(45) FOXL2-induced BPES and POI with Hyperandrogenism and Normal Estradiol: A Clinical Conundrum

Background: Patients with FOXL2 resulting in BPES (blepharophimosis, ptosis, epicanthus inversus syndrome) are at an increased risk of premature ovarian failure (POI). Hyperandrogenism alongside normal estradiol levels in the setting of POI is not noted in the literature.

Case: A 15-year-old female with a known history of FOXL2 gene and BPES presented to pediatric gynecology (PAG) due to secondary amenorrhea after experiencing only one episode of menses at age 12. Thelarche occurred at age 9 and prior workup was notable for elevated free and total testosterone, DHEAS, and FSH. She had a prior normal estradiol, prolactin, karyotype, 21-hydroxylase antibodies, thyroid antibodies, and Fragile X screen. Her physical exam was remarkable for tanner 4 tuberous breast and thick course hair on the face, check, and back consistent with hirsutism. Repeat FSH remained extremely elevated and estradiol remaining within normal pubertal range. Given persistent androgen excess on labs and physical exam findings, a pelvic ultrasound and CT abdomen/pelvis was completed to rule out tumors of the adrenal glands or ovaries which were unremarkable. Because her FSH remained persistently elevated with normal estradiol, an AMH was completed and noted to be 0.1. She also completed a DEXA scan which showed normal bone mineral density. She subsequently completed a congenital adrenal hyperplasia (CAH) panel which was normal with the exception of elevated testosterone. The patient attempted a Provera challenge with no withdrawal bleed.

With known genetic predisposition and two FSH levels markedly elevated, patient formally met criteria for POI. Despite extensive workup, no etiology was identified for her persistent androgen excess but given her clinical and laboratory findings, she did meet criteria for PCOS. Interestingly her estrogen level remained within normal limits despite the diagnosis of POI. She was started on oral contraceptive pills for hirsutism, hormone replacement, and contraception.

Comments: Given the rarity of documented associations between BPES, hyperandrogenism, and normal estradiol levels in the setting of POI, other conditions like PCOS should be considered in said patients. This case emphasizes the importance of extensive laboratory and imaging workup for unique patients as well as the value of multidisciplinary teamwork between genetics, PAG, and reproductive endocrinology. In addition, the providers recognized the importance of monitoring bone health and contraceptive needs in this unusual clinical scenario.