Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.

Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Transiently increased risk of breast cancer after childbirth: implications for fertility treatments and surrogacy.

Whereas longstanding dogma has purported that pregnancies protect women from breast cancer, a recent meta-analysis now mandates reconsideration since it reported an actual higher breast cancer risk for more than two decades after childbirth before the relative risk turns negative. Moreover, the risk of breast cancer appears higher for women having their first birth at an older age and with a family history and it is not reduced by breastfeeding. The process of obtaining informed consent for all fertility treatments, therefore, must make patients aware of the facts that every pregnancy, to a small degree, will increase the short-term breast cancer risk. This observation may be even more relevant in cases of surrogacy where women agree to conceive without deriving benefits of offspring from assuming the risk, thus creating a substantially different risk-benefit ratio. Consequently, it appears prudent for professional societies in the field to update recommendations regarding consent information for all fertility treatments but especially for treatments involving surrogacy.

Should the Risk of Invasive Cancer in Pregnancy and the Safety of Loop Electrosurgical Excision Procedure During the First 15 Weeks Change Our Practice?

OBJECTIVE: The aim of this article was to describe the outcome of women diagnosed with cervical intraepithelial neoplasia (CIN) grades 2 or 3 in pregnancy either observed or treated by loop electrosurgical excision procedure (LEEP) in the first 15 weeks of gestation. METHODS: Loop electrosurgical excision procedure during the first 15 gestational weeks compared with observation of CIN2/3. This is a retrospective analysis of a nonrandomized study at tertiary, academic, and referring centers in Israel. Ninety-three pregnant women diagnosed with CIN2/3 between 2006 and 2016 were included in this study. Fifty patients with CIN2/3 on cervical biopsy were conservatively followed-up, and 43 patients have undergone LEEP during the first 15 gestational weeks. Main outcome measures were ultimate diagnosis of invasive cancer or CIN, pregnancy outcome, and complications. RESULTS: In 5.4% of CIN2/3 during pregnancy, the final diagnosis was invasive cancer. The postpartum results of 50 women who were conservatively observed were as follows: 3 (6.0%) had cervical cancer and undergone radical hysterectomy, 33 (66.6%) had CIN2/3, and 14 (28%) had CIN1 or normal histology. The diagnoses of the 43 patients who have undergone LEEP were invasive cancer in 2 patients (4.6%) but did not undergo hysterectomy, CIN2/3 or adenocarcinoma in situ (AIS) in 38 patients (88.4%), and 3 women (7%) had CIN1 or normal histology. None of them suffered severe bleeding. Thirty-seven women continued their pregnancy, 34 (91.9%) had term deliveries, 2 (5.4%) gave birth at 34 and 36 weeks, and 1 patient had missed abortion (2.7%). CONCLUSIONS: The LEEP procedure during the first 15 weeks of pregnancy is safe. A total of 5.4% of the women with CIN2/3 during pregnancy were diagnosed with invasive cancer. It is time to reconsider the recommendations about CIN2/3 in early gestation.

Transient Distention of Right Posterior Located Sigma, a New Sonographic Sign for the Prenatal Diagnosis of Anal Atresia.

We describe a new sonographic sign for the detection of anal atresia in the early midtrimester on transvaginal sonography. In six cases of fetal anal atresia, the finding of a transient, distended, and right-sided sigmoid colon was observed at 13-16 weeks' gestation. Three cases have undergone pregnancy termination due to multiple anomalies. In the other three, the colonic distension resolved by 19 weeks' gestation. In two of these, the finding was isolated, and no other anomalies were detected. In all six cases, anal atresia or cloaca was confirmed on postabortal autopsy or after delivery. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:160-162, 2017.

Detection Rate and Sonographic Signs of Trisomy 21 Fetuses at 14-17 Weeks of Gestation.

