FRI453 Genetic Heterogeneity of Hypothalamic Hypogonadism DIsorders

Abstract

Abstract Disclosure: C. Bheeman: None. O. Astapova: None. Title: Genetic Heterogeneity of Hypothalamic Hypogonadism disorders. Introduction: Hypothalamic hypogonadism (HH) can be defined as having inappropriately low serum concentrations of gonadotropins in the presence of low circulating concentrations of sex steroids. It represents a group of genetically and clinically heterogeneous disorders. Case A 32-year-old female who presented to the endocrine clinic for evaluation of infertility. Patient had menarche at age 12 but became amenorrhoeic at age 14. Her physical exam was notable for normal female secondary sexual characteristics and intact sense of smell. She had no history of bone fracture or menopausal symptoms. The patient had failed the progesterone withdrawal test twice, but had withdrawal bleeding with the birth control pill or with hormonal replacement therapy. She had failed ovulation induction with clomiphene citrate, but was able to conceive 3 pregnancies through in vitro fertilization. Patient’s labs off of hormonal replacement and birth control were: LH <0.3. FSH 0.6, Estradiol <5, Progesterone 0.4. Her prolactin level was within normal limits at 6.6 and her TSH was 1.08. MRI of the brain showed no abnormalities in the pituitary gland. Genetic testing showed that the patient was heterozygous for a duplication mutation in the ANOS1 gene. Conclusion The genotypic and phenotypic heterogeneity that can be seen in HH disorders is due to the numerous genes involved in hypothalamic hypogonadism and their intricate interactions. Mutations contributing to HH can be involved in either the neurodevelopmental or neuroendocrine pathways of the hypothalamic pituitary gonadal axis or in both. There are mutations that can be inactivating variants while some can play the role of the modifier genes. The later may be able to explain the incomplete penetrance and variable expressivity sometimes seen in HH. It is important to note that though > 60 genes have been implicated in HH 50% of the cases remain genetically undiagnosed. This case is particularly interesting as this patient is a female with a heterozygous mutation on the ANOS1 gene, the primary gene associated with Kallmann syndrome. Kallmann syndrome is a X-linked recessive disorder and therefore the patient having phenotypical expression of the mutation is unexpected. Through the presentation of this case we aim to explore different modes of genetic expression and the different mechanisms that could have led to this patient hypothalamic hypogonadism. Presentation Date: Friday, June 16, 2023