Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome (autoimmune polyglandular syndrome). It causes the dysfunction of multiple

endocrine gland The endocrine system is a network of glands and organs located throughout the body. Along with the nervous system, it makes the neuroendocrine system, which controls and regulates many of the body's functions. Endocrine glands are ductless gland ...

s due to

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...

. It is a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

, inherited in autosomal

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

fashion due to a defect in the ''AIRE'' gene (autoimmune regulator), which is located on

chromosome 21 Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 46.7 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cell ...

and normally confers

immune tolerance Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specif ...

Signs and symptoms

APS-1 tends to cause severe symptoms. These are present from early in life, usually around 3.5 years of age. Common symptoms of APS-1 include: * Chronic mucocutaneous candidiasis. *

Hypoparathyroidism Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary m ...

. *

Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adr ...

. * Ectodermal dystrophy (skin, dental enamel, and nails). APS-1 may also cause: * Autoimmune hepatitis. *

Hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

. *

Vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...

. *

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

. *

Malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a varie ...

. *

Pernicious anemia Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of Vitamin B12, vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are Fatigue, feeling tired and weak. Other ...

. *

Cataract A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...

. * Cerebellar ataxia.

Cause

Human male karyotpe high resolution - Chromosome 21 cropped

APS-1 is caused by a mutation in the ''AIRE'' gene, encoding a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

called autoimmune regulator. This is found on the 21q22.3

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

location, hence

. The ''AIRE'' gene may be affected by any of at least 186

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

. APS-1 may be inherited in an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

manner. Different mutations are more common in different geographic regions. R139X is a common mutation in

Sardinia Sardinia ( ; ; ) is the Mediterranean islands#By area, second-largest island in the Mediterranean Sea, after Sicily, and one of the Regions of Italy, twenty regions of Italy. It is located west of the Italian Peninsula, north of Tunisia an ...

. R257* is a common mutation in

Finland Finland, officially the Republic of Finland, is a Nordic country in Northern Europe. It borders Sweden to the northwest, Norway to the north, and Russia to the east, with the Gulf of Bothnia to the west and the Gulf of Finland to the south, ...

. Both of these mutations are nonsense mutations: the asterisk and the "X" both indicate a

stop codon In molecular biology, a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the additio ...

. A 13-base-pair deletion in the ''AIRE'' gene, c.967-979del13bp, has been identified in APS-1 patients in

Norway Norway, officially the Kingdom of Norway, is a Nordic countries, Nordic country located on the Scandinavian Peninsula in Northern Europe. The remote Arctic island of Jan Mayen and the archipelago of Svalbard also form part of the Kingdom of ...

Britain Britain most often refers to: * Great Britain, a large island comprising the countries of England, Scotland and Wales * The United Kingdom of Great Britain and Northern Ireland, a sovereign state in Europe comprising Great Britain and the north-eas ...

and

North America North America is a continent in the Northern Hemisphere, Northern and Western Hemisphere, Western hemispheres. North America is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South Ameri ...

Pathophysiology

APS-1 is due to problems with

. APS-1 causes considerable reactions with both interferon omega and interferon alpha. There may also be a reaction against interleukin 22. This leads to damage to endocrine organs. Common problems include

hypercalcaemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defin ...

and nephrocalcinosis (due to a lack of

calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...

from the

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

), and pituitary problems (such as

growth hormone deficiency Growth hormone deficiency (GHD), or hyposomatotropism, is a medical condition resulting from not enough growth hormone (GH). Generally the most noticeable symptom is that an individual attains a short height. Newborns may also present low blood ...

). Antibodies against NLRP5 may lead to

hypoparathyroidism Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary m ...

Diagnosis

Diagnosis of APS-1 is based on a number of tests, including

endoscopy An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...

, a

CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

, a

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...

(with histological testing), and serum

endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...

autoantibody screening.

Treatment

Autoimmune polyendocrine syndrome type 1 treatment is based on the symptoms that are presented by the affected individual. Treatments may involve

hormone therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are hormonal therap ...

, systemic

antifungal An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...

treatments, and

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

. The JAK-STAT inhibitor

ruxolitinib Ruxolitinib (sold under the brand names Jakafi and Jakavi among others, and as Opzelura in cream form) is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the b ...

is being investigated as a treatment specifically for its normalizing effect on

interferon-gamma Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...

History

APS-1 may also be known as autoimmunity endocrinopathy candidiasis ectodermal dystrophy / dysplasia (APECED), autoimmune polyglandular syndrome type 1, Whitaker syndrome, or candidiasis-hypoparathyroidism-Addison's disease syndrome.

References

External links

PubMed
{{Transcription factor deficiencies Endocrine diseases Autoimmune diseases Transcription factor deficiencies Syndromes