Mutation Spectrum of Familial Adenomatous Polyposis Patients in Turkish Population: Identification of 3 Novel APC Mutations

BackgroundFamilial adenomatous polyposis (OMIM #175100) and MUTYH-associated polyposis (OMIM #608456) are rare cancer-prone disorders characterized by hundreds of adenomatous polyps in the colon and rectum, which have a high probability of malignant transformation. Attenuated familial adenomatous polyposis is a variant of familial adenomatous polyposis, which is a term used for the condition in which patients have less than 100 colorectal polyps. Germline heterozygous Adenomatous polyposis coli (APC) and biallelic MUTYH (mutY DNA glycosylase) pathogenic variations are responsible for familial adenomatous polyposis and MUTYH-associated polyposis respectively. The aim of this study is to discuss the clinical manifestations of patients having pathogenic APC and MUTYH variations.MethodsWe included 27 probands who have more than 10 colonic polyps in this study. After evaluation of their clinical and family histories, the probands were screened for APC and MUTYH variations via next generation sequencing. The family members of the probands carrying pathogenic variations were screened via Sanger sequencing. ResultsAmong 27 probands, pathogenic APC and MUTYH variations were detected in 3 and 6 probands respectively. In the APC gene, 3 novel truncating variations (p.Leu360*, p.Leu1489Phefs*23, and p.Leu912*) were detected in 3 unrelated probands. In the MUTYH gene, only 2 distinct pathogenic variations were detected (p.Pro295Leu and p.Glu480del) in the homozygous or compound heterozygous state.ConclusionIn this study, molecular etiology was clarified in 9 familial polyposis patients. The p.Pro295Leu and p.Glu480del variations seem to be common in the Turkish population and may be considered as a first-step genetic test in Turkish familial polyposis patients showing autosomal recessive inheritance. However more studies are needed to reveal the exact frequency of these variations.     

Factors affecting live birth rate in intrauterine insemination cycles with recombinant gonadotrophin stimulation

The objective of this cross-sectional study was to identify the prognostic factors that influence the outcome of ovarian stimulation with intrauterine insemination (IUI) cycles using gonadotrophins in couples with unexplained and mild male-factor subfertility. A total of 838 cycles in 456 women with unexplained and mild male-factor subfertility attending a university-based infertility clinic was evaluated. Of these cycles, 139 resulted in pregnancy (16.6% per cycle) and 96 out of 98 ongoing pregnancies resulted in live term birth. Live birth rate per patient and per cycle was 21.1% and 11.4%, respectively. Multivariate logistic regression analysis demonstrated that duration of infertility (P = 0.034), type of infertility (P = 0.003), aetiology of infertility (P = 0.004), number of treatment cycles (P = 0.0001) and number of dominant follicles before human chorionic gonadotrophin (HCG; P = 0.024) were significant independent factors to predict clinical pregnancy. The duration of infertility (P = 0.043), number of treatment cycles (P = 0.0001) and number of dominant follicles before HCG (P = 0.024) were significant independent factors to predict live birth. In conclusion, for subfertile couples having shorter duration of subfertility, multifollicular response to gonadotrophins and in their first treatment cycle are more likely to succeed a live birth with IUI treatment using recombinant gonadotrophins.     

Integrated testing and management in fetal growth restriction

Growth-restricted fetuses are at higher risk for poor perinatal and long-term outcome than those who are appropriately grown. Multiple antenatal testing modalities can help document the sequence of fetal deterioration. The full extent of this compromise is best identified by a combination of fetal biometry, biophysical profile scoring, and arterial and venous Doppler. In the preterm growth-restricted fetus, timing of delivery is critically determined by the balance of fetal versus neonatal risks. In the near-term fetus, accurate diagnosis continues to be a challenge as unrecognized growth restriction contributes to a significant proportion of unexplained stillbirths. In this review, we present an integrated diagnostic and surveillance approach that accounts for these factors.     

