Holoprosencephaly

SAN FRANCISCO -- One of the most useful rules about genetic counseling for CNS abnormalities is this: Amniocentesis doesn't tell you everything.

That advice was offered by Dr. Mary Norton at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco.

Often more detailed testing, including fetal MRIs and genetic counseling, is needed for families with fetal CNS abnormalities. "The family history and pedigree, for instance, are critically important in making a diagnosis," said Dr. Norton, director of the Prenatal Diagnosis Center at the university.

Other important rules to keep in mind in genetic counseling are that the presence of a second anomaly greatly impacts the outlook for the fetus, and that the prognosis for a fetus is often not the same as for a neonate.

One example is bilateral clubfoot. In an infant, clubfoot is often not a big problem. "The infant may just need surgery or casting and can live a completely normal life," Dr. Norton said. But clubfoot in a fetus is frequently a marker for other chromosomal abnormalities, such as trisomy 18, which has a 60%-70% stillborn rate.

Although amniocentesis informs the obstetrician about chromosomal abnormalities, it shouldn't be overly relied upon. "It doesn't tell you much about categories of genetic disease that don't stem from chromosomal abnormalities," Dr. Norton said.

Amniocentesis detects chromosomal abnormalities with close to 100% accuracy and it can diagnose other genetic disease if the DNA or biochemical basis is known. But a routine amniocentesis cannot tell you about genetic problems, such as autosomal dominant or recessive disease or X-linked or congenital malformations.

In holoprosencephaly, for instance, a disease that results in abnormal midline separation of the brain's cerebral hemispheres and diencephalic structures, the cause cannot always be determined from standard ultrasound or amniocentesis. And though many of these fetuses are stillborn, knowing the cause of the abnormality is crucial for counseling about recurrence rates in future pregnancies.

Holoprosencephaly can be due to aneuploidy syndromes, the HPE3 gene, poorly controlled maternal diabetes, or familial genetic diseases such as Smith-Lemli-Opitz syndrome. While trisomy 13 and 18 and diabetes (if it's well controlled) are unlikely to cause a recurrence of holoprosencephaly, the chance of having a second fetus in families with the HPE3 gene or a history of Smith-Lemli-Opitz syndrome ranges from 25% to 50%.

"In these cases, the families may want to consider sperm or egg donation for a second pregnancy," Dr. Norton said.

Another hard and fast rule about genetic counseling is that one anomaly increases the chance that there are other abnormalities. "The second anomaly is often subtle and the hardest to find on standard ultrasound or with amniocentesis," Dr. Norton said.

One example is mild ventriculomegaly, which is associated with an increased risk of CNS and non-CNS anomalies. When ventriculomegaly is the only abnormality, there's usually a normal outcome for the fetus. But in some cases of ventriculomegaly, there can also be early manifestation of other anomalies such as hydrocephalus and agyria.

"That's why we offer fetal MRIs to all our patients with ventriculomegaly. Finding this as an isolated condition, without other anomalies, can be very reassuring to families," Dr. Norton said.

COPYRIGHT 2002 International Medical News Group
COPYRIGHT 2002 Gale Group