ODP400 A Mutation in the Gonadotropin Releasing Hormone Receptor Associated with Congenital Hypogonadotropic Hypogonadism with Absence of Uterus and Ovaries

INTRODUCTION: Mutations in the GNRH receptor may result in congenital hypogonadotropic hypogonadism (CHH) due to a deficiency in gonadotropins. Both autosomal dominant and recessive transmission patterns have been described. In young women, this presents with primary amenorrhea and a failure to progress through puberty with their peers. Here we present a case of CHH in a woman found to have a mutation in the GNRH receptor. CLINICAL CASE: A 24-year-old woman with no significant medical history presented to the endocrine clinic for the evaluation of primary amenorrhea and infertility. The patient had recently migrated to the U. S. from Guatemala. She was well appearing with Tanner stage 2 breast and pubic hair development. Normal external genitalia and vagina were noted without anosmia. Her family history was significant for delayed puberty in her mother, primary amenorrhea and delayed puberty in her 22-year old sister and a 16-year old brother who underwent puberty with his peers. The patient was unaware of any other family members with similar symptoms. Laboratory data revealed Prolactin 9.47 ng/ml (4.79-23.3),FSH 0.6*, LH 0.1*, estradiol <5. 0 pg/ml*, Total testosterone 6.2 ng/dl(10-55), Free testosterone 0.3 pg/ml (0-4.2), TSH 1.88 U/L (0.47-6.90), Free T4 1.14 ng/dl(7.5-2. 0),IGF1 302 ng/ml(100-311) Cortisol 7.6 ug/dl (6.9-29), ACTH 17 pg/ml (7.2-63.3), 17 OHP 10 ng/dl* [(*) Low ]. MRI of the sella revealed a normal pituitary. Pelvic ultrasound revealed absence of uterus and ovaries. A CT of the pelvis confirmed the absence of uterus and ovaries and noted a normal vagina with partial cervix. Karyotype revealed a 46XX pattern with multiple regions of homozygosity suggesting shared ancestry between her parents. Further testing revealed ahomozygous mutation in the GNRH receptor c.247C>G (p. Leu 83Val),classified as a variant of unknown significance. Testing was offered for her sister and other first-degree family members but was declined as they reside in Guatemala. Low dose estrogen therapy delivered by transdermal routewas initiated. She was referred to a geneticist and counseled on the impact of her diagnosis and the absence of uterus and ovaries on fertility. Psychological support was offered. CONCLUSION: This is the first reported case of a GNRH receptor mutation associated with primary amenorrhea and the complete absence of uterus and ovaries. Testing first-degree relatives is necessary to clarify its role in the above phenotype, and its mode of inheritance. Referral to a geneticist and specialists in difference of sex development (DSD) is a cornerstone of therapy in CHH. In women, treatment involves the induction of puberty with gradually escalating doses of estrogen, followed by the addition of progesterone in those patients with an intact uterus. Ovulation induction with gonadotropin therapy may be considered in appropriate patients with CHH, if fertility is desired. Presentation: No date and time listed