Harvey Bennett1, Amy Presti2, Darius Adams3, Jose Rios4, Carlos Benito5, Daniel Cohen5. 1. Division of Child Neurology, Goryeb Children's Hospital, Morristown, New Jersey. Electronic address: harvey.bennett@atlantichealth.org. 2. Division of Neonatology, Goryeb Children's Hospital, Morristown, New Jersey. 3. Division of Genetics and Metabolism, Goryeb Children's Hospital, Morristown, New Jersey. 4. Division of Neuroradiology, Atlantic Health System, Morristown, New Jersey. 5. Atlantic Maternal Fetal Medicine, Atlantic Health System, Morristown, New Jersey.
Abstract
OBJECTIVE: This report outlines how current fetal neuroimaging and genomic technologies can aid in determining the causes of prenatal microcephaly. BACKGROUND: The differential diagnosis and prognosis of fetal microcephaly is a challenging and common presenting problem to the child neurologist and perinatologist. There was a time that the prospective parents could only be told that the child would be microcephalic. Not much could be determined in regard to exact diagnosis or prognosis. METHODS: At 20 weeks' gestation the fetus was observed to have isolated microcephaly on fetal ultrasound. Karyotyping and a nontargeted genomic microarray were performed at 21&4/7 weeks gestation on amniocytes and the results were normal. At this time, toxoplasmosis, rubella, syphilis, cytomegalovirus and herpes studies were also negative. Fetal magnetic resonance imaging at 31 weeks' gestation revealed severe microcephaly with an anomaly consistent with holoprosencephaly. Whole-exome sequence analysis was performed. RESULTS: Postnatal whole-exome sequence analysis revealed two novel compound heterozygous mutations in the STIL gene (c.2354_2355dupGA and c.3835C>T), which is consistent with microcephaly and migrational anomalies. The postnatal magnetic resonance imaging reveals agenesis of the corpus callosum, agyria of the frontal and temporal lobes, and a large cyst along the interhemispheral fissure extending to the parietal and occipital regions in addition to pontine and cerebellar dysgenesis. CONCLUSION: This case demonstrates the state-of-the-art approach to the clinical challenge of prenatal microcephaly and defines unique findings associated with compound heterozygous STIL gene mutations c.2354_2355dupGA and c.3835C>T.
OBJECTIVE: This report outlines how current fetal neuroimaging and genomic technologies can aid in determining the causes of prenatal microcephaly. BACKGROUND: The differential diagnosis and prognosis of fetal microcephaly is a challenging and common presenting problem to the child neurologist and perinatologist. There was a time that the prospective parents could only be told that the child would be microcephalic. Not much could be determined in regard to exact diagnosis or prognosis. METHODS: At 20 weeks' gestation the fetus was observed to have isolated microcephaly on fetal ultrasound. Karyotyping and a nontargeted genomic microarray were performed at 21&4/7 weeks gestation on amniocytes and the results were normal. At this time, toxoplasmosis, rubella, syphilis, cytomegalovirus and herpes studies were also negative. Fetal magnetic resonance imaging at 31 weeks' gestation revealed severe microcephaly with an anomaly consistent with holoprosencephaly. Whole-exome sequence analysis was performed. RESULTS: Postnatal whole-exome sequence analysis revealed two novel compound heterozygous mutations in the STIL gene (c.2354_2355dupGA and c.3835C>T), which is consistent with microcephaly and migrational anomalies. The postnatal magnetic resonance imaging reveals agenesis of the corpus callosum, agyria of the frontal and temporal lobes, and a large cyst along the interhemispheral fissure extending to the parietal and occipital regions in addition to pontine and cerebellar dysgenesis. CONCLUSION: This case demonstrates the state-of-the-art approach to the clinical challenge of prenatal microcephaly and defines unique findings associated with compound heterozygous STIL gene mutations c.2354_2355dupGA and c.3835C>T.