MON-155 The Association of TSHR with Hypothyroidism and Early Pregnancy Loss

Abstract Disclosure: K. Verma: None. R.G. Handelsman: None. S.F. Witchel: None. A. Rajkovic: None. R.B. Lathi: None. S.A. Yatsenko: None. Background: The thyroid-stimulating hormone receptor (TSHR) regulates thyroid hormone production and release, which is essential for growth, metabolism, and reproduction. While the relationship between overt hypothyroidism and early pregnancy loss is well-established, the genetic basis of this association remains poorly understood. Loss-of-function variants in TSHR can cause resistance to thyroid-stimulating hormone (TSH) which leads to a spectrum of thyroid dysfunction, ranging from subclinical hypothyroidism to overt congenital hypothyroidism. We identified an association between hypothyroidism and early pregnancy loss in a family with multiple affected individuals, of which the proband was found to have a novel variant in TSHR. Case Presentation: A 38-year-old G2P0 female with hypothyroidism diagnosed at age 14 presented with two first-trimester pregnancy losses at ages 35 and 37. The second loss was confirmed to be euploid on postnatal chromosomal microarray. The patient’s medical history included polycystic ovarian syndrome, hypertension, and non-alcoholic fatty liver disease. She has a family history of hypothyroidism in her mother, 3 maternal aunts, and maternal grandmother. Both her mother and one maternal aunt have a history of one prior miscarriage. Despite thyroid monitoring and levothyroxine dose adjustments, TSH levels fluctuated significantly during her pregnancies (peak TSH 3.23 mIU/L and 26.48 mIU/L in first and second pregnancies, respectively). Additional causes of recurrent pregnancy loss (RPL) were ruled out including antiphospholipid syndrome and congenital uterine anomalies. The patient was enrolled in the Trio Analysis of Recurrent Pregnancy Loss Integrated Bioinformatics Genomics Study (TRIOS) and had exome sequencing to assess for variants in genes associated with RPL. She was found to have a variant in TSHR (NM_000369.5: c.1342G>A; p.Val448Ile), located in the transmembrane region (exon 10) of the TSH receptor gene. This variant has not been previously reported in individuals affected with hypothyroidism due to genetic changes in TSHR. Conclusions: This case identifies a novel TSHR variant potentially contributing to both hypothyroidism and early pregnancy loss, suggesting a genetic basis for this clinical association. The presence of this variant, in combination with a strong family history of hypothyroidism, may contribute to suboptimal thyroid hormone regulation and subsequent miscarriage. The identification of this variant through genetic testing provides valuable insights into a potential maternal contributor to pregnancy loss. These findings underscore the importance of preconception carrier screening to assess genetic risks prior to conception. Functional studies of this TSHR variant and screening in larger cohorts of patients with RPL may help establish its role in pregnancy maintenance. Presentation: Monday, July 14, 2025