Genetic Counseling of Fetal Microcephaly.

Fetal microcephaly is a small head with various losses of cerebral cortical volume. The affected cases may suffer from a wide range in severity of impaired cerebral development from slight to severe mental retardation. It can be an isolated finding or with other anomalies depending on the heterogeneous causes including genetic mutations, chromosomal abnormalities, congenital infectious diseases, maternal alcohol consumption, and metabolic disorders during pregnancy. It is often a lifelong and incurable condition. Thus, early detection of fetal microcephaly and identification of the underlying causes are important for clinical staff to provide appropriate genetic counseling to the parents and accurate management.

Prenatal diagnosis and genetic counseling of uniparental disomy.

Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from a single parent. Most chromosomes involving UPD have no pathogenic effects. However, abnormal phenotypes in cases with UPD can be mainly caused by disrupting genetic imprinting and by uncovering harmful autosomal recessive mutations. The documented phenotypes of UPD associated with imprinted genes include maternal UPD for chromosomes 7, 11, 14, 15, 16, and 20, and paternal UPD for chromosomes 6, 11, 14, 15, and 20. Prenatal awareness of UPD is important to provide accurate genetic counseling and prenatal UPD test is suggested when abnormal fetal ultrasound with suspicious phenotypes for UPD syndromes caused by genetic imprinting disorders or presence of chromosomal aberrations involving the imprinted chromosomes.

Prenatal detection and characterization of a psu idic(8)(p23.3) which likely derived from nonallelic homologous recombination between two MYOM2-repeats.

Mosaicism with an isodicentric 8 with a breakpoint at p23.3 [idic(8)(p23.3)] is very rare. We report the first prenatal case on a male fetus, in which obstetric ultrasound revealed multiple congenital anomalies at 28 weeks of gestation. Cytogenetic analysis of amniocytes showed mos 45,XY,-8,psu idic(8)(p23.3)[16]/46,XY,psu idic(8)(p23.3)[4], and that of cord blood lymphocytes revealed mos 46,XY, psu idic(8)(p23.3)[37]/45,XY,-8,psu idic(8)(p23.3)[13]. Fluorescence in situ hybridization studies revealed that the break-reunion occurred at the cytoband 8p23.3 within the physical position 2.08 Mb from the 8p telomere. Chromosomal microarray analyses further assigned the duplication/deletion breakpoint at 2.16 Mb (Agilent 244K) and at 2.19 Mb (Affymetrix SNP6.0). Analysis of microsatellite DNA indicated that the psu idic(8)(p23.3) was derived from the maternal chromosome 8. Together, these findings indicate that the fetus was nullisomic for ~2.2 Mb from 8pter, trisomic for the rest of chromosome 8 in mosaic condition, and likely had breaks in MYOM2 repeats of the maternal chromosome 8.

Repairing the ventral root is sufficient for simultaneous motor and sensory recovery in multiple complete cervical root transection injuries.

AIM: In multiple cervical root transection injuries, motor and sensory recovery has been demonstrated after repairing both dorsal and ventral roots with autologous grafts applied to the dorsal and ventral aspects, respectively. However, in clinical situations, autologous grafts may not be sufficient to repair both roots in this situation. In this study, the authors evaluated whether repairing ventral root alone is sufficient for simultaneous sensory and motor function recovery. MAIN METHODS: In the transected group, the left 6th-8th cervical roots were pulled and transected at the spinal cord junction. In the repair group, the transected root was anastomosed to a single autologous nerve graft, which was inserted into the ventral horn through a pial incision. Acidic fibroblast growth factor mixed with fibrin glue was applied to the surgical area. Motor function, sensory function, cortical somatosensory evoked potentials (SSEPs), axon tracing, and CGRP(+) fibers were evaluated. KEY FINDINGS: The repaired rats exhibited simultaneous sensory and motor function recovery. At the 16th weeks, SSEPs reappeared in all animals of the repair group, but not in the transected group. Retrograde axon tracing demonstrated an increased number of sensory neurons in the dorsal root ganglia and regenerating nerve fibers in the dorsal horn. CGRP(+) fibers were significantly increased in the repair group and restricted to laminae I and II. SIGNIFICANCE: This is the first report that in multiple root avulsions with insufficient grafts, repairing ventral roots alone leads to both sensory recovery and motor recovery. This finding may help patients with multiple cervical root avulsions.

Chromosomal deletions detected at amniocentesis.