Fetal growth restriction

Normal fetal growth is determined by the genetically predetermined growth potential and further modulated by maternal, fetal, placental, and external factors. Fetal growth restriction (FGR) is a failure to reach this potential and is clinically suspected if sonographic estimates of fetal weight, size, or symmetry are abnormal. Integration of fetal anatomy assessment, amniotic fluid dynamics, uterine, umbilical, and fetal middle cerebral artery Doppler is the most effective approach to differentiate potentially manageable placenta-based FGR from aneuploidy, nonaneuploid syndromes, and viral infection. Although placental dysfunction results in a multisystem fetal syndrome with impacts on short- and long-term outcome, only cardiovascular and behavioral responses are helpful to guide surveillance and intervention. Early-onset FGR before 34 weeks gestation is readily recognized but challenging to manage as questions about optimal delivery timing remain unanswered. In contrast, near-term FGR provides less of a management challenge but is often missed as clinical findings are more subtle. Once placenta-based FGR is diagnosed, integrating multivessel Doppler and biophysical profile score provides information on longitudinal progression of placental dysfunction and degree of fetal acidemia, respectively. Choosing appropriate monitoring intervals based on anticipated disease acceleration and intervention when fetal risks exceed neonatal risks are the prevailing current management approaches.     

Diagnosis and prognosis in double-outlet right ventricle

The aim of this study was to examine prenatal diagnosis of double-outlet right ventricle (DORV)-associated anomalies and prognosis of each case. Medical records were reviewed of fetuses with DORV who had fetal echocardiography at our institution from 2002 to 2006. Pre- and postnatal diagnosis and outcome were compared and evaluated. Twenty-one fetuses were diagnosed with DORV. The pregnancy was terminated in seven cases. Three cases had chromosomal abnormalities; three cases, hypoplastic left ventricle; and one case, encephalocele. Accurate prenatal diagnosis of the ventricular septal defect, outflow obstruction, and great artery relationship was achieved in 14 of 16 cases (87.5%). Only 2 of 13 live-born cases survived beyond 6 months. The overall prognosis for fetuses with DORV is poor. DORV is found in fetuses with a huge spectrum of associated cardiac and extracardiac anomalies. Careful assessment by fetal echocardiography can determine important anatomic details with adequate correctness for precise counseling.     

Protease inhibitor therapy and fetal growth potential in HIV-positive women

Our objective was to test if protease inhibitors (PIs) increase the incidence of fetal growth restriction (FGR). Human immunodeficiency (HIV)-seropositive women were studied. At birth the neonatal weight percentile was assigned by predicted growth potential (GP), accounting for race, parity, weight, height, gestational age, birthweight, and gender (Gardosi, 1992). FGR was defined as GP < 10% percentile. Maternal age, CD4 count, viral load, weight gain, prenatal care, tobacco, alcohol, substance abuse, and PI use were related to FGR using chi-square and multiple regression analysis. Ninety-three of 191 women received PI. In these, FGR occurred in 27 (29%) compared with 15 (15.3%) in the non-PI group ( P = 0.02). Maternal CD4 count ( P < 0.0001) was the primary determinant, and smoking ( P = 0.037) was an independent cofactor for FGR (Nagelkerke r2 = 0.24). Twenty-six of 82 (31.7%) smokers had FGR, versus 16 of 109 (14.7%) of nonsmokers (odds ratio, 2.69; 95% confidence interval, 1.33 to 5.46; P = 0.005). After exclusion of the CD4 count, PI became a cofactor for FGR ( P = 0.021 and Nagelkerke r2 = 0.104). We concluded that maternal HIV status and smoking determine the risk for FGR. Although PIs increase the risk for FGR, this effect appears to depend on maternal disease severity.     

Ultrasound screening for fetal major abnormalities at 11-14 weeks

BACKGROUND: This study was planned to evaluate the efficiency of the 11-14 week scan in detecting fetuses with major fetal structural abnormalities. METHODS: Some 1,290 pregnant women were submitted to a routine ultrasound scan between the 11th and 14th week after the detection of the fetal viability. The fetal anatomy was examined transabdominally, and in suspected cases transvaginally. Following the scans, the patients were examined in the second or third trimester of pregnancy. Fetal structural abnormalities classified as major and early onset were noted. Isolated choroid plexus cysts, cardiac defects not requiring treatment, mild ventriculomegaly, and mild renal pelviectasis in second trimester were not included. RESULTS: Twenty-four (1.86%) fetuses with various defects were identified, and 17 of these were diagnosed at the 11-14 week scan. The antenatal ultrasound detection rate of the fetuses with major anomalies was 95%, and 70% were detected in the first-trimester assessment. Four cardiac defects associated with genetic syndromes or requiring operation were included (0.31%) in this series. Two of the fetuses with cardiac defects (50%) had an increased nuchal translucency thickness. In this group, none of the fetuses with karyotype anomalies was born alive. CONCLUSIONS: The first-trimester scan is important in routine antenatal care for early detection of fetal defects, and determination of the fetuses at risk of cardiac anomalies and genetic syndromes.