SUN-438 Spontaneous Recovery of the Hypothalamic-Pituitary-Gonadal (HPG) Axis in a Female with Kallmann Syndrome

Abstract

Background: Kallmann Syndrome (KS) is characterized by hypogonadotropic hypogonadism (HH) due to isolated GnRH deficiency (IGD) and anosmia. While reversal of KS has been described, predominantly in males, few cases have been described in females. We report a female with KS who demonstrated spontaneous recovery of her HPG axis. Case Report: A 34-year-old woman with a history of KS was referred to the NIH Clinical Center for evaluation. She was evaluated for absent thelarche and primary amenorrhea at age 18 when, due to her history of vigorous exercise and low BMI, she was assumed to have hypothalamic amenorrhea. At age 22, she was first noted to be anosmic by her endocrinologist who diagnosed her with KS. She underwent bilateral breast augmentation, and oral contraceptive pills (OCPs) induced regular menstrual bleeding. OCPs were self-discontinued after 1 year and amenorrhea recurred. By her late 20s, her level of exercise had decreased and her BMI normalized. She reported 3 episodes of spontaneous menstrual spotting in the six months preceding her visit, cyclical but irregular breast tenderness and emotional lability in the absence of hormonal treatment. Her medications included only fluoxetine. Physical examination revealed a BMI of 19.1 kg/m2, bilateral breast implants, a high-arched palate and bilateral fifth digit clinodactyly. Her laboratory evaluation revealed a serum LH of 8 U/L, FSH of 9 U/L and E2 of 19 pg/mL; all other anterior pituitary hormones were normal. Frequent blood sampling revealed a high-frequency pattern of LH pulsatility (24 pulses/24 hrs) with sleep augmentation and mean LH of 6.8 U/L. Formal smell testing confirmed anosmia. Her pelvic ultrasound revealed normal ovaries with follicles and normal uterus with a 4 mm endometrial stripe. A brain MRI was normal except for absent olfactory bulbs. Clinical testing of 14 IGD genes showed a novel heterozygous ANOS1 variant (c.298C>A p.Q100K) of unknown significance that was also present in her unaffected mother. A maternal half-uncle was reportedly anosmic but is now deceased. Discussion: This KS female exhibited spontaneous recovery of her HPG axis, which has been reported in very few cases. Her olfactory bulb aplasia is consistent with a congenital defect in GnRH neuronal development given their common ontogeny, suggesting that her HH and recovery were not simply due to changes in body weight nor exercise. Although females with heterozygous ANOS1 variants have been reported to demonstrate features of HH, the role of this novel ANOS1 variant remains unclear due lack of functional data and the presence of the same variant in her asymptomatic mother. Conclusions: Reversal of the reproductive phenotype in women with KS is rare with little known about their genetic abnormalities and long-term outcomes. Further study of such cases is warranted to gain insight into the mechanisms required for activation of the HPG axis.