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PURPOSE: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes. METHODS: Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing. RESULTS: Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified. CONCLUSION: We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

Purpose Geographic disparities for assisted reproductive technology (ART) continue to exist. Travel cost and time off work may create additional barriers for patients living remotely. Implementing telehealth can alleviate these barriers by reducing office visits. The aim of this study was to evaluate patient satisfaction with telehealth during ART. Methods This was a cross-sectional survey and retrospective cohort study. Patients living remotely who underwent ART utilizing telehealth between 2015 and 2018 at a single institution were selected for the telehealth group. The non-telehealth control group included randomly selected patients who underwent IVF at the same institution between 2015 and 2018. Demographic variables and treatment outcomes were obtained for both groups. A patient satisfaction questionnaire was distributed to telehealth patients. Statistical analysis using χ2 test was performed to compare ART outcomes between both groups. Results Ninety-seven control and 97 telehealth patients were included. For telehealth patients, the mean number of office visits and distance traveled was 2.9 (± 0.8 SD) and 143.1 miles (± 49.2 SD) respectively. 58.8% of patients completed the survey. 44/57 participants had an oocyte retrieval and 42/44 underwent embryo transfer. For those who completed the survey, the clinical pregnancy rate was 31/44 and the live birth rate was 25/44. There was no difference in treatment outcomes between telehealth compared to controls. 73% of patients were highly satisfied with telehealth. Conclusions Telehealth can improve access to ART in underserved areas and results in high patient satisfaction. Reproductive health providers could consider telehealth as a safe and efficacious tool to ameliorate geographic disparities.

Background: Unexplained or idiopathic infertility comprises approximately 30% of couples who present with infertility. This has led to investigations seeking to determine the cause(s) of this important diagnosis of exclusion. Estrogen’s role in reproduction has been well- established. Estrogens bind to two hormone receptors (namely estrogen receptor-alpha and estrogen receptor-beta), which are distributed differentially throughout the body. Specifically, the estrogen receptor-beta, coded by the Estrogen Receptor 2 (ESR2) gene, is highly expressed in granulosa cells and growing follicles. The one female patient reported with an ESR2 mutation presented with hypergonadotropic hypogonadism. However, subfertility with inefficient ovulation and resistance to exogenous ovulatory stimulation is seen in an ESR2 knockout mouse model. We therefore hypothesized that less severe ESR2 variants could lead to a normal female phenotype and pubertal development but could be a cause subfertility. Methods: DNA samples from 200 women with unexplained infertility were obtained from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial, which investigated optimal ovulation induction medications for unexplained infertility. These samples were subjected to targeted next-generation sequencing (NGS) for the ESR2 gene. Likely pathogenic variants that occurred with a minor allele frequency of < 0.01 in the gnomAD database and a Combined Annotation Dependent Depletion (CADD) score of > 20 were selected for confirmation by Sanger sequencing. Results: From the 200 patient samples, five heterozygous missense variants and one heterozygous in-frame deletion identified by targeted NGS were confirmed by Sanger sequencing. Further studies will need to be performed in vitro to confirm the likely pathogenicity of these variants. Conclusion: These studies raise the possibility that If these variants in ESR2 that impair estrogen signaling, they could be a potential newly recognized etiology of unexplained infertility in women with unexplained infertility. Conclusion: These studies raise the possibility that variants in ESR2 that impair estrogen signaling could be a potential newly recognized etiology of unexplained infertility in women.

In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2-0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasing concentrations of DMPS alter oocyte quality as judged by changes in microtubule morphology (MT) and chromosomal alignment (CH) of metaphase II mice oocyte. The oocytes were directly exposed to increasing concentration of DMPS (10, 25, 50, 100 and 300μM) for four hours (time of peak plasma concentration after administration) and reactive oxygen species (mainly hydroxyl radical and superoxide) and zinc content were measured. This data showed DMPS plays an important role in deterioration of oocyte quality through a mechanism involving zinc deficiency and enhancement of reactive oxygen species a major contributor to oocyte damage. Our current work, for the first time, demonstrates the possibility of DMPS to negatively impact fertility. This finding can not only help in counseling reproductive age patients undergoing such treatment but also in the development of potential therapies to alleviate oxidative damage and preserve fertility in people receiving heavy metal chelators.

Background. Catastrophic APS (CAPS) is a rare but life-threatening form of APS defined as multiorgan thrombosis affecting a minimum of three organs with confirmation by histopathology of small vessel occlusions in at least one organ or tissue. The development of CAPS in pregnancy poses many diagnostic challenges as a result of its broad range of clinical presentations and its overlap with other obstetric complications and microangiopathic diseases. Because of the high associated mortality rate, prompt recognition and treatment are paramount. Case. A twenty-five-year-old G3P0111 with a history of multiple thromboembolisms presented at 21 weeks and 3 days of gestation with complaints of right upper quadrant pain, visual disturbances, headache, and syncopal episodes. Laboratory evaluation demonstrated microangiopathic disease with hemolysis (confirmed on peripheral smear), elevated liver enzymes, and abnormal 24-hour urine protein with vital signs within the normal range. Presence of significantly elevated antiphospholipid antibodies was noted, facilitating the diagnosis of probable CAPS. Proper workup was achieved based on clinical suspicion, allowing immediate and appropriate management. Conclusion. CAPS is a life-threatening condition rarely seen in pregnancy making early recognition difficult. A low threshold to initiate urgent and aggressive treatment should be maintained to minimize the risk of adverse outcomes.

