Two new homozygous intron mutations in the AIRE gene in a patient with an atypical course of APECED

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive condition characterized by at least two of the three major clinical symptoms that can be present (hypoparathyroidism, Addison's disease, chronic mucocutaneous candidiasis). The etiology of APECED is directly linked to mutations within the coding region of the AIRE (autoimmune regulator) gene. We present a 20-year-old adolescent, who was followed in our pediatric endocrine outpatient clinic for the last 12 years. After an uneventful pregnancy and postnatal course, from the age of 16 months he suffered on from recurrent pneumonias, sometimes requiring assisted ventilation. At the age of 4 years mucocutaneous candidiasis and a psychomotor retardation was documented. At 8 9/12 years the boy developed Addisons disease and one-year later a malabsorption syndrome with fatty voluminous stools. In the following years the boy presented more signs of the APECED phenotype, including pernicious anemia, hypoparathyroidism and ectodermal dystrophies such as vitiligo, alopecia, keratopathy and nail dystrophy. Further he developed symptoms not considered to be part of the disease like unexplained short stature, clubbing of fingers and psychomotor retardation. Analysis of the complete coding sequence of the AIRE gene revealed two novel mutations. In intron 5 a homozygous nucleotid exchange at position +14 (C to T) was found and in intron 13 a homozygous nucleotid change at position -2 (A to G) was identified. Especially the transition of the acceptor splicing site in intron 13 is suspected to produce a skip of exon 13. The mother of the consanguineous patient is heterozygous for both mutations, blood of the father is not available. Since a second underlying disease was not found, we hypothize that the atypical symptoms of the patient are caused by a putative truncated translation product.