APECED & APS-1

Candida infections develop early in life and are often the first symptom to appear, usually in the form of oral candidiasis, commonly known as thrush. Thrush can range in severity from redness and soreness at the corners of the mouth to whole mouth involvement; it can interfere with eating spicy or acidic foods. Chronic inflammation of the mouth and throat makes some individuals with APECED (approximately 5%) susceptible to developing oral squamous cell carcinoma, a type of cancer. Candidiasis can also affect the esophageal, intestinal, or vaginal mucosal surfaces, as well as the nails. People with APECED are not susceptible to developing systemic Candida infections that would involve the blood or deep organs, like the liver, lungs, or bone. 

In addition to oral candidiasis, individuals with APECED commonly have reduced tooth enamel (the outer covering of the teeth) beginning early in childhood, resulting in frequent cavities and need for dental procedures. Other individuals may develop symptoms of dry mouth and decreased salivary production with or without accompanying dry eye symptoms.

A characteristic rash called an urticarial eruption typically appears as early as the first year of life and before the age of 3 in the majority of North American individuals with APECED. The rash appears as many individual, pink-red spots on the trunk of the body, face, arms, and legs. The spots may be flat or raised and they are sometimes accompanied by a high fever. The rash may recur many times over months to years before resolving without any treatment. No apparent trigger, such as a viral illness or prior vaccination, is identified in the majority of individuals. Other skin manifestations may include loss of skin pigmentation (vitiligo) and hair loss (alopecia). Abnormal nail growth called nail dystrophy may also occur in the absence of nail fungal infection.

As the acronym APECED indicates, endocrine problems are a very common feature of the syndrome. Hypoparathyroidism and adrenal insufficiency are the most frequent endocrine manifestations. Hypoparathyroidism typically occurs earlier than any other endocrinopathy and causes low calcium levels in the blood resulting in muscle cramping and seizures if not treated. 

Adrenal insufficiency causes low blood pressure, called hypotension, which can lead to adrenal crisis, a dangerous and potentially fatal complication. Salt craving is an early clinical observation in individuals with subclinical adrenal insufficiency. Darkening of the skin can also be seen. 

Other endocrine manifestations, which occur less often than hypoparathyroidism and adrenal insufficiency, include hypothyroidism, growth hormone deficiency, and ovarian failure or testicular failure that may affect puberty and childbearing. Type-1 diabetes is a relatively uncommon feature of APECED.

There are several intra-abdominal manifestations seen in APECED. The most common are intestinal symptoms presenting as chronic diarrhea, chronic constipation, or an alternating pattern of both, frequently causing malabsorption of fat. This causes abdominal bloating, distention, and excessive flatulence. The cause of fat malabsorption is indefinable in most individuals, but in a small proportion of them, it is caused by exocrine pancreatic insufficiency, a condition where there is a lack of or decreased pancreatic enzymes that are important for digestion and responds clinically to pancreatic enzyme replacement therapy. 

Inflammation of the liver (autoimmune hepatitis), the stomach (autoimmune gastritis), and, rarely, the small intestines (autoimmune enteritis) may occur and are diagnosed by biopsy where cells are seen invading the corresponding tissue. Lastly, some individuals with APECED develop pernicious anemia that is caused by an inability to absorb vitamin B12 in the gut. Autoimmune gastritis and B12 deficiency increase the risk for the development of gastric cancer in individuals with APECED.

Autoimmunity affecting the lung and causing inflammation (pneumonitis) presents with symptoms of chronic cough (particularly prolonged after a viral illness and often occurring at night) and shortness of breath. Often, pneumonitis in APECED is misdiagnosed as asthma or bronchitis. Without immunosuppressive treatment, prolonged inflammation can cause damage to the airways (called bronchiectasis) and lead to recurrent bacterial respiratory infections and eventual respiratory failure. Inflammation is visible on computed tomography (CT) of the chest and in lung tissue biopsies. 

Autoimmune attack against the spleen over time reduces its size and function. This makes the immune system weak at fighting certain types of bacteria, such as Streptococcus pneumoniae, and can result in serious bloodstream infections. Those individuals without a spleen require vaccinations against pneumococcus and meningococcus and prophylactic antibiotic therapy to protect against these bacteria. 

There are several eye problems that may occur in individuals with APECED. Inflammation affecting the cornea and conjunctiva (keratoconjunctivitis) is the most common. Other individuals may develop inflammation of the retina (retinitis) and/or along the eyelid (blepharitis). 

The most common kidney problem in APECED results from taking calcium supplementation for hypoparathyroidism for many years. Calcium is excreted from the blood into the kidneys, and it can accumulate in the kidney tissue and form kidney stones (nephrolithiasis). Rarely (less than 10%), inflammation can occur in the tubules of the kidneys (tubulointerstitial nephritis); if this condition is untreated, it may result in kidney failure.