BACKGROUND: Early prenatal ultrasound is an important part of prenatal screening in Israel. No studies have described the rate of trisomy 21 [T21] identification at 14-17 weeks gestation. OBJECTIVES: To describe the rate of T21 identification by transvaginal sonograms (TVS) at 14-17 weeks gestation. METHODS: We conducted a historical prospective study. Since 1986, early TVS of 72,000 fetuses at 14-17 weeks gestation have been prospectively recorded together with prenatal screening data at a private ultrasound center (AL-KOL, Haifa). We calculated the fraction of T21 cases by dividing the total number of cases with abnormal sonographic findings by the total number of diagnosed T21 cases. We also examined the percentage of verified T21 cases that had completely normal prenatal screening tests prior to the early prenatal TVS, thus revealing the contribution of this examination to the existing prenatal screening. Fisher's exact test was used to calculate odds ratios for each sonographic marker. RESULTS: Of 137 T21 fetuses, 123 had sonographic markers on early TVS, yielding a prediction capability of at least 89.87%. Of all T21 cases, 14% had completely normal nuchal translucency/first-trimester screening prior to the abnormal 14-17 week TVS findings. Isolated abnormal sonographic findings, which were found to increase the risk for T21, were common atrioventricular septal canal (odds ratio 88.88), duodenal atresia (OR 88.23), nuchal edema (OR 39.14), and hydrocephalus (OR 15.78). Fetal hydronephrosis/pyelectasis was non-significant when isolated (OR 1), and cardiac echogenic focus was associated with a decreased risk (OR 0.13). CONCLUSIONS: Early prenatal TVS at 14-17 weeks may identify almost 90% of T21 and adds 14% to the identification rate at the first-trimester screening.

Endocrine prevention of chemotherapy-induced ovarian failure.

PURPOSE OF REVIEW: Fertility preservation has recently gained a worldwide interest among fertility specialists, oncologists, and all healthcare providers. Thus, the protection against iatrogenic infertility caused by chemotherapy assumes a high priority. Specifically, the issue of endocrine prevention of gonadotoxicity is still a controversial subject. RECENT FINDINGS: During the last year, many publications on this subject appeared, swinging the pendulum toward the beneficial role of gonadotropin-releasing hormone agonist (GnRHa) cotreatment for fertility preservation despite gonadotoxic chemotherapy. Here, we summarize the recent publications on fertility preservation and minimizing chemotherapy-induced gonadotoxicity. SUMMARY: More than 10 recent meta-analyses have concluded that GnRHa is beneficial and may decrease the risk of premature ovarian failure and increase the pregnancy rate in survivors. Furthermore, two recent international meetings of experts have concluded that GnRHa is effective and should be offered to every young woman facing gonadotoxic chemotherapy.

Gonadotropin-Releasing Hormone Agonist Cotreatment During Chemotherapy May Increase Pregnancy Rate in Survivors.

BACKGROUND: The use of gonadotropin-releasing hormone analogs (GnRHas) for fertility preservation is not unequivocally accepted. It is controversial whether GnRHa can increase the pregnancy rate in survivors. PATIENTS AND METHODS: This is a retrospective cohort study. Every patient referred for fertility preservation was offered cryopreservation of embryos, ova, and ovarian tissue and GnRHa. The patients were consecutively included. The primary outcome was spontaneous pregnancies. The secondary outcome was cyclic ovarian function (COF) versus premature ovarian failure (POF). These outcomes were assessed 2 years or more after chemotherapy. RESULTS: We compared 286 patients who received gonadotropin-releasing hormone agonist (GnRHa) with chemotherapy with 188 patients who were treated with chemotherapy alone. Ovarian function could be determined in 217 patients. Overall, 87% (127 of 146) of the patients in the GnRHa group retained COF and 13% (19 of 146) suffered POF, whereas in the control group, 49% (35 of 71) experienced COF and 51% (36 of 71) suffered POF (p = .0001). The odds ratio (OR) for preserving COF was 6.87 for the patients who received GnRHa (95% confidence interval [CI] 3.4-13.4). Overall 60% (112 of 188) of the survivors conceived: 69.3% (84 of 122) of the patients in the GnRHa group compared with 42.4% (28 of 66) in the control group (p = .006). In the GnRHa group, 123 healthy newborns were delivered, versus 40 in the controls. Spontaneous pregnancies occurred in 65.6% (80 of 122) of the survivors in the GnRHa group versus 37.9% (25 of 66) in the control group (p = .0004, OR 3.12, 95% CI 1.7-5.8). CONCLUSION: Adding GnRHa to chemotherapy significantly increases the OR for spontaneous conception, in addition to COF. It is suggested that GnRHa cotreatment should be added before and during gonadotoxic chemotherapy. IMPLICATIONS FOR PRACTICE: The use of gonadotropin-releasing hormone analogs (GnRHa) for fertility preservation is not unequivocally accepted and is even controversial. This study compared 286 patients who received GnRHa with chemotherapy with 188 patients who were treated with chemotherapy alone. Ovarian function could be determined in 217 patients. The odds ratio for preserving cyclic ovarian function was 6.87 for the patients who received GnRHa. Furthermore, the total and spontaneous pregnancy rate was significantly higher for those who received the agonist (p = .006). Adding GnRHa to chemotherapy significantly increased the odds ratio for spontaneous conception, in addition to preserving regular ovarian function. It is suggested that GnRHa cotreatment should be administered to young women in conjunction with gonadotoxic chemotherapy.

