FRI307 Gigantism Due To Transcriptional Activation Of GHRH: The First Case Of Hormone-encoding Gene Overexpression Underlying A Congenital Disorder

Disclosure: A. Hattori: None. Y. Katoh-Fukui: None. R. Zhang: None. M. Terao: None. S. Takada: None. K. Nakabayashi: None. K. Hata: None. Y. Yamada: None. N. Matsuura: None. M. Fukami: None. Background: Pituitary gigantism is characterized by tall stature due to GH overproduction. To date, known genetic causes of pituitary gigantism are invariably associated with predispositions to tumors producing GH or GHRH. Clinical and genetic findings of the patient: The patient was a Japanese woman who was born mildly large for gestational age. Her overgrowth started in her first year of life. Despite radiation and pharmacotherapy starting at age three years, she reached an adult height of 197 cm (+7.4 SD). She developed panhypopituitarism associated with empty sella in adulthood and was deceased during sleep at age 53 years. Exome sequencing identified no pathogenic variant causing acromegaly or gigantism. Chromosomal microarray analysis detected a 752-kb deletion upstream of GHRH. This deletion was predicted to create a chimeric gene consisting of the 5´-UTR of TTI1, a ubiquitously expressed gene, and the coding region of GHRH. Reverse transcription PCR (RT-PCR) using mRNA of immortalized lymphoblastoid cells detected the chimeric transcript. Analysis of model mice: We established a mouse model harboring a 676-kb deletion upstream of Ghrh using the CRISPR/Cas9 system. RT-PCR detected a chimeric transcript consisting of the 5´-UTR of Tti1 and the coding region of Ghrh, which mimicked the patient’s chimeric transcript. Mutant mice started to overgrow at two weeks of age and showed high serum GH levels and long tibia at 12-13 weeks of age. Quantitative RT-PCR showed that the median level of Ghrh expression in the hypothalamus of the mutant mice was three-fold higher than that of the wildtype mice. Furthermore, the mutant mice had ectopic Ghrh expression in all analyzed tissues (the pituitary, thymus, heart, liver, and gonad). Discussion: Our findings propose a novel etiology of gigantism. In the present case, the GHRH gene obtained a constitutively active promoter through germline genomic microdeletion. The newly acquired promoter likely led to the constant expression of GHRH in various tissues including the hypothalamus. Possible explanations for GH overproduction in the present case include (1) GHRH overproduction in the hypothalamus, (2) paracrine and autocrine effects of GHRH secreted from the pituitary, and (3) endocrine effects of GHRH produced outside the hypothalamic-pituitary unit. The patient’s clinical course suggests that prenatal GHRH overproduction only mildly affects human growth. More importantly, this is the first case in which transcriptional activation of a hormone-encoding gene caused a human congenital disorder. Presentation: Friday, June 16, 2023