ESPE Abstracts

MIRAGE syndrome is characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy. It was established in 2016 as a new syndromic disorder caused by a gain-of-function mutation in the SAMD9 gene, which encodes a protein that suppresses cell proliferation. Due to the poor life prognosis, there are few reports on the long-term survival. Therefore, we herein report the clinical course of a 24-year-old male patient with particular focus on endocrinological, genetic and immunological abnormalities. At birth, he had extreme skin pigmentation, hypospadias and a bipartite scrotum. During the neonatal period, he had granulocytopenia, which improved spontaneously after blood transfusion, and cerebral hemorrhaging. At 7 days old, hydrocortisone replacement therapy was started due to adrenal crisis. At 12 years old, allergic purpura developed. At present, he now also has psychomotor retardation, short stature, epilepsy, colon dilation and immature pubertal development. He had been hospitalized 2-3 times annually for adrenal crisis associated with viral or bacterial infections, but the frequency decreased from 20 years old. In 2016, a genetic test revealed a heterozygous Asp769Asn variant in the SAMD9 gene, leading to the diagnosis of MIRAGE syndrome. At 24 years old, we examined his endocrinological condition and re-evaluated his genetic and immunological features. Primary adrenal insufficiency and hypergonadotropic hypogonadism were confirmed on the CRH test, insulin tolerance test and LHRH test. In contrast, GH secretion, the thyroid function, and glucose metabolism were normal. On a genetic re-evaluation using leukocyte-derived DNA, the heterozygous Asp769Asn variant was confirmed as before with an allele frequency of 47%, which suggested the absence of monosomy 7 or UPD7. A rare variant, Cys420Arg, was simultaneously detected with an allele frequency of 35%. This variant was present in 2% at 3 years old and 17% at 18 years old. Expression experiments revealed that Cys420Arg is a loss-of-function variant that mitigates the exaggerated antiproliferative effect of Asp769Asn. However, an immunological re-evaluation revealed that his immunological condition had deteriorated in some cell populations. Namely, decreased plasmacytoid dendritic cells (pDCs) and transitional B cells were observed. T-cell receptor excision circles were not detected, a finding compatible with the decrease in recent thymic emigrant cells (RTEs; CD3+4+45RA+31+). While the frequency of contraction of infectious diseases decreased, while that of a reversion variant in the SAMD9 gene increased, his immunological condition deteriorated. His further follow-up will help clarify the long-term prognosis of MIRAGE syndrome.