ESPE Abstracts

Introduction: MIRAGE syndrome (Myelodysplasia, Infections, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy, OMIM# 617053), is a congenital disorder caused by heterozygous gain of function mutations in the growth repressor gene SAMD9, inherited autosomal dominantly, although de novo variants are often reported. The syndrome was first described in 2016 and to date various cases have been reported, presenting a wide spectrum of phenotypes.

Patient and Methods: A 46, XY, male, born after 35 weeks of gestation with a birthweight of 1410gr, presented during the neonatal period with adrenal insufficiency due to adrenal hypoplasia and Disorder of Sex Development (DSD)- characterized by hypospadias and bifid scrotum, as well as hypothyroidism. Substitutive treatment with hydrocortisone, fludrocortisone and thyroxine was initiated during the first days of life. He had mild global developmental delay. His postnatal growth was poor and watery diarrhea was often observed during the first four years of life. At the age of 9 years, he displayed hypoalbuminemia with normal renal function and urine analysis demonstrated mild proteinuria without hematuria. Renal biopsy showed focal segmental glomerulosclerosis and treatment with ramipril was initiated. At the same time due to recurrent infections with vomiting, esophageal dysmotility was revealed. Heavy proteinuria, prominent edema due to severe hypoalbuminemia was first noted at age 17 yrs and cyclosporine therapy was initiated. Molecular genetic analysis was initially carried out by Sanger sequencing the NR0B1 and NR5A1 genes, because of the adrenal hypoplasia and the DSD phenotype. Later, further analysis was carried out employing Whole Exome Sequencing (WES) and Sanger sequencing of the patient’s and parents’ DNA was undertaken to verify the mode of inheritance.

Results: WES revealed the presence of a novel variant in the SAMD9 gene (NM_017654) c.137T>C: p.Leu46Ser. This variant is classified as Likely Pathogenic according to ACMG criteria (PM2, PP3 and PS2). Sanger sequencing of the only coding exon of SAMD9 gene confirmed the presence of the variant in the patient, but not in his parents confirming that it is a de novo variant.

Conclusions: Over the course of 17 years our patient exhibited the whole spectrum of Mirage Syndrome: infection (I), growth restriction (R), adrenal hypoplasia (A), genital phenotypes (G) and enteropathy (E) except of Myelodysplasia (M). He reached the age of 17 years and constitutes a paradigm of the success of multidisciplinary management of a syndrome with high mortality rate, even though genetic etiology was achieved only recently.