The Importance of Chromosome Analysis for Assessing

the Recurrence Risk in Cases of Anencephaly

Gary S. Frohlich, David B. Rogers, and Maya Thangavelu
Genzyme Genetics - Orange, California

Introduction Case Report

The medical literature has documented a variety of chromosome abnormalities
that are associated with prenatally detected neural tube defects. The proportion
of chromosomally abnormal cases have varied from 3 to 17%. The most
common chromosome abnormality is trisomy 18, but others encountered
include other trisomies, triploidy, ring(13), dup(2)(p13-pter), dup(3)(q23-qter),
del(13) and mosaic trisomies 8 and 9. Few have looked particularly at anen-
cephaly alone where the proportion that are chromosomally abnormal has been
approximately 2%. We report a case of isolated anencephaly associated with a
partial duplication of chromosome 2. We have reviewed information from two
large databases to ascertain the frequency and types of chromosomal defects
associated with prenatally diagnosed cases of anencephaly.
The patient is an 18 year-old Gravida 3 who was referred for prenatal diagnosis
because of an elevated maternal serum alphafetoprotein screen. The family
history was unremarkable. The patient had two previous miscarriages, etiology
undetermined. The fetus was diagnosed as anencephalic on ultrasound.
The patient indicated that she wanted to pursue termination of pregnancy
but she agreed to amniocentesis first. Amniotic fluid analysis revealed an
amniotic fluid alphafetoprotein assay of 26.22 MoM, with a "positive"
Acetylcholinesterase. Cytogenetic analysis revealed a karyotype of
46,XX,add(2)(p23). The pregnancy was terminated and the fetus was evaluat-
ed, with no other abnormal findings noted on autopsy. The maternal karyotype
revealed 46,XX. The father of the pregnancy was unavailable for karyotype.

Results Table 1.
Anencephaly Cases With Abnormal Karyotypes

Genzyme Genetics Table 3.

Genzyme Genetics maintains a database of the cytogenetic analyses it performs on the Rates of Chromosome Abnormalities Among Prenatally
Detected Neural
amniotic fluid specimens received from practitioners throughout the United States. All 47,XX,+18
47,XY,+18
4
6 Tube Defects (NTDs)
successfully completed cases acquired because of the prenatal ultrasound detection of 47,XY,+15 1
69,XXY 1
anencephaly were reviewed to identify aberrant chromosome results. A total of 292 cases 46,XY[12]/47,XXY[8] 1
46,XX,?del(13)(q31.2) 1 Source Anencephaly All NTDs
fit this profile, and 17 (5.8%) were found to have abnormal karyotypes. As seen in the 46,XX,?inv(5)(q15q23.2) 1 Drugan, et al, 1989 1/18 (6%) 4/39 (10.3)*
46,XX,add(2)(p23) 1
medical literature, the most common abnormality is trisomy 18 (n = 10), comprising 59% of 46,XX,del(18)(p10) 1 Claussen, et al, 1994 0/2 (0%) 13/68 (19%)
the abnormal cytogenetic cases. Seven different karyotypic abnormalities accounted for the Total 17
Halliday, et al, 1994 Excluded 1/33 (3.0%)
remaining anomalous results. (See Table 1) Babcook, et al, 1995 Excluded 9/52 (17.3%)
Harmon, et al, 1995 Excluded 7/43 (16.3%)
Table 2. Hume, et al, 1996 1/44 (2.3%) 6/106 (5.7%)
The Genetic Disease Branch (GDB) in the State of California's Department of Health was Anencephaly Cases With Abnormal Karyotypes
Kennedy, et al, 1998 2/88 (2.3%) 13/200 (6.5%)
queried regarding its cytogenetic results on reported cases of anencephaly. The Neural Tube California Neural Tube Defect Registry O'Reilly, et al, 2000 0 2/18 (11%)*
Defect Registry, which accumulates pre- and postnatal cases reported to the GDB, reported Genzyme (current study) 17/292 (5.8%) Excluded
47,XX,+18 2
20 cytogenetically abnormal cases among the 3366 cases of anencephaly reported to date. 47,XY,+18 9
*"Isolated" NTDs only
47,XX,+21 2
The 20 abnormal karyotypes again show a preponderance of trisomy 18 (n = 11, 55%), 45,X 1
46,XX/47,XX,+21 1
followed by other chromosome aneuploidy (n = 4, 20%), and structural defects (n = 5, 25%). 46,XX/47,XX,+MAR 1
(See Table 2) Our 292 case represent the largest collection of anencephaly screened to date 46,XY,-1,+der(1)t(1;?)(p36.3;?)
46,XX,add(2)(p23)
1
1
for chromosome abnormality. (See Table 3) 46,XY,13p+ 1
46,XY,add(13)(q33) 1

Total 20

Discussion variability and practitioner inexperience. Therefore prenatal ultrasound alone

can't rule out a possible malformation syndrome in all cases of prenatally
The prenatal diagnosis of anencephaly commonly leads to a recurrence risk
detected anencephaly. Cytogenetic and post-delivery/mortem evaluations
based on multifactorial inheritance. However, if a chromosome abnormality is
provides the patient with the best opportunity for accurate genetic counseling,
detected, the risk for recurrence can lead to vastly different genetic counseling
particularly with respect to recurrence risk.
for the patient. The incidence of chromosome abnormalities in anencephalic
fetuses is, at best, poorly documented in the literature. We have reviewed the
When the chromosome abnormality is a sporadic aneuploidy (i.e., trisomy) the
Genzyme Genetics database of cytogenetic analyses performed (n = 292) on
recurrence risk is probably not greater that 1% or, in many cases, not
pregnancies affected with anencephaly. The indications for analysis and
significantly increased over the women's age related risk. In addition, in cases of
cytogenetic abnormalities were reviewed. Our review revealed chromosome
aneuploidy associated with anencephaly the risk to first degree relatives is not
abnormalities consisting of numerical (n = 13, 4.4%) and structural (n = 4, 1.4%)
thought to be increased. Similarly, when a structural chromosome abnormality
defects, accounting for greater than 5% of the total number of anencephaly
(insertion, deletion, ring, inversion, or duplication) is identified in association with
cases.
isolated anencephaly it is prudent to karyotype the parents in order to establish a
precise recurrence risk. These results will also help to determine whether other
Genetic counseling for the parents of a fetus identified with anencephaly should
family members may be at increased risk and and may lead to them being
always take into account the etiology on the condition. It has long been thought
karyotyped as well. Given these possible case scenarios, cytogenetic analysis
that the appropriate recurrence risk for isolated cases be in the range of 1-3%.
should be considered in the evaluation of anencephaly.
In keeping with this multifactorial model, first degree relatives are at a somewhat
higher risk than that of the general population. While this still pertains to most References
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