Michal Berkenstadt

Frequency of Down's syndrome and neural-tube defects in the same family

BACKGROUND There is evidence that some mothers of infants with Downs syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Downs syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately. METHODS We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Downs syndrome. FINDINGS In the families at risk of NTD, there were a total of 11 pregnancies affected by Downs syndrome in 1492 at-risk pregnancies (compared with 1.87 expected on the basis of maternal age), which was a significant increase (p<0.00001). In the families at risk of Downs syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1.37 expected (p<0.001). INTERPRETATION In this study, we provide direct evidence of a link between Downs syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Downs syndrome.

Three‐dimensional ultrasound demonstration of the fetal palate in high‐risk patients: the accuracy of prenatal visualization

The aim of this research was to evaluate the ability of three‐dimensional (3D) ultrasound for demonstrating the palate of fetuses at high risk for cleft palate.

SECOND-TRIMESTER ULTRASONOGRAPHIC DIAGNOSIS OF SEGMENTAL VERTEBRAL ABNORMALITIES ASSOCIATED WITH NEUROLOGICAL DEFICIT: A POSSIBLE NEW VARIANT OF OCCULT SPINAL DYSRAPHISM

Sonographic evaluation of the fetal spine in a second‐trimester, low‐risk patient revealed segmentary, low thoracic vertebral abnormalities, including hemi‐ and butterfly vertebrae, resulting in severe fetal scoliosis with fetal paraplegia and bilateral club‐feet. X‐ray and magnetic resonance imaging studies of the abortus confirmed the prenatal vertebral findings in addition to rib defects and transection of the spinal cord. We believe that these findings which, to the best of our knowledge, have not been previously reported, represent a new variant of occult spinal dysraphism.

Brachydactyly type A-7 (Smorgasbord): a new entity

We report a family with a form of brachydactyly that involves characteristic features of types A2 and D brachydactyly plus features found in other types of brachydactyly and also features not previously noted. This set of findings represents a new syndrome, which we have termed brachydactyly type A7 (Smorgasbord).

LMOD3-Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings: LMOD3-Associated Nemaline Myopathy

To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3‐related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole‐exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron‐dense protein inclusions in skeletal myofibers. Although clinically, nemaline myopathy can be viewed as a common pathway phenotype, its molecular basis is heterogeneous, with mutations in 11 identified genes implicated in its pathogenesis so far. Whole‐exome sequencing revealed that the affected fetuses were compound heterozygous for 2 newly reported pathogenic variants in the LMOD3 gene, which encodes leiomodin 3. To our knowledge, this article is the first report of LMOD3‐related nemaline myopathy since the original reported cohort. We provide a detailed description of the prenatal imaging of these affected fetuses, which we hope, in combination with next‐generation sequencing, may contribute to further diagnosis in additional families.

Prenatal diagnosis of fetal adducted thumbs

Abstract Purpose: One of the greatest challenges with the finding of adducted thumbs in the prenatal setting is the determination of whether this finding is associated with an underlying genetic syndrome. The aim of the present study is to describe the characteristics and outcome of prenatal sonographic diagnosis of adducted thumbs. Methods: A retrospective study was conducted over a period of 17 years in a tertiary referral center. All fetuses diagnosed prenatally with adducted thumbs comprised the study group. Prenatal sonographic assessment and neonatal outcome are presented. Results: Six fetuses were evaluated for adducted thumbs over the 17-year period. In three cases, the parents elected termination of pregnancy for severe associated anomalies. In one case partial resolution was observed during the third trimester. Of the remaining two fetuses, one had a single umbilical artery and in the second the adducted thumbs were an isolated finding. Post-natal evaluation in both cases revealed bilateral adducted thumbs. Apart from orthopedic follow up no further interventions were needed. Conclusions: Prenatal diagnosis of adducted thumbs should be followed by a meticulous fetal ultrasound examination combined with genetic counseling. According to our cohort, if associated anomalies are excluded, isolated cases seem to have a favorable diagnosis.

Diaphanospondylodysostosis: Refining the prenatal diagnosis of a rare skeletal disorder

Diaphanospondylodysostosis (DSD) is a rare autosomal recessive skeletal disorder, characterized mainly by ossification defects in vertebrae, thorax malformations, renal cystic dysplasia and usually death in the perinatal period. DSD is caused by mutations in the bone morphogenetic protein-binding endothelial regulator (BMPER) gene. We describe the prenatal findings of a non-consanguineous Jewish couple (shared Balkan origin), with three affected fetuses that presented with malformations in the spine and chest, reduced ossification of the skull and spine, horseshoe kidney and increased nuchal translucency. The unique combination of these ultrasound (US) features raised the possibility of DSD, which was confirmed by whole exome sequencing (WES) performed on a single fetal DNA and familial segregation. In the three fetuses, a novel homozygous mutation in BMPER (c.410T > A; p.Val137Asp) was found. This mutation, which segregated in the family, was not found in 65 controls of Jewish Balkan origin, and in several large databases. Taken together, the combination of a detailed prenatal US examination and WES may be highly effective in confirming the diagnosis of a rare genetic disease, in this case DSD.

Nonobstructive Diffuse Dilated Bowel Loops: Prenatal Diagnosis, Fetal Characteristics and Neonatal Outcomes

The purpose of this study was to describe the characteristics and outcomes of fetuses with a diagnosis of nonobstructive diffuse dilated bowel loops.

Prenatal Ultrasonographic Diagnosis of Cataract: In Utero Manifestations of Cryptic Disease

PURPOSE  To report and review our experience with antenatal evaluation for fetuses diagnosed with congenital cataract. MATERIALS AND METHODS  We retrospectively identified pregnancies diagnosed with fetal cataract during antenatal ultrasound. Evaluation of fetal eyes included intraocular anatomy and biometry. Data on fetal malformations, serology and fetal karyotype were collected. RESULTS  8 cases, identified over the course of 10 years, were reviewed. Week 15 was the mean time for diagnosis (range 11 - 34). Extraocular anomalies were demonstrated in 6 cases (central nervous system, cardiac and renal systems). Additional intraocular abnormalities were detected in two cases: one fetus had persistent hyperplastic primary vitreous and another had bilateral retinal detachment. All cases but one involved cataracts in both eyes. The unilateral case was associated with microphthalmic aphakia. All cases had negative serology for TORCHs. 7 out of the 8 fetuses were terminated. The only one who survived developed in utero cataracts secondary to maternal steroid therapy. He underwent bilateral cataract extraction during the first weeks of life and ophthalmologic evaluation at 2 years of age was unremarkable, without any visual impairment. CONCLUSION  In most cases, fetal cataract was associated with additional abnormalities, both intra- and extra-ocular. In instances when cataracts are isolated, we suggest conducting a detailed and thorough in utero ophthalmic examination in order to improve antenatal parental counselling.