Choroid plexus cysts: Significance and current management practices

Choroid Plexus Cysts: Significance and Current Management Practices Kathleen A. Kennedy and John C. Caret Choroid plexus cysts are commonly found in normal fetuses in the second trimester, but the presence of cysts is an indication for a targeted ultrasound scan for signs associated with aneuploidy. In this review the authors explain the histological basis for choroid plexus cyst formation, the association with aneuploidy, and the management controversies that continue to be debated in the literature. Copyright9 1993 b y W.B. Saunders Company

HE CHOROID PLEXUS is a secretory

