ECE2015 Guided Posters Adrenal (8 abstracts)
Clinical and genetic findings of an Italian series of patients with ACTH resistance syndromes
Marco Bonomi 1, , Paolo Duminuco 2 , Domenico Vladimiro Libri 2 , Valeria Vezzoli 2 , Alessandro Salvatoni 3 , Valentino Cherubini 4 , Anna Ficcadenti 5 , Giorgio Radetti 6 , Antonella Meloni 7 & Luca Persani 1,
1Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milano, Italy; 2Divisione di Medicina ad Indirizzo Endocrino–Metabolico e Lab di Ricerche Endocrino–Metaboliche, IRCCS Istituto Auxologico Italiano, Milano, Italy; 3Dipartimento di Pediatria, Università dell’Insubria, Ospedale Filippo del Ponte, Varese, Italy; 4Ospedali Riuniti ‘Umberto I – G.M.Lancisi – G.Salesi’, SC Diabetologia Pediatrica, Ancona, Italy; 5Clinica Pediatrica, Università Politecnica delle Marche, Ancona, Italy; 6Ospedale Regionale di Bolzano, UO Pediatria, Bolzano, Italy; 7UO DH II Clinica Pediatrica, Ospedale Microcitemico, Cagliari, Italy.
ACTH resistance syndromes (ARS) are rare, severe and heterogeneous diseases that include either familial glucocorticoid deficiency (FDG) or Allgrove syndrome (AS). FDG is a rare autosomal recessive disorder resulting from mutation in genes encoding either the ACTH-receptor (ACTHR) in FDG1, or its accessory protein MRAP, in FDG2. AS is characterized by adrenal insufficiency due to ACTH resistance, alacrimia, and achalasia secondary to mutations in the AAAS gene, which encodes a protein called ALADIN. Here we describe the clinical and genetic findings in six males with ARS (age at diagnosis: 2 days–14 years). Seizures, recurrent infection, hypoglycaemia, skin, and mucosal hyperpigmentation were common features, while achalasia and alacrimia were present in three patients, indicating AS. The genetic analyses of the three FGD patients were negative in one, but revealed a known causative heterozygous intronic variation (IVS 3ds+3insT) in MRAP in another one; and a known causative homozygous variation in ACTHR (p.Y254C), in association with two novel heterozygous non-synonimous SNPs in exons 2 and 3 of the MRAP, in the last patient. The molecular analysis of the three patients with AS showed: one known causative nonsense homozygous mutation (p.R194X) in the ALADIN gene in two brothers; in the last AS case, a novel homozygous intronic variant (IVS11–2) inherited from the two non-consanguineous heterozygous parents, both from Sardinia. This patient presented a congenital twisted feet and achalasia already at birth, but came to the diagnosis of AS only at the age of 14 years. The molecular characterisation of this novel variant, based on the mRNA analysis, demonstrated that it is affecting the splicing site of the exon 11 in ALADIN gene causing the formation of an aberrant protein with a premature stop codon. In conclusion, the frequency of FDG and AS in this short Italian series is similar, and we described a novel IVS in the Aladin gene that is causative for AS.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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