Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.

The identification of disease causing mutation in patients with neurodegenerative disorders originating from small, non-consanguineous families is challenging. Three siblings were found to have ventriculomegaly at early gestation; postnatally, there was no acquisition of developmental milestones, and the muscles of the children were dystrophic. Plasma and CSF lactate levels were normal, but the activities of mitochondrial complex I and IV were markedly decreased. Using linkage analysis in the family, followed by whole exome sequencing of a single patient, we identified a pathogenic mutation in the AIFM1 gene which segregated with the disease state and was absent in 86 anonymous controls. This is the second report of a mutation in the AIFM1 gene, extending the clinical spectrum to include prenatal ventriculomegaly and underscores the importance of AIF for complex I assembly. In summary, linkage analysis followed by exome sequencing of a single patient is a cost-effective approach for the identification of disease causing mutations in small non-consanguineous families.

Application of 3-dimensional ultrasonography to imaging the fetal anal canal.

OBJECTIVE: Ultrasonography has been applied previously to the assessment of the fetal anal canal. We aimed to examine the potential of 3-dimensional ultrasonography (3DUS) in the evaluation of the fetal anal canal and to obtain normal fetal anal canal measurements. METHODS: Patients were recruited from an unselected population of gravidas with known gestational age (by dates or first-trimester ultrasonography) and without known fetal anomalies presenting for fetal evaluation in the ultrasound units of 2 tertiary care centers between 16 and 39 gestational weeks. In addition to the ordered scan, 3DUS imaging of the fetal anal canal was performed. Transverse and sagittal views and volumes were obtained. Measurements of the fetal anal canal anteroposterior diameter, lateral diameter, and length were performed in transverse and sagittal planes, respectively, and scatterplots of these dimensions were created. Measurements were performed and repeated on raw data sets by 2 independent observers, and the results were analyzed to estimate interobserver and intraobserver reliability. RESULTS: A total of 186 patients were examined for this study at 16 to 39 weeks' gestation (mean, 27.4 weeks). The anteroposterior diameter of the fetal anal canal in this study group ranged from 4 to 21 mm (mean, 11.2 mm; SD, +/-3.5 mm), whereas the lateral diameter ranged from 7 to 18 mm (mean, 9.1 mm; SD, +/-3.0 mm). The length of the fetal anal canal in this study group ranged from 3 to 24 mm (mean, 14.3 mm; SD, +/-3.8 mm). CONCLUSIONS: Ultrasonographic assessment of the fetal anal canal with 3DUS is feasible. Scatterplots were created for internal anal sphincter width and length measurements from 16 to 39 weeks' gestation. Larger studies are necessary to establish nomograms of these measurements and their application to the evaluation of pathologic cases. We speculate that 3DUS assessment of the fetal anal canal may improve detection rates of disorders involving this system.

Severe infantile carnitine palmitoyltransferase II deficiency in 19-week fetal sibs.

Antenatal presentation of carnitine palmitoyltransferase type II deficiency due to mutations in the CPT2 gene has been rarely reported. We report an Ashkenazi Jewish family with 3 terminated pregnancies for multicystic kidneys and/or hydrocephalus. Fetal autopsy after termination of the couple's 4th pregnancy (sib 2) showed renal parenchyma replaced by cysts that appeared to increase in diameter toward the medulla. Fetopsy after termination of the 7th pregnancy (sib 3) revealed micrognathia; hypospadias; cystic renal dysplasia; hepatosteatosis; and lipid accumulation in the renal tubular epithelium, myocardium, and skeletal muscle. Microvascular proliferative changes and focal polymicrogyria were seen in the brain. A beta-oxidative enzyme deficiency was suspected. CPT2 gene analysis showed a homozygous complex haplotype for the F448L mutation associated with a c.del1238_1239AG (p.Q413fs) truncating mutation in exon 4. Carnitine palmitoyltransferase type II deficiency should be included in the differential diagnosis in fetuses of Ashkenazi origin with multicystic kidneys and unusual cerebral findings.

The clinical spectrum of fetal Niemann-Pick type C.

Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.

Rudimentary horn pregnancy: first-trimester prerupture sonographic diagnosis and confirmation by magnetic resonance imaging.

OBJECTIVE: Two cases of rudimentary horn pregnancy diagnosed in the first trimester by sonography and confirmed by magnetic resonance imaging (MRI) are reported. We suggest criteria for early, prerupture sonographic diagnosis of this rare condition. METHODS: We report a case in which pregnancy in a rudimentary horn was suspected on routine sonographic examination. In the second case, sonographic examination at 11 weeks' gestation revealed a right unicornuate uterus and a noncommunicating left rudimentary horn containing a gestational sac. In both cases, MRI clearly confirmed the sonographic diagnosis, showing an empty cavity of the uterine body and a pregnant uterine horn without an endometrial communication to the uterine body. RESULTS: Both patients underwent surgery, and the pregnant rudimentary horns were resected with no complications. CONCLUSIONS: We suggest the following criteria for sonographic diagnosis of rudimentary horn pregnancy: (1) a pseudopattern of a asymmetrical bicornuate uterus, (2) absent visual continuity tissue surrounding the gestational sac and the uterine cervix, and (3) the presence of myometrial tissue surrounding the gestational sac. Typical hypervascularization of placenta accreta may support the diagnosis. Additionally, MRI can be used to confirm the diagnosis before an invasive procedure is undertaken.

The role of magnetic resonance imaging in the evaluation of isolated mild ventriculomegaly.

OBJECTIVE: Isolated mild ventriculomegaly is defined as dilatation of the lateral ventricle from 10 to 15 mm, with no other structural abnormalities observed at the time of diagnosis. Its reported frequency is between 1 per 50 and 1 per 700 deliveries. There are no universal recommendations for evaluation of isolated mild ventriculomegaly. Targeted sonography, karyotype analysis, and viral antigen testing, particularly for cytomegalovirus, are most often used for further investigation of this finding. We studied the role of magnetic resonance imaging as part of the prenatal evaluation of isolated mild ventriculomegaly. METHODS: Thirty-six pregnant women were referred to 2 Hadassah hospitals between 1999 and 2002 for evaluation of isolated mild ventriculomegaly. They underwent targeted sonography to exclude other anomalies, genetic amniocentesis for fetal karyotype, and serologic cytomegalovirus tests. Mild ventriculomegaly was the only pathologic finding diagnosed. Fetal brain magnetic resonance imaging was performed to evaluate the correlation between sonographic and magnetic resonance imaging findings and the additional contribution of magnetic resonance imaging in evaluating isolated mild ventriculomegaly. RESULTS: Thirty-six magnetic resonance imaging studies were performed. All tests were adequate for evaluation. In 3 (8.3%) of 36 cases, magnetic resonance imaging showed additional findings: in a severely obese woman, ventricular dilatation up to 18 mm and periventricular cystic lesions with abnormal sulcation suggestive of diffuse parenchymal abnormality were diagnosed, and in 2 cases, bleeding in germinal centers was found. On subsequent sonographic examination, no other finding but isolated mild ventriculomegaly was diagnosed. In the remaining 33 women (91.7%), magnetic resonance imaging studies correlated well with sonographic findings. Further sonographic follow-up in this subgroup failed to reveal any other pathologic findings. CONCLUSIONS: Our study supports the view that magnetic resonance imaging should be considered as part of the evaluation of isolated mild ventriculomegaly, especially when objective difficulties preclude detailed sonographic examination.

Utero-ovarian morphology and blood flow after tubal ligation by the Pomeroy technique.

OBJECTIVES: The objectives of this study were to evaluate ovarian sonographic morphology and pelvic blood flow in patients who had undergone bilateral tubal ligation by the Pomeroy technique. DESIGN: Twenty women who had undergone bilateral tubal ligation during cesarean section by the Pomeroy techniques were compared to 20 matched controls who had undergone cesarean section alone. Ovarian morphology as well as ovarian and uterine pulsatility index (PI), resistance index and peak systolic velocity were evaluated using transvaginal sonography and Doppler velocimetry. RESULTS: Patients post tubal ligation by the Pomeroy technique were found to have a significantly higher rate of polycystic appearance of the ovaries (60% vs. 5%; p < 0.005). Six patients (30%) had post tubal ligation symptoms, as compared to none of the controls. Five of the six symptomatic tubal ligation patients (83%) had ovarian polycystic appearance, which was not significantly different than asymptomatic patients. Ovarian artery PI was significantly higher in symptomatic patients (2.7 +/- 1.9) compared to asymptomatic patients (1.5 +/- 0.9) (p < 0.05). CONCLUSIONS: We therefore conclude that patients post bilateral tubal ligation by the Pomeroy technique may acquire an ovarian polycystic appearance and increased ovarian PI, which may be associated with a tendency to develop post tubal ligation symptoms.

A multidisciplinary team approach for management of a giant congenital cervical teratoma.

Congenital cervical teratomas are associated with a high rate of perinatal mortality due to airway obstruction. We describe a multidisciplinary management of a neonate with prenatal diagnosis of giant cervical teratoma. An 'operation on placenta support' (OOPS) technique was carried out during delivery, and intubation was successfully performed with no perinatal anoxic damage. Postnatal computed tomography and angiography showed a huge teratoma covering both sides of the neck with agenesis of the big blood vessels on the left side. A rapidly developing third space phenomenon and deterioration in the general status of the neonate, required early surgical intervention. During surgical excision, the left carotid artery and internal jugular vein, the left lobe of the thyroid gland and the left recurrent laryngeal nerve were not detected. The left vagus, accessory and hypoglossal nerves were positioned between the skin and the tumor, at a distance from their normal anatomical location. Pathologic examination confirmed the diagnosis indicating immature teratoma with no signs of malignancy. The postoperative period was complicated by neurological deterioration, pharyngo-cutaneous fistula and paresis of the left hypoglossal nerve. However, all the symptoms resolved spontaneously. Tracheotomy was performed when the baby was 6 weeks old due to paralysis of the left vocal cord and to severe laryngo-tracheomalacia. She was decannulated when she was 3 years old. Today, she is suffering only from dysphonia. This report confirms the efficacy of a multidisciplinary team-approach and the usefulness of the OOPS technique in prenatally diagnosed cervical masses. It emphasizes the extraordinary characteristics of this case, mainly the development of a third space phenomenon and the unusual surgical findings.