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The Risk of Recurrence of Holoprosencephaly in Euploid Fetuses

From the ¹Fetal Medicine Unit, Elizabeth Garrett Anderson and Obstetric Hospital, University College London Hospitals NHS Trust; and ²Academic Department of Clinical and Molecular Genetics, Institute of Child Health, London, United Kingdom.

OBJECTIVES: To determine the cause of and devise a management strategy for holoprosencephaly cases seen at a regional tertiary referral fetal medicine unit.

METHODS: Holoprosencephaly cases referred to University College London Hospital's Fetal Medicine Unit in the past 15 years were ascertained from a fetal database. We examined maternal, neonatal, genetic, and pathology records for prenatal and postnatal management, outcome, and genetic follow-up.

RESULTS: Forty-three women presented with a diagnosis of holoprosencephaly in one or more pregnancy. In one woman with a single affected pregnancy, there were incomplete data, and the postnatal diagnosis was not holoprosencephaly. For the remaining 41 women with complete outcome data, parental consent for fetal karyotyping was given in 36 women (88%) and was abnormal in 21 women (58%). Fifteen women had a euploid fetus or fetuses, of whom three women (20%, 95% confidence interval 4–48%) had a recurrence of holoprosencephaly. One woman had six affected pregnancies, the first diagnosed at 20 weeks of gestation and then at 12–14 weeks. The parental karyotypes were normal, but molecular analysis showed a mutation in the sonic hedgehog gene. In two women, holoprosencephaly was diagnosed at 27 weeks and birth, with a recurrence diagnosed at 22 and 24 weeks of gestation, respectively.

CONCLUSION: In this series there was a 20% recurrence risk for parents whose fetus had holoprosencephaly and a normal karyotype. Genetic review for parental examination, magnetic resonance imaging scanning, and mutation analysis is important in these cases. First-trimester ultrasound scanning is advised to detect recurrence early in gestation.

LEVEL OF EVIDENCE: III