The purpose of this chapter is not to provide an in-depth discussion of particular fetal malformations, nor to cover a comprehensive list of fetal malformations. Rather our purpose is to discuss the genetic implications of common ultrasound-detected fetal malformations, and outline the general principles for evaluating and managing fetal structural abnormalities.

Cleft lip with, or without, cleft palate is one of the most common birth defects in the United States, occurring in approximately 1 in 1000 live births annually.¹ Most cases of clefting appear multifactorial; that is, a combination of genetic determinants and environmental factors. Certain medications, such as anticonvulsants, are associated with an increased risk for cleft lip/cleft palate. Likewise, poorly controlled diabetes in pregnancy can increase the risk of fetal clefts. Most importantly, a significant number of clefts, especially cleft palate, are part of a genetic syndrome, and the prognosis for the child will depend on the underlying condition, and not the severity of the cleft.

Initial evaluations should be aimed at determining if the cleft is an isolated finding.² Amniocentesis should be performed for standard chromosome testing and microarray testing. A fetal echocardiogram should be done to exclude cardiac malformations that would suggest a genetic syndrome. Equally important is a complete family history to determine if other family members are known to have facial clefts, or other birth defects. Counseling of the patient regarding prognosis for her child should be done by a multidisciplinary team with experience in managing infants and children with craniofacial abnormalities.

Neural tube defects (NTD) are common birth defects occurring in 1 to 2 per 1000 live births. Included in the category of NTD are anencephaly, myelomeningocele, and encephalocele. Most are characterized by multifactorial inheritance, with the one known environment factor being maternal folic acid intake. With most pregnancies now being screened by maternal serum alpha-fetoprotein (MSAFP) and/or a second trimester ultrasound, most cases of NTD are being detected in utero. Once the ultrasound diagnosis of a specific NTD is made, an appropriate genetic work-up should be done to provide both prognostic and recurrence risk information to the couple.

Anencephaly is characterized by a complete absence of skull development, and after the second trimester of pregnancy, absence of the cerebral hemispheres. However, on first trimester ultrasounds, fetal brain can be seen and the terms, “exencephaly” and “acrania,” are often used. Both are describing what will ultimately be anencephaly. Midline defects are associated with anencephaly, including spina bifida, cleft lip/palate, and omphalocele. A small number of cases are the result of amniotic bands, and the fetus/infant should be carefully assessed for evidence of amniotic bands, as the likelihood of recurrence would be markedly less in subsequent pregnancies. Chromosome abnormalities are rarely the etiology of anencephaly, but too few cases have been evaluated using microarray technology to know whether microdeletion/microduplication will be an important etiology for anencephaly.

Encephaloceles (Figure 10-2) are skull defects that allow brain tissue to protrude outside the cranial cavity. The majority are skin-covered and, therefore, will not be detected by MSAFP. Among the NTD, it is the malformation most likely to be a part of genetic syndromes, and a detailed search for other abnormalities on ultrasound, a fetal echocardiogram, and genetic studies, such as microarray testing should be performed once an encephalocele has been detected. Should the couple choose pregnancy termination, an autopsy and genetic studies likewise should be done, as recurrence risk, subsequent prenatal testing, and possible preconception therapy all depend on a precise diagnosis. For example, the genetic condition, Meckel-Gruber syndrome, is characterized by the triad of encephalocele, polycystic kidneys, and polydactyly. It is inherited in an autosomal recessive fashion with a 25% chance of recurrence, not the 2% to 3% recurrence risk for an isolated NTD. More importantly, determining the exact gene mutation would allow a precise first-trimester diagnosis by CVS, rather than depending on ultrasound in the second trimester to look for features that may have variability from one fetus to the next. In addition, recommending increased folate intake, as is appropriate in the context of a previous child with an NTD, would have no benefit in the setting of a previous pregnancy with the Meckel-Gruber syndrome.

Myelomeningocele (see Figure 10-3), or spina bifida, is the most common form of NTD. Approximately 80% of the open (non-skin covered) lesions will be detected by MSAFP, and in experienced centers ultrasound will detect more than 90%, including many of the closed defects, because of the additional cranial findings (“lemon” sign and “banana” sign) that are associated with spina bifida. Although the majority (90%) of spina bifida cases are isolated defects, it is essential to rule out the minority that are the result of specific genetic syndrome, such as trisomy 18.³ Chromosome studies and microarray analysis should be performed for prognosis and recurrence risk determination, and prior to any discussion of in utero repair options.