PMON115 Long term follow-up of patient with gigantism harboring an exon 2 deletion in the AIP gene

Abstract

Abstract Introduction Pituitary gigantism is a rare endocrinopathy that has been linked to inactivating germline mutations in AIP gene with a prevalence of 30%. AIP is a tumor suppressor gene associated with high predisposition to pituitary adenoma. Thus, the genetic screening of AIP mutations has been recommended to cases with sporadic young-onset pituitary adenoma. Even with a phenotype suggesting gigantism the diagnosis could be delayed, making the treatment more complex, due the large pituitary tumor. Here we describe a giant patient with deletion of exon 2 of the AIP gene detected by Multiplex Ligation-dependent Probe Amplification assay (MLPA) 33 years after the diagnosis. Material and Methods In 1988, a 13-year-old afro-descendent boy with no history of familial pituitary adenoma, presented with seizures and tall stature. On exam he showed signs of gigantism and hypopituitarism: height 2.05 m (SD: + 7), target height was 1.65 (SD: -1), weight 75 kg (SD: + 3.2), no signs of puberty and impaired vision field. Basal GH was > 40 ng/mL, IGF-1: > 1200 ng/mL (ULN: +4). MRI revealed an invasive macroadenoma (Knosp IV). He underwent pituitary surgery twice with an adenoma GH/PRL positive with no remission. He did not respond to the treatment with somatostatin receptor analogue presenting remission only after radiotherapy, developing permanent deficiency of ACTH/TSH/LH/FSH/GH and diabetes insipidus. Peripheral blood was collected to genetic analysis in 2021. Results The genetic analysis supported by Sanger sequencing resulted negative to pathogenic germline variants in intron-exon frontiers and coding areas of the AIP and MEN1 genes. Thus, MLPA was performed using the SALSA MLPA kit P244 designed to detect large deletions or amplifications in AIP, CDKN1B and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). Once the exon 2 heterozygous deletion from the AIP gene was found via MLPA the confirmation was carried out through long-range PCR covering full open reading frame of the AIP gene. By agarose gel electrophoresis, the presence of two bands of different sizes confirmed this deletion. Discussion More than 130 AIP mutations have been described over the last decade and most of them, 70% generate truncated proteins (including insertions/deletions). However, gross AIP deletions were exceptionally reported so far (13 cases only: 11 had gigantism or acromegaly). Despite rarity, the present case reinforces the importance of investigate large AIP deletions, especially in gigantism. Cases harboring AIP mutations are associated with more aggressive tumors, lesser response to somatostatin receptor analogues needing, frequently, of an extensive multidisciplinary approach. It was also suggested that cases harboring truncated AIP mutations may develop pituitary adenoma in younger age than patients with non-truncated mutations. Thus, the characterization of genotype could help to refine making-decision on management of this complex disorder in an earlier stage avoiding multimodal treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.