Autoimmune polyendocrinopathy type 1 (ORPHA:3453)
A rare, genetic, disease that manifests in childhood or early adolescence with a combination of chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal failure.
Epidemiology
It is a rare disease that is more common in populations with higher rates of consanguineous marriage and, because of a founder effect, in Finland where the prevalence is estimated at 1/25,000. In the north-west of France the prevalence is estimated at 1/500,000.
Clinical description
The first manifestation of the disease (usually candidiasis) occurs in childhood with other manifestations appearing progressively. Candidiasis affects particularly the mucosa of the mouth, nails and, more rarely, the genitals, and rarely causes cutaneous effects. The most common autoimmune endocrine involvement is hypoparathyroidism (79-96% of cases). Adrenal failure most often manifests with concurrent mineralocorticoid and glucocorticoid deficiency (78% of cases). Ovarian failure is possible. Diabetes type 1, autoimmune thyroiditis, and lymphocytic hypophysitis are rarer. Other auto-immune manifestations are common: intestinal malabsorption, atrophic gastritis, autoimmune hepatitis, alopecia, vitiligo, hypoplasia of dental enamel, ungual dystrophy, keratoconjunctivitis, and rheumatologic, bony, muscular, renal, bronchiol and hematologic impairments. Splenic atrophy increases the likelihood for severe infections. There is high phenotypic variability, sometimes within the same family, and the number of manifestations is very variable, ranging from 1 to 10.
Etiology
The disease is caused by mutations of the AIRE gene (21q22.3) coding for the AIRE transcription factor, which is involved in immune tolerance mechanisms and contributes to the negative selection of autoreactive T lymphocytes in the thymus, lymph nodes and spleen.
Diagnostic methods
Diagnosis is based on the presence of at least two of the three following pathologies: mucocutaneous candidiasis, hypoparathyroidism and adrenal failure. In cases where one of the patient's siblings is affected, one of the three criteria is sufficient for initial diagnosis, which can then be confirmed by molecular analysis. The presence of a litany of antibodies, specifically organ antibodies (sometimes forewarning of a visceral attack) or more general antibodies (anti-interferon AC) can support the diagnosis.
Differential diagnosis
Differential diagnoses include IPEX syndrome and, principally, autoimmune polyendocrinopathy type 2 (see these terms).
Genetic counseling
Transmission is autosomal recessive. Although prenatal diagnosis is not recommended, genetic counseling should be offered.
Management and treatment
Management is essentially symptomatic. Hormone replacement is used to treat endocrine disorders. A long course of oral systemic antifungal treatment is effective to treat candidiasis, although some patients remain resistant. Immunosuppressive treatment is recommended for cases with autoimmune hepatitis or with severe malabsorption.
Prognosis
The prognosis is variable. The more early the manifestations appear, the more numerous the organs involved. The prognosis can be threatened by: oral or esophageal squamous cell carcinoma, sepsis, fulminant hepatitis, renal failure due to interstitial nephritis or bronchial involvement. On average patients live into their forties, but this varies considerably between patients depending on the severity of disorders.

                            Last update: 
                            February 2009


                            - Expert reviewer(s): 
                            Dr Emmanuelle PROUST-LEMOINE  - Pr Jean-Louis WEMEAU