Why more is less and less is more when it comes to ovarian stimulation.

PURPOSE: The purpose of the present study is to describe the possible mechanisms which may explain the apparent paradox of "less is more." Mild ovarian stimulation for in vitro fertilization (IVF) minimizes ovarian hyperstimulation syndrome (OHSS) and multiple gestations without compromising the pregnancy rate (PR). METHODS: The pertinent English literature (PubMed) addressing mild stimulation for IVF/assisted reproductive technology (ART) and publications addressing "mild" or "soft" controlled ovarian stimulation (COS) vs conventional COS for IVF, OHSS, natural cycle IVF, and IVF outcome in association with COS was searched. RESULTS: Four possible mechanisms can be put forward to explain the apparent paradox of "less is more." (1) In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of "quality for quantity"; (2) high estradiol (E2) in the late follicular phase significantly correlated with higher rates of small for gestational age (SGA) and low-birth-weight (LBW) neonates; (3) anti-Mullerian hormone (AMH), LH, testosterone, and E(2) are significantly higher in natural cycle (NC)-IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles; and (4) supraphysiological E(2) may increase the growth hormone-binding protein (GH-BP) bio-neutralizing GH and diminishing the resultant insulin-like growth factor (IGF) levels, necessary for optimal synergism with follicle-stimulating hormone (FSH). CONCLUSIONS: It is suggested to aim at the retrieval of around eight to ten eggs. Mild stimulation should be the common practice for IVF. In cases where more than ten ova are retrieved or high E(2) levels are reached, either intentionally or unintentionally, "freeze-all policy" should be considered and embryo transfer (ET) done in a subsequent natural cycle.

Fetal demise in the early second trimester: sonographic findings.

PURPOSE: To report the etiology and the sonographic findings of fetal demise at 14-17 weeks' gestation. METHODS: A prospective transvaginal sonographic search of fetal anomalies was performed in 61 early second-trimester cases of fetal demise. The findings were compared with the results of sonographic examinations of 22,500 viable fetuses between weeks 14 and 17. RESULTS: Of 61 cases of early fetal demise in 60 women (1:370), more than half of the fetuses (35/61, 57%) were associated with fetal edema, ranging from nuchal edema and cystic hygroma to fetal hydrops. In 9/61 (14.7%) fetuses, major anatomic anomalies were detected. There was no significant difference between the study group (nonviable fetuses) and the control group (viable fetuses) regarding maternal age and the prevalence of maternal fever, maternal thrombophilic mutations, vaginal bleeding, fertility treatments, maternal diseases, or use of medications. CONCLUSIONS: The incidence of early midtrimester fetal demise is 1:370 pregnancies. The sonographic findings in fetal demise in the early second trimester suggest that 57% of them are associated with fetal edema and 14.7% are associated with major fetal malformations. We did not identify any significant maternal risk factor for fetal demise in the study group.