OBJECTIVE: The aim of this study is to present the incidence, prenatal and postnatal findings, and modes of ascertainment in chromosomal deletions detected at amniocentesis. MATERIALS AND METHODS: We reviewed all the cases with chromosomal deletions, which were detected by amniocentesis in Mackay Memorial Hospital, Taipei, Taiwan, between January 1987 and December 2012. Data on the locations and types of deletion, reasons for performing amniocentesis, maternal age, gestational age at amniocentesis, fetal karyotypes, inheritance of deletions, and relative prenatal findings were collected. RESULTS: Amniocentesis was performed in 33,305 cases within this period of time. Among these, 31 cases of chromosomal deletions were considered for the study. The mean gestational age at amniocentesis was 21.0 weeks (range from 15 weeks to 32 weeks) and the mean maternal age at amniocentesis was 32.1 years (range from 26 years to 37 years). Nineteen cases (61.3%) manifested fetal structural abnormalities on ultrasound, nine (29.0%) presented no ultrasound abnormalities, and three had an unknown status. The main modes of ascertainment included abnormal ultrasound findings in 10 cases (32.2%), advanced maternal age in 11 cases (35.5%), abnormal maternal serum screening results in six cases (19.6%), and other reasons in four cases (13.0%). Of the 27 cases with known inheritance, the deletion was inherited in two (6.6%) and de novo in 25 (92.6%). Males accounted for 11 (35.5%) and females for 20 (64.5%) cases. Chromosomal deletions are more often to occur in chromosomal 5(4 cases, 12.9%), chromosomal 18 (4 cases, 12.9%), chromosomal 4 (3 cases, 9.7%), chromosomal 7 (3 cases, 9.7%), chromosomal 10 (3 cases, 9.7%), chromosomal 11 (3 cases, 9.7%), and chromosomal 1 (2 cases, 6.5%). There were four cases of chromosomal mosaicism: two involved chromosome 5, one involved chromosome 10, and one involved chromosome 18. Twenty-three cases (74.2%) had terminal deletions and the other eight cases (26.7%) had interstitial-type deletions. CONCLUSION: In summary, we have presented the results of prenatal diagnosis for chromosomal deletions using amniocentesis. Chromosomal deletions are more likely to occur in females and more often in chromosomal 5p and 18q. Prenatal diagnosis at amniocentesis is frequently associated with advanced maternal age, abnormal ultrasound findings, and abnormal maternal serum screening. The frequency of ascertainment in chromosome deletion seems to be directly correlated with advanced maternal age and abnormal ultrasound findings. In cases with terminal deletions, prenatal ultrasound plays a more important role for prenatal diagnosis.

The use of misoprostol in termination of second-trimester pregnancy.

Misoprostol, a synthetic prostaglandin E1 analog, is initially used to prevent peptic ulcer. The initial US Food and Drug Administration-approved indication in the product labeling is the treatment and prevention of intestinal ulcer disease resulting from nonsteroidal anti-inflammatory drugs use. In recent two decades, misoprostol has approved to be an effective agent for termination of pregnancy in various gestation, cervical ripening, labor induction in term pregnancy, and possible management of postpartum hemorrhage. For the termination of second-trimester pregnancy using the combination of mifepristone and misoprostol seems to have the highest efficacy and the shortest time interval of abortion. When mifepristone is not available, misoprostol alone is a good alternative. Misoprostol, 400 µg given vaginally every 3-6 hours, is probably the optimal regimen for second-trimester abortion. More than 800 µg of misoprostol is likely to have more side effects, especially diarrhea. Although misoprostol can be used in women with scarred uterus for termination of second-trimester pregnancy, it is recommended that women with a scarred uterus should receive lower doses and do not double the dose if there is no initial response. It is also important for us to recognize the associated teratogenic effects of misoprostol and thorough consultation before prescribing this medication to patients regarding these risks, especially when failure of abortion occurs, is needed.

Factors associated with operative hysteroscopy outcome in patients with uterine adhesions or submucosal myomas.

OBJECTIVE: To determine the factors associated with hysteroscopic surgery long-term outcome in patients with intrauterine adhesions or submucosal myomas. METHODS: Factors thought to be associated with outcome were retrospectively evaluated from the records of 591 patients who were followed up for at least 5years after undergoing hysteroscopic adhesiolysis (n=203) or myomectomy (n=388). RESULTS: The major factors affecting outcome were degree of adhesion (OR, 1.91; P=0.03) in the former group and parity (OR, 0.55; P=0.005) and depth of intramural penetration of the myoma (OR, 30.74; P<0.001) in the latter. Severe intrauterine adhesion, low parity, and deep intramural penetration of submucosal myoma had an associated increase risk of poor outcome. The overall complication rate was 1.35% and, respectively, 12.8% and 9.3% of the patients who underwent hysteroscopic adhesiolysis or myomectomy needed a second intervention. CONCLUSION: Hysteroscopic surgery is a safe and effective procedure. Degree of adhesion or parity and depth of intramural penetration of myomas are the major factors affecting outcome in patients with these lesions.

