APECED (autoimmune polyendocrinopathy – candidiasis – ectodermal dystrophy)

Essentials

  • Suspect the disease in all children and young adults with one or more of the following, otherwise unexplained symtoms or conditions:

Epidemiology

  • Around 400 cases have been diagnosed worlwide.
  • Autosomal recessive inheritance: mutations of both AIRE genes (chromosome 21q22.3)
  • Occurs in all populations; so far most frequently recognized in people of Finnish, Sardinian and Iranian Jewish origin
  • Mutations of the AIRE genes in certain regions (that encode amino acids in the regions p.299–340 and p.228) may also cause an autoimmune disease with autosomal dominant inheritance.

Clinical picture

  • The clinical picture and course of the disease are highly variable. Most frequently the first symptoms are sore mouth corners, often together with candidal coatings of the mucosal membranes of the mouth, symptoms of hypocalcaemia (clumsiness, vague tetany, convulsions, often in connection to febrile infection), or weakness, fatigue and weight loss.
  • However, instead of candidiasis, hypoparathyroidism and Addison’s disease, the early clinical picture may be predominated by any other disease component (see table T1), e.g. keratoconjunctivitis, flashing erythema with fever, or autoimmune hepatitis.
  • The first components usually appear before the age of 15 years, but sometimes only in adulthood. New components may develop throughout life.

Table 1. Prevalence (%) of disease components of APECED at ages 10 and 40 years in Finnish series of 91 patients
Component at 10 years at 40 years
Candidiasis in the mouth and/or on the skin 83 100
At least one endocrinopathy 74 100
Hypoparathyroidism 65 87
Addison’s disease 40 81
Diabetes mellitus 3 23
Hypothyroidism 1 21
Ovarian atrophy 69
Male hypogonadism 28
Keratoconjunctivitis 18 22
Pernicious anaemia 3 28
Hepatitis, active or inactive 12 18
Chronic diarrhoea 13 22
Severe obstipation 10 26
Lack of spleen 9 ≥ 19
Tubulointerstitial nephritis 2 ≥ 7
History of flashing erythema with fever 12 14
History of ocular choroiditis ≥ 2 ≥ 8
Alopecia (loss of hair) 16 39
Vitiligo 9 31

Basic disorder

  • In the lack of a functioning AIRE gene, the elimination of autoreactive T-lymphocytes in the thymus does not take place normally; the patient is predisposed to autoimmune destruction of a number of organs. Associated with this, the patient is unable to fend off superficial candida infections.

Important investigations

  • Almost all patients have interferon alpha autoantibodies in their plasma, often already before the first disease components appear. This is the primary laboratory investigations when a suspicion of APECED is raised. Its sensitivity and specificity are even better than those of DNA diagnostics.
  • More extensive determination of autoantibodies may reveal an on-going destruction of the adrenal cortex, ovaria and parietal cells of the stomach and is therefore useful in the follow-up of the patients. Antibodies associated with type 1 diabetes and autoimmune thyroiditis are common, but their predictive value is weaker, i.e. they are more common than actual diabetes or hypothyroidism.

Treatment and follow-up

  • An endocrinologist (possibly specialized in paediatric endocrinology) should be consulted in suspected cases, and he/she is also responsible for the follow-up of the patient. Follow-up and treatment are multi-professional.
  • The possible development of new disease components should be monitored with regular laboratory investigations. In principle, each disease component is treated as if it were an independent disease. The endocrine components and their treatment will, however, affect each other. Common immunological treatment is not available so far.
  • Oral and oesophageal candidiasis must be effectively controlled, because it is carcinogenic. Oral ulceration that does not heal within a week warrants biopsy.

Disease burden

  • The burden varies depending on the clinical picture. A shared burden for all the patients is the awareness that at any time they may develop new, possibly life-threatening (mucosal carcinoma, hepatitis) components of the disease.
  • Endocrinological disturbances, especially hypoparathyroidism, Addison’s disease and diabetes, as well as autoimmune inflammatory bowel diseases, particularly when at least two of these occur in the same patient, require in addition to daily medication strict follow-up and may restrict functional ability.
  • Cosmetic problems (alopecia, vitiligo, abnormalities of the mouth and teeth) may be psychologically demanding.
  • Life expectancy is normal for the majority of the patients, if the quality of follow-up and treatment is good and the patient together with the family learns to take responsibility for it. This may be very problematic especially in the adolescence.

References

1. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006;91(8):2843-50.  [PMID:16684821]

2. Oftedal BE, Hellesen A, Erichsen MM et al. Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases. Immunity 2015;42(6):1185-96.  [PMID:26084028]

3. Ferre EM, Rose SR, Rosenzweig SD et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight 2016;1(13):.  [PMID:27588307]


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