Editors

JarmoJääskeläinen

Apeced (Autoimmune Polyendocrinopathy - Candidiasis - Ectodermal Dystrophy)

Suspect the syndrome in all children and young adults with one or more of the following, otherwise unexplained symtoms or conditions:
- persistent or recurrent oral candidiasis (picture 1); may also occur in the oesophagus, on the skin and in the nails
  - In mild cases rhagades of the corners of mouth only (picture 2)
- hypoparathyroidism
- Addison's disease.
The first symptom or sign of APECED may be also
- alopecia
- chronic keratoconjunctivitis (symptoms: reddened eyes sensitive to light)
- autoimmune hepatitis
- recurrent fever and flashing erythema and no findings indicative of an infection
- chronic diarrhoea or severe obstipation
- dental enamel hypoplasia of permanent teeth (picture 3)
- pitted nail dystrophy (picture 4)
- pneumonitis.

The prevalence varies between countries and is approximately 1-9 / 1 000 000 http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=3035.
Autosomal recessive inheritance: mutations of both AIRE genes (chromosome 21q22.3)
Occurs in all populations; so far most frequently recognized in people of Finnish (about 100 diagnosed cases in a population of 5.5 million), 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. In Finnish patients, dominant inheritance is very rare.

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.

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

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.

Almost all patients have antibodies against type 1 interferon 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.
Detection of major mutations of the AIRE gene, exome sequencing or a suitable gene panel test may be used as secondary alternative in diagnostics. In the Finnish population, three major mutations (c.769C>T, c.967_979del13 and c.1163_1164insA) cover about 90% of mutations in patients with APECED.
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.

An endocrinologist or paediatric endocrinologist should be consulted in suspected cases, and usually 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.

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.
The disease is associated with an increase in premature mortality.

Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006;91(8):2843-50. [PubMed]
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. [PubMed]
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):. [PubMed]
Borchers J, Pukkala E, Mäkitie O et al. Patients With APECED Have Increased Early Mortality Due to Endocrine Causes, Malignancies and infections. J Clin Endocrinol Metab 2020;105(6). [PubMed]