The first case of novel variants of the FSHR mutation causing primary amenorrhea in 2 siblings in Korea
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Follicle-stimulating hormone receptor (FSHR) mutation is a rare cause of amenorrhea. We report the first case of FSHR mutations in Korea. Two female siblings aged 16 (patient 1) and 19 (patient 2) years were referred to the pediatric endocrinology clinic because of primary amenorrhea despite normal breast budding. Gonadotropin-releasing hormone stimulation test showed markedly elevated luteinizing hormone and follicle-stimulating hormone with a relatively low level of estrogen, suggesting hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a bicornuate uterus in patient 1 and uterine hypoplasia with thinning of the endometrium in patient 2. The progesterone challenge test revealed no withdrawal of bleeding. After 2 months of administration of combined oral contraceptives, menarche was initiated at regular intervals. To determine the genetic cause of amenorrhea in these patients, whole-exome sequencing (WES) was performed and revealed a compound heterozygous FSHR mutation, i.e., c.1364T>G (p.Val455Gly) on exon 10 and c.374T>G (p.Leu125Arg) on exon 4. Both of these were novel mutations and were confirmed by Sanger sequencing. Both patients maintained regular menstruation and improved bone mineral density while taking combined oral contraceptives, calcium, and vitamin D. Therefore, FSHR mutations can be the cause of amenorrhea in Koreans, and WES facilitates the diagnosis of rare causes of amenorrhea.
Abstract
Follicle-stimulating hormone receptor (FSHR) mutation is a rare cause of amenorrhea. We report the first case of FSHR mutations in Korea. Two female siblings aged 16 (patient 1) and 19 (patient 2) years were referred to the pediatric endocrinology clinic because of primary amenorrhea despite normal breast budding. Gonadotropin-releasing hormone stimulation test showed markedly elevated luteinizing hormone and follicle-stimulating hormone with a relatively low level of estrogen, suggesting hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a bicornuate uterus in patient 1 and uterine hypoplasia with thinning of the endometrium in patient 2. The progesterone challenge test revealed no withdrawal of bleeding. After 2 months of administration of combined oral contraceptives, menarche was initiated at regular intervals. To determine the genetic cause of amenorrhea in these patients, whole-exome sequencing (WES) was performed and revealed a compound heterozygous FSHR mutation, i.e., c.1364T>G (p.Val455Gly) on exon 10 and c.374T>G (p.Leu125Arg) on exon 4. Both of these were novel mutations and were confirmed by Sanger sequencing. Both patients maintained regular menstruation and improved bone mineral density while taking combined oral contraceptives, calcium, and vitamin D. Therefore, FSHR mutations can be the cause of amenorrhea in Koreans, and WES facilitates the diagnosis of rare causes of amenorrhea.
참고문헌 (28)
- Sperling MA, "Sperling pediatric endocrinology E-Book" (2020), Elsevier Health Sciences
- Simoni M, "The follicle-stimulating hormone receptor : biochemistry, molecular biology, physiology, and pathophysiology", Endocr Rev, 18, pp.739~773 (1997)
- Fan QR, "Structure of human folliclestimulating hormone in complex with its receptor", Nature, 433, pp.269~277 (2005)
- Richards JS, "The ovary : basic biology and clinical implications", J Clin Invest, 120, pp.963~972 (2010)
- Ulloa-Aguirre A, "FSH receptor signaling : complexity of interactions and signal diversity", Endocrinology, 159, pp.3020~3035 (2018)
- He WB, "Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome", Reprod Biomed Online, 38, pp.397~406 (2019)
- Aittomäki K, "Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene", J Clin Endocrinol Metab, 81, pp.3722~3726 (1996)
- Shemesh M, "Actions of gonadotrophins on the uterus", Reproduction, 121, pp.835~842 (2001)
- Stilley JAW, "FSH actions and pregnancy : looking beyond ovarian FSH receptors", Endocrinology, 159, pp.4033~4042 (2018)
- Danilovich N, "Emergence of uterine pathology during accelerated biological aging in FSH receptor-haploinsufficient mice", Endocrinology, 143, pp.3618~3627 (2002)
- Sun L, "FSH directly regulates bone mass", Cell, 125, pp.247~260 (2006)
- Kim NK, "Molecular variants of the FSH receptor exon 10(Thr307Ala; A919G)in premature ovarian failure(POF)women by PCR-SSCP", Korean J Obstet Gynecol, 43, pp.1144~1146 (2000)
- Choi YM, "Follicle stimulating hormone receptor gene mutation in Korean women with premature ovarian failure and normal karyotype", Korean J Obstet Gynecol, 43, pp.836~841 (2001)
- Nam Y, "Analysis of follicle stimulating hormone receptor gene mutation in Korean", Clin Exp Reprod Med, 25, pp.281~286 (1998)
- França MM, "A novel homozygous missense FSHR variant associated with hypergonadotropic hypogonadism in two siblings from a Brazilian family", Sex Dev, 11, pp.137~142 (2017)
- Liu H, "A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency", Fertil Steril, 108, pp.1050~1055 (2017)
- Bramble MS, "A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure : a fertility application of whole exome sequencing", Hum Reprod, 31, pp.905~914 (2016)
- Katari S, "Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure", J Clin Endocrinol Metab, 100, pp.2154~2157 (2015)
- Achrekar SK, "Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea", J Assist Reprod Genet, 27, pp.317~326 (2010)
- Kuechler A, "An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor(FSHR)gene and causes FSH resistance", Eur J Hum Genet, 18, pp.656~661 (2010)
- Nakamura Y, "A novel mutation in exon8 of the follicle-stimulating hormone receptor in a woman with primary amenorrhea", Gynecol Endocrinol, 24, pp.708~712 (2008)
- Allen LA, "A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism : clinical and molecular characteristics", Hum Reprod, 18, pp.251~256 (2003)
- Meduri G, "Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor : clinical, histological, and molecular studies", J Clin Endocrinol Metab, 88, pp.3491~3498 (2003)
- Doherty E, "A novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure", J Clin Endocrinol Metab, 87, pp.1151~1155 (2002)
- Touraine P, "New natural inactivating mutations of the follicle-stimulating hormone receptor : correlations between receptor function and phenotype", Mol Endocrinol, 13, pp.1844~1854 (1999)
- Beau I, "A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor", J Clin Invest, 102, pp.1352~1359 (1998)
- Gromoll J, "Functional and clinical consequences of mutations in the FSH receptor", Mol Cell Endocrinol, 125, pp.177~182 (1996)
- Aittomäki K, "Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure", Cell, 82, pp.959~968 (1995)