ESPE Abstracts

MIRAGE syndrome is a genetic disorder that involves multiple organs and it is characterized by myelodysplasia, immunodeficiency, growth restriction, adrenal hypoplasia, hypogonadism, and enteropathy. Due to a poor prognosis in patients with this syndrome, it is not clear how patients with MIRAGE syndrome grow or how puberty develops. As we are currently managing the oldest known male patient with this syndrome in Japan, we have a record of his growth and pubertal development from birth to adulthood. We herein report the pattern of growth and pubertal development with endocrinological evaluations and the molecular background of this patient. The patient was a 23-year-old male. A gain-of-function mutation (c.2305G>A, p.Asp769Asn) in SAMD9 was identified at 17 years of age, thus leading to the diagnosis of MIRAGE syndrome. He had been growing with a height SD score of approximately -4.0, and a weak growth spurt started at 16 years of age. He is currently 153.2 cm in height and 34.5 kg in weight (BMI 14.1 kg/m²). The patient’s pubertal timing was delayed, but physically confirmed at 16 years and 6 months of age based on Tanner stages PI and PHII with a testicular volume of 3 ml. Thereafter, he grew gradually and reached his present adult height at 20 years of age. Interestingly, his pubertal development progressed slowly until 20 years of age. However, the increase in testicular volume was insufficient. An endocrinological evaluation revealed hypergonadotropic hypogonadism, whereas GH secretion was normal (presented in ESPE 2023). The mechanisms underlying the delayed pubertal development and the continuation of pubertal development for longer than usual are unknown. However, because of the increasing frequency of the reversion variant (c.1258T>C, p.Cys420Arg) in the SAMD9 gene, which recovers cell growth activity in vitro (presented in ESPE 2023), this rescue mechanism of the SAMD9 gene mutation might have had some effect on the progress of his growth and pubertal development.