Rare rearrangements: a "jumping satellite" in one family and autosomal location of the SRY gene in an XX male.

A satellited short arm of the Y chromosome (Yps) is rare. Only one de novo case of Yps has been documented. Here we report the prenatal diagnosis of Yps in a male fetus with a karyotype, 46,XYps. Family chromosome study showed that the father and a sister had a satellited short arm of the X chromosome (Xps). A phenotypically normal male child with the Yps was delivered. This is the first familial case showing a satellite "jumping" from Xp to Yp. We propose that it resulted from a crossover within the pseudoautosomal region 1 (PAR1) on the distal Xp and Yp during paternal meiosis. In addition to the rare translocation mentioned above, relocation of the SRY gene onto an autosome in XX males is also a rare event. Herein we report a phenotypically normal male fetus with a 46,XX karyotype. Fluorescence in situ hybridization (FISH) study showed that the SRY locus had been transferred to the terminal short arm of a chromosome 3. The terminal short arm deletion of this chromosome 3 was also confirmed by FISH study with a subtelomeric probe and the breakpoint of the terminal deletion was estimated between 446 and 664 kb from the 3p telomere by real-time qPCR study with a gene sequence and STS markers in this region. A healthy boy was delivered at 37 weeks of gestation. At 1-year follow-up, the child's growth pattern and development were appropriate for age.

Prenatal diagnosis of mos45,X/46,X,+mar in a fetus with normal male external genitalia and a literature review.

OBJECTIVE: Prenatal diagnosis of mos45,X/46,X,+mar is difficult in genetic counseling. Patients with the presence of a Y-derived marker may manifest male or female external genitalia. Here, we report a fetus with phenotypically male external genitalia of mos45,X/46,X,+mar. In addition, the cases with prenatally detected mos45,X/ 46,X,del(Y)(q11.2) and normal male external genitalia are reviewed. CASE REPORT: A 30-year-old, primigravid woman was referred for amniocentesis because of an abnormal Down syndrome screening result at 20 weeks' gestation. Cytogenetic analysis showed mos45,X/46,X,+mar without a normal Y chromosome. Prenatal ultrasound detected symmetric intrauterine growth restriction and normal male external genitalia. After termination of the pregnancy, a phenotypically normal male fetus was delivered smoothly without apparent structural defects. Based on conventional G-banded analysis, the marker chromosome appeared as a Y chromosome that originated with a deleted Yq, designated as del(Y)(q11.2). CONCLUSION: Based on a literature review, the addition of fluorescence in situ hybridization and molecular analysis to the conventional cytogenetic techniques can provide more accurate identification of a Y chromosome aberration in the prenatal detection of mos45,X/46,X,+mar, thus allowing more appropriate genetic counseling for the family.

Prenatal 3-dimensional sonographic and MRI findings in omphalocele-exstrophy-imperforate anus-spinal defects complex.

We describe the second-trimester 3D sonographic and MRI findings of omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex. We suggest that fetal 3-dimensional sonography with tomographic ultrasound imaging and MRI are useful adjuncts to conventional 2-dimensional sonography in the prenatal diagnosis of OEIS complex.

Use of multiplex PCR and CE for gene dosage quantification and its biomedical applications for SMN, PMP22, and alpha-globin genes.

Many genetic diseases are caused by the presence of point mutations, small insertions, and deletions in respective genes, and the number of diseases known to be caused by deletions and duplications involving large DNA genomes is increasing. These changes lead to underexpression or overexpression of the gene, according to changes in gene dosage. The methods for the detection of point mutations, small insertions, and deletions are well established, but the detection of larger genomic deletions or duplications is more difficult. Due to the lack of efficient and technically feasible protocols for gene dosage quantification, we describe a diagnostic protocol employing a combination of available methods. The efficient and accurate gene dosage quantification platform is combined with multiplex PCR and CE, and applied to detect dosages of several genes, including SMN, PMP22, and alpha-globin genes. The reliability of this novel methodology shows that it is a relatively speedy and low-cost procedure and a significant tool for genetic diagnosis. Its sensitivity and specificity for identifying deletion and duplication genotypes approach 100%. Moreover, once we establish this powerful system, we will further apply this technique to the rapid detection of trisomy syndromes and microdeletion syndromes, including trisomy 13, Down syndrome, DiGeorge syndrome, and others.