Background. In 2013, the abortion rate in the United States was found to be 200 abortions per 1,000 live births. Of these, the CDC estimates that nearly 49% were performed using unsafe measures. Even when these procedures are safely performed, patients are at risk for immediate or delayed complications. In second-trimester terminations, mechanical dilation with an osmotic dilator is common to allow for delivery of the fetus. The Japanese seaweed Laminaria japonica is used to achieve this purpose. Case. A 28-year-old primigravida presented with chronic pelvic pain and infertility. She had irregular menstrual cycles and reported scant yellow discharge. A transvaginal ultrasound revealed an abnormally appearing endometrium with an elongated structure suspicious for a foreign body. The patient reported a voluntary termination of pregnancy twelve years earlier, for which laminaria were placed prior to the dilation and extraction. She underwent an operative hysteroscopy confirming our suspicion for retained laminaria. The pathology report demonstrated chronic severe endometritis and plant based material. Conclusion. Retained laminaria are associated with chronic pelvic pain and chronic infertility. Since they can be difficult to detect on conventional imaging, proper counting prior to insertion and after removal is an essential physician responsibility.

The human umbilical cord (UC) and placenta are non-invasive, primitive and abundant sources of mesenchymal stromal cells (MSCs) that have increasingly gained attention because they do not pose any ethical or moral concerns. Current methods to isolate MSCs from UC yield low amounts of cells with variable proliferation potentials. Since UC is an anatomically-complex organ, differences in MSC properties may be due to the differences in the anatomical regions of their isolation. In this study, we first dissected the cord/placenta samples into three discrete anatomical regions: UC, cord-placenta junction (CPJ), and fetal placenta (FP). Second, two distinct zones, cord lining (CL) and Wharton's jelly (WJ), were separated. The explant culture technique was then used to isolate cells from the four sources. The time required for the primary culture of cells from the explants varied depending on the source of the tissue. Outgrowth of the cells occurred within 3 - 4 days of the CPJ explants, whereas growth was observed after 7 - 10 days and 11 - 14 days from CL/WJ and FP explants, respectively. The isolated cells were adherent to plastic and displayed fibroblastoid morphology and surface markers, such as CD29, CD44, CD73, CD90, and CD105, similarly to bone marrow (BM)-derived MSCs. However, the colony-forming efficiency of the cells varied, with CPJ-MSCs and WJ-MSCs showing higher efficiency than BM-MSCs. MSCs from all four sources differentiated into adipogenic, chondrogenic, and osteogenic lineages, indicating that they were multipotent. CPJ-MSCs differentiated more efficiently in comparison to other MSC sources. These results suggest that the CPJ is the most potent anatomical region and yields a higher number of cells, with greater proliferation and self-renewal capacities in vitro. In conclusion, the comparative analysis of the MSCs from the four sources indicated that CPJ is a more promising source of MSCs for cell therapy, regenerative medicine, and tissue engineering.

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) in reproductive-aged women poses major dilemmas concerning its associated teratogenicity as observed in many animal studies. Much controversy exists regarding continuation versus discontinuation of its use in pregnancy with some studies suggesting safety of TKIs before and during pregnancy and others reporting toxicity and adverse outcomes. TKIs have become a well-established treatment option for CML, significantly improving prognosis, and yet have been reported to be fetotoxic. We present a case of a 25-year-old woman who achieved successful pregnancy and delivery after withholding treatment, meanwhile relapsing, eventually achieving complete molecular remission after reinitiation of high dose dasatinib.

Background: Moyamoya disease is a progressive occlusive cerebrovascular disorder most prevalent in Asia. It results in neovascularization that can lead to hemorrhagic stroke. Pregnancy physiologic changes can further exacerbate the risk of fatal hemorrhagic stroke. Case: We present the case of a 31 year-old woman gravida 2 para 1 presenting to the emergency department with neurologic symptoms. She carried a diagnosis of Moyamoya disease and had multiple cerebrovascular accidents. She was found to be pregnant in the third trimester. Concerns regarding the patient’s care and treatment plan are outlined and addressed in this case report. Conclusion: The care of a patient with a rare medical condition requires a multidisciplinary care plan with members of the team directly and closely involved in the patient’s care.

Ectopic breast tissue is a rare condition caused by remnants of the mammary ridges that fail to involute during embryologic development. To date, only 39 cases have been reported in the literature worldwide. Here, we report the 40th case of a 69-year-old G3P2 postmenopausal Caucasian woman who presented with complaint of vulvar swelling. Biopsy of the mass revealed the presence of a benign mammary gland-like adenoma which was completely excised shortly thereafter. Clinical presentation of vulvar breast tissue is highly variable depending on the amount of breast tissue developed and its functionality. Diagnosis is ultimately made by tissue biopsy and histopathologic examination. Due to the scarce evidence that exists pertaining to supernumerary breast tissue located on the vulva, specific management guidelines are lacking. Since this ectopic tissue serves no function, but rather may provide a source for future malignancy, surgical excision is recommended.