[The advantages of early midtrimester targeted fetal systematic organ screening for the detection of fetal anomalies--will a global change start in Israel?].

INTRODUCTION: Despite more than three decades of universal popularity of fetal sonography as an integral part of pregnancy evaluation, there is still no unequivocal agreement regarding the optimal dating of fetal sonographic screening and the type of ultrasound (transvaginal vs abdominal). METHODS: TransvaginaL systematic sonography at 14-17 weeks for fetal organ screening. RESULTS: The evaluation of over 72.000 early (14-17 weeks) and late (18-24 weeks) fetal ultrasonographic systematic organ screenings revealed that 96% of the malformations are detectable in the early screening with an incidence of 1:50 gestations. Only 4% of the fetal anomalies are diagnosed later in pregnancy. Over 99% of the fetal cardiac anomalies are detectable in the early screening and most of them appear in low risk gestations. CONCLUSIONS: Therefore, we suggest a new platform of fetal sonographic evaluation and follow-up: The extensive systematic fetal organ screening should be performed by an expert sonographer who has been trained in the detection of fetal malformations, at 14-17 weeks gestation. This examination should also include fetal cardiac echography Three additional ultrasound examinations are suggested during pregnancy: the first, performed by the patient's obstetrician at 6-7 weeks for the exclusion of ectopic pregnancy, confirmation of fetal viability, dating, assessment of chorionicity in multiple gestations, and visualization of maternal adnexae. The other two, at 22-26 and 32-34 weeks, require less training and should be performed by an obstetrician who has been qualified in the sonographic detection of fetal anomalies. SUMMARY: The advantages of early midtrimester targeted fetal systematic organ screening for the detection of fetal anomalies may dictate a global change.

Early prenatal diagnosis of tricuspid stenosis.

Although the prenatal diagnosis of heart anomalies has improved dramatically during the last 2 decades, the diagnosis of heart anomalies remains a challenge. Tricuspid stenosis has not been previously diagnosed in the early second trimester. The sonographic signs of early detection of tricuspid stenosis at 15 weeks of gestation included normal sized right atrium, small right ventricle, narrow pulmonary artery, and diminished flow through the tricuspid valve. The diagnosis was confirmed by postabortal examination. In this case report we describe, for the first time, early prenatal diagnosis of tricuspid stenosis at 15 weeks' gestational age.

A 10-year experience with treatment of high and standard risk Hodgkin disease: six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved.

Therapy of Hodgkin lymphoma (HL) is designed to prolong survival and minimize toxicity. A total of 124 patients with newly diagnosed HL and adverse prognostic factors were prospectively studied between July, 1999 and August, 2005. Patients with early unfavorable and advanced disease were eligible for the study. Patients were assigned to therapy based on international prognostic score (IPS). Those with IPS ≥ 3 received three cycles of escalated BEACOPP (EB). All others received two cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned according to early interim GA(67) or positron emission tomography (PET)/computerized tomography (CT). Four cycles of EB or SB were administered following a positive or negative scan, respectively. Complete remission rate, 10-year progression free (PFS), and overall survival (OS) were 97, 87, and 88%, respectively, at a median follow-up of 89 months (5-144). PFS and OS were similar in both groups. Fertility status was assessed in 38 females aged <40 years; 94% of females younger than 40 years preserved their cyclic ovarian function. Nineteen conceived during follow-up for 30 pregnancies, delivering 24 babies. Deliveries were reported up to 7 years from diagnosis. Predictive value of negative interim Ga(67) or PET/CT was 87 and 93%, respectively. Six cycles of tailored BEACOPP, for patients with adverse prognostic factors, provide encouraging long-term PFS and OS, and fertility is preserved in most females.

Transient abnormal fetal cardiac flow patterns at 13 to 17 gestational weeks.

OBJECTIVE: To report the outcome of transient abnormal cardiac flow patterns (ABCFP) at 13 to 17 weeks' gestation. METHODS AND RESULTS: Observational single operator study of transvaginal sonography scans of 13,183 fetuses. Of the 22 fetuses with ABCFP (1:600) high pulmonary valvular velocity was detected in 11 (8 of them transient), an abnormal blood flow in the coronary region in 6, mitral regurgitation in 3, and high aortic valvular velocity in 2 cases. In over 90%, these findings were transient. At birth, there were two cases of mild pulmonary stenosis, one meconium ileus, and two cases of asymptomatic bicuspid aortic valve without stenosis. All the remaining neonates were healthy. CONCLUSIONS: The transient sonographic findings at 13 to 17 weeks' gestation of mitral regurgitation, pulmonary or aortic high valvular flow, and coronary sinus flow have a good prognosis, and in most cases are not associated with persistent cardiac anomalies. The etiology, incidence, and the prognosis of fetuses with transient ABCFP at 13 to 17 weeks' gestation are different from what is observed when the same occurs later in gestation.

Fetal transient clitoromegaly and transient hypertrophy of the labia minora in early and mid pregnancy.

OBJECTIVE: The purpose of this study was to describe a series of cases of transient changes in the female fetal external genitalia. METHODS: In our practice area, most pregnant women usually undergo a detailed sonographic survey of all fetal organs, including the external genitalia in early and mid pregnancy. RESULTS: During the study period (1987-2010), 62,145 consecutive pregnant women were scanned. We detected 4 fetuses with an isolated finding of clitoromegaly at 15 to 16 weeks' gestation, which disappeared at 22 to 26 weeks. Maternal hormonal study results were normal. There was 1 case of clitoromegaly and a cloacal anomaly at 15 weeks' gestation, in which the clitoris retuned to a normal size at 22 weeks. In addition, there were 3 cases of hypertrophy of the labia minora in early pregnancy, which disappeared at 26 to 32 weeks. All fetuses in these series had a normal XX karyotype and normal external genitalia at birth. CONCLUSIONS: Transient changes in the appearance of the fetal external genitalia may occur in chromosomally normal female fetuses.

Successful Delivery in 17,20-Lyase Deficiency.

CONTEXT: Pregnancy achievement in an infertile patient with 17,20-lyase deficiency. OBJECTIVE: To study and describe the achievement of successful pregnancy and delivery in a patient with 17,20-lyase deficiency. METHOD: Controlled ovarian stimulation (COS) and in vitro fertilization (IVF), cryopreservation of embryos and frozen-thawed embryo transfer (ET). Controlled ovarian stimulation, follicular aspiration egg retrieval, IVF, embryo cryopreservation, thawed ET. A 24-year-old, infertile patient with 17,20-lase deficiency. RESULTS: Isolated 17,20-lyase deficiency is caused by mutations in the CYP17A1 gene (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase), and CYB5A (coding for microsomal cytochrome b5) genes. A 24-year-old patient with 17,20-lyase deficiency had undergone IVF with gonadotropin releasing hormone agonist (GnRHa) protocol, prednisone, and gonadotropins. After the human chorionic gonadotropin (hCG) trigger, 37 oocytes were retrieved, 25 ova fertilized, and 17 embryos cryopreserved. After menstrual bleeding, the endometrium was stimulated with oral estradiol, under progesterone suppression with long acting GnRHa and prednisone. When endometrial width of 8.5 mm was reached, vaginal progesterone was added, while gradually decreasing prednisone. On the fourth day of progesterone supplement, 2 thawed embryos were transferred. After 11 days of human menopausal gonadotropin (hMG), estradiol concentration moderately increased, but progesterone levels remained high; therefore, no fresh ET was performed. Twelve days after thawed ET, hCG was positive, and 7 days later, an intrauterine gestational sac was detected, but the pregnancy ended in missed abortion. After 2 months, another frozen-thawed embryo transfer (FET) was performed, generating a normal gestation, which ended in successful delivery. CONCLUSION: Pregnancy can be achieved in patients with 17,20-lyase deficiency, by IVF, freezing all embryos, and ET in a subsequent cycle, while suppressing endogenous ovarian progesterone with a GnRHa and adrenal suppression with high-dose glucocorticoids.