It usually involves dealing with infections caused by yeast-like fungi and hormone imbalances.

One common symptom is oral candidiasis, or thrush, which manifests as a yeast-like fungal infection in the mouth. This is typically treated with antifungal medications applied directly to the mouth for around a month. If the infection comes back, it may be treated with antifungal medication given every three weeks. Infections at the corner of the mouth can be treated with natamycin or chlorhexidine gel. If the candidiasis spreads to the vagina, it can be treated with an antifungal medication called fluconazole. Fungal infections under the nails can be harder to get rid of and may need help from a foot doctor, or a podiatrist.

Another symptom of APS-1 is hypoparathyroidism, which results in unusually low levels of calcium in the blood. Severe cases may require an emergency injection of calcium. For everyday management, taking oral calcium and vitamin D supplements may be enough to keep calcium levels within a healthy range. In certain cases, if usual treatments don’t manage to keep calcium levels in the right range, a medication known as recombinant PTH might be an option.

APS-1 can also lead to adrenal insufficiency, a condition where the adrenal glands don’t produce enough hormones. The main treatment for this involves taking a medication called hydrocortisone, which replaces some of the hormones the body is lacking. The medication is usually taken twice a day. If the body doesn’t absorb this medication properly, a higher dose may be needed. Some people may also need another medication called fludrocortisone to replace hormones called mineralocorticoids, but the exact dose can vary a lot from person to person. To avoid any potential health risks, the dose is adjusted to prevent side effects like swollen feet and to keep blood potassium levels normal. All patients with adrenal insufficiency need to wear a medical alert bracelet in case they need emergency medical help.

The conditions that need to be considered when diagnosing symptoms but have different underlying causes or impacts include:

Chromosomal disorder
Congenital rubella
Hemochromatosis
Hypogonadism
Kearns-Sayre syndrome
Wolfram syndrome

Frequently asked questions

Polyglandular Autoimmune Syndrome Type I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is an autoimmune disease where the body's immune system mistakenly attacks its own cells and organs. It is marked by three conditions happening together: hypoparathyroidism, Addison disease, and chronic mucocutaneous candidiasis.

Polyglandular Autoimmune Syndrome Type I affects about 1 in 2 to 3 million newborns worldwide.

Signs and symptoms of Polyglandular Autoimmune Syndrome Type I (APS-1) include: - Chronic mucocutaneous candidiasis, which is the most common sign of APS-1. It primarily affects the mouth, but can also affect the nails. Symptoms include redness and ulcers around the mouth, white or grey plaques, and in rare cases, precancerous nodules or patches. It may also cause chest pain and difficulty swallowing if it affects the esophagus. - Hypoparathyroidism, which is the second most common feature of APS-1. It often presents as numbness or tingling around the mouth and fingertips, muscle cramps, or seizures. Chvostek and Trousseau signs, which indicate neuromuscular irritability, may also be present. - Addison's disease, which typically occurs about 5 years after the onset of hypoparathyroidism. Symptoms include fatigue, abdominal pain, dizziness, weight loss, and skin darkening. Physical examination may reveal darker skin on the knuckles, joints, inside of the mouth, and scars. Other signs and symptoms of APS-1 may include: - Alopecia (hair loss), often around 40 years of age. - Keratitis (inflammation of the eye), often around 20 years of age, presenting as decreased tear production, sensitivity to light, and muscle spasms in the eyelid. - Gastritis and pernicious anemia due to antibodies that reduce vitamin B12 absorption. - Asplenia, which is the absence of a spleen in some cases, increasing susceptibility to certain infections. - Type 1 diabetes, usually diagnosed in patients aged 30-50 years through fasting blood sugar tests or hemoglobin A1c tests. - Primary hypogonadism, which may be seen in patients with specific antibodies, presenting as fatigue, muscle loss, and decreased sexual desire. - Pituitary failure, which may occur early in the disease due to antibodies against certain proteins leading to deficiencies. - Autoimmune hepatitis, which is present in 20% of patients with APS-1 and is characterized by elevated levels of certain liver enzymes. - Autoimmune hypothyroidism, or Hashimoto hypothyroidism, characterized by weight gain, loss of appetite, cold intolerance, and constipation. - Enamel dysplasia, observable in some patients, warranting prompt dental examination and extensive dental treatment. - Vitiligo, a skin condition that causes white patches on the skin, seen in 33% of patients with APS-1.

Polyglandular Autoimmune Syndrome Type I is caused by changes or mutations in the autoimmune regulatory (AIRE) gene. It is inherited in an autosomal recessive manner, meaning that you need to inherit a defective copy of the gene from both parents to develop the disorder.

The conditions that need to be ruled out when diagnosing Polyglandular Autoimmune Syndrome Type I include: - Chromosomal disorder - Congenital rubella - Hemochromatosis - Hypogonadism - Kearns-Sayre syndrome - Wolfram syndrome

To properly diagnose Polyglandular Autoimmune Syndrome Type I, doctors may order the following tests: - Genetic testing to search for mutations in both AIRE genes - Testing for at least two of the three main components of the syndrome, which include long-term skin and mucous membrane infections, hypoparathyroidism, or Addison's disease - Testing for specific conditions such as chronic diarrhea, keratitis, periodic rash with fever, severe constipation, autoimmune hepatitis, vitiligo, alopecia, or enamel hypoplasia - Testing for antibodies that attack proteins such as NALP5, aromatic L-amino acid decarboxylase (AADC), tryptophan hydroxylase (TPH), or tyrosine hydroxylase (TH) These tests can help doctors make a definitive or probable diagnosis of Polyglandular Autoimmune Syndrome Type I.

Polyglandular Autoimmune Syndrome Type I (APS-1) is treated through a combination of medications and specialized care. The treatment usually involves a team of specialists due to the complex nature of the disorder. APS-1 can cause various symptoms, including oral candidiasis (thrush), hypoparathyroidism, and adrenal insufficiency. Oral candidiasis is typically treated with antifungal medications applied directly to the mouth. In severe cases, an antifungal medication called fluconazole may be used if the infection spreads to the vagina. Hypoparathyroidism is managed by taking oral calcium and vitamin D supplements, and in some cases, recombinant PTH medication may be necessary. Adrenal insufficiency is treated with hydrocortisone medication, which replaces the hormones the body lacks. Some individuals may also require fludrocortisone to replace mineralocorticoids. The dosage of these medications is adjusted based on individual needs to prevent side effects and maintain normal blood potassium levels. It is important for individuals with adrenal insufficiency to wear a medical alert bracelet in case of emergency.

A team of specialists is recommended for the treatment of Polyglandular Autoimmune Syndrome Type I.

Autoimmune Hormones and Body Chemistry