ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 11 P62

APECED (Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy) syndrome with atypical or incomplete presentation: report of 4 cases with AIRE mutations in heterozygosity

C Mazza1, I Sparapani2, L Costa2, S Zanola2, M Filisetti2, A Pilotta2, F Lombardi3, MI Spagnuolo3, G Valerio3, A Franzese3, G Radetti4 & F Buzi2

1Institute of Molecular Medicine ‘A. Nocivelli’, Brescia, Italy; 2Department of Paediatrics, University of Brescia, Brescia, Italy; 3Department of Paediatrics, University of Naples, Naples, Italy; 4Department of Paediatrics, General Hospital, Bolzano, Italy.

APECED is an autosomal – recessive syndrome defined by two of the following conditions: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP) or Addison disease (AD). Other autoimmune endocrine or non-endocrine conditions may be associated, like thyroiditis, celiac disease, alopecia and nail dystrophy. APECED is caused by mutations in the AIRE gene, mapping to 21q22.3. We report here 4 cases with atypical or incomplete presentation, that have been genetically defined and found to show AIRE mutations in heterozygosity. DR presented at 7 years with hypocalcaemia and undetectable PTH levels, and HP was diagnosed. ST presented at 14 years for alopecia aerata and pitted nail dystrophy and goitre. Thyroid function was normal in the presence of thyroid antibodies (Ab). AP at 7 years was found to have celiac disease. At 13 years developed type 1 diabetes, followed by euthyroid thyroiditis. At 15 yr, she also showed oral and vaginal candidiasis. DC was 4.3 when presented with hyponatraemia, hyperkalaemia, metabolic acidosis, low serum cortisol and elevated plasma ACTH. He was diagnosed AD, confirmed by adrenal Abs. Genetic analysis was by PCR amplification and direct sequencing of AIRE by ABI Prism 3130 sequencer (Applied Biosystem), and revealed: a typical mutation (R257X) on a single allele in DR; a novel heterozygous mutation (V484M) involving one of the zinc fingers (ZF) of the 2nd plant homeodomain (PHD) of the protein in ST; a novel heterozygous mutation (R316G) involving one of the ZF of the 1st PHD in AP; a novel heterozygous mutation (T441M), involving the ZF of the 2nd PHD in DC. The 3 latter mutations reside in transcription sites (ZFs of PHDs) and are likely to affect the AIRE protein function. These cases underline the importance of performing genetic analysis of AIRE in the presence of even one only major condition or minor signs and symptoms of APECED.