Ann Pediatr Endocrinol Metab.  2023 Mar;28(1):54-60. 10.6065/apem.2142116.058.

The first case of novel variants of the FSHR mutation causing primary amenorrhea in 2 siblings in Korea

• Yoo S
• Yoon JY
• Keum C
• Cheon CK

• KMID: 2540788
• DOI: http://doi.org/10.6065/apem.2142116.058

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 two 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, which revealed a compound heterozygous FSHR mutation, c.1364T>G (p.Val455Gly) on exon 10, and c.374T>G (p.Leu125Arg) on exon 4; both of which were novel mutations and were confirmed by Sanger sequencing. The 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 diagnosing the rare cause of amenorrhea.

Keyword

Amenorrhea; Hypogonadism; Follicle-stimulating hormone receptor

Figure

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  Fig. 1. Pelvic magnetic resonance imaging of patients. (A) Sagittal T1-weighted and coronal oblique T2-weighted BLADE sequence imaging of patient 1 revealing a bicornuate uterus (arrow) with a pair of endometrial canals widely separated by the myometrial septum extending to the internal cervical os. Note the fundal cleft of the outer uterine contour. (B) Sagittal T2 BALDE sequence imaging of patient 2 showed hypoplasia of the uterus (1.3 cm×3.7 cm) (arrowheads) with thinning of the endometrium. Size, shape, and enhancement were normal in both ovaries (not seen in this image).

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  Fig. 2. Two novel heterozygous variants in the FSHR gene. (A) Sanger sequencing confirmed novel variants of c.374T>G (p.L125R) or c.1364T>G (p.V455G) in FSHR in 2 siblings, respectively. L125R is located on the leucine-rich repeats domain, and V455G is located on the transmembrane receptor domain, as shown in the red triangle and square. (B, C) Wild-type and mutant residues (p.L125R and p.V455G) in the FSHR protein are shown in light-green and also are represented as sticks alongside the surrounding residues, indicating any type of interaction. Green dots represent hydrophobic contacts with a surrounding residue. Red dots represent hydrogen bonds with a surrounding residue. The crystal structure of the domain from wild-type FSHR was generated by SWISS-MODEL (https://swissmodel.expasy.org/) and has been depicted as a cartoon representation. All structural images were generated using PyMOL (https://pymol.org/).

Reference

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