Genetics of non-isolated hemivertebra: A systematic review of fetal, neonatal, and infant cases.

Hemivertebra is a congenital vertebral malformation caused by unilateral failure of formation during embryogenesis that may be associated with additional abnormalities. A systematic review was conducted to investigate genetic etiologies of non-isolated hemivertebra identified in the fetal, neonatal, and infant periods using PubMed, Cochrane database, Ovid Medline, and ClinicalTrials.gov from inception through May 2022 (PROSPERO ID CRD42021229576). The Human Phenotype Ontology database was accessed May 2022. Studies were deemed eligible for inclusion if they addressed non-isolated hemivertebra or genetic causes of non-isolated hemivertebra identified in the fetal, neonatal, or infant periods. Cases diagnosed clinically without molecular confirmation were included. Systematic review identified 23 cases of non-isolated hemivertebra with karyotypic abnormalities, 2 cases due to microdeletions, 59 cases attributed to single gene disorders, 18 syndromic cases without known genetic etiology, and 14 cases without a known syndromic association. The Human Phenotype Ontology search identified 49 genes associated with hemivertebra. Non-isolated hemivertebra is associated with a diverse spectrum of cytogenetic abnormalities and single gene disorders. Genetic syndromes were notably common. Frequently affected organ systems include musculoskeletal, cardiovascular, central nervous system, genitourinary, gastrointestinal, and facial dysmorphisms. When non-isolated hemivertebra is identified on prenatal ultrasound, the fetus must be assessed for associated anomalies and genetic counseling is recommended.

Kabuki syndrome as a cause of non-immune fetal hydrops/ascites.

Kabuki syndrome (MIM 147920) is a well-described, multiple congenital anomaly syndrome characterized by growth and developmental delay, cardiac, renal, and vertebral anomalies, as well as persistent fetal finger pads and distinct facial features. Facies are characterized by long palpebral fissures with eversion of lateral third of the lower eyelid, resembling the "Kabuki make-up" theatre genre after which the syndrome is named. Kabuki syndrome is estimated to affect 1/32,000 births, with 55-80% of patients showing nonsense or frameshift mutations in the KMT2D (MLL2) gene, which encodes a histone transferase located on chromosome 12q. Additionally, owing to the heterogeneous nature of Kabuki syndrome, a smaller number of diagnosed patients have been identified with mutations or deletions in KDM6A (a component of the same transcriptional complex as KMT2D) with no mutations in KMT2D, or as those diagnosed with Kabuki syndrome and without alterations in either KMT2D or KDM6A. Diagnosis of the syndrome in newborns and infants is difficult, as the facial features are not as evident as in toddler- or childhood. There are no known "tell-tale" signs of Kabuki syndrome prenatally, and there are no reports of common, specific findings in fetuses that might suggest the diagnosis. We present here two infants who presented with prenatal hydrops/ascites, who were subsequently diagnosed with Kabuki syndrome. Although relatively non-specific, we suggest that Kabuki syndrome be added to the list of genetic syndromes that are suspected in cases of prenatal hydrops, review the molecular etiology of Kabuki syndrome, and broaden the phenotype of this well-described disorder. © 2016 Wiley Periodicals, Inc.

Fetal cardiac axis and congenital heart defects in early gestation.

OBJECTIVE: To investigate the association between cardiac axis and fetal congenital heart defects to demonstrate the potential clinical applicability of cardiac axis measurement for detection of congenital heart defect in early gestation. METHODS: This case-control study was undertaken in three tertiary centers with expertise in fetal imaging in early gestation. Fetal cardiac axis was evaluated between 11 0/7 and 14 6/7 weeks of gestation in 197 fetuses with confirmed congenital heart defects. A control group was selected by matching each fetus with a congenital heart defect with two fetuses in the control group with similar crown-rump length (± 5 mm) and date of study (± 2 months). Cardiac axis was measured on the four-chamber view as the angle between the line that traces the long axis of the heart and the line that bisects the thorax in an anteroposterior direction. RESULTS: In the control group, mean cardiac axis was 44.5 ± 7.4°. The cardiac axis did not significantly change in early pregnancy. In the congenital heart defect group, 25.9% of fetuses had cardiac axis measurements within normal limits. In 74.1%, the cardiac axis was abnormal including 110 fetuses in the case group with left deviation (cardiac axis > 97.5th percentile), 19 fetuses in the case group with right deviation (cardiac axis < 2.5th percentile), and 17 fetuses in the case group with nonidentifiable cardiac axis. The performance of cardiac axis measurement in detection of major congenital heart defect was significantly better than enlarged nuchal translucency, tricuspid regurgitation, or reversed A-wave in ductus venosus used alone or in combination. CONCLUSION: Abnormal cardiac axis is present in two-thirds of fetuses with congenital heart defect in early gestation. Adding cardiac axis assessment to the nuchal translucency measurement is helpful in defining a population at risk for fetal congenital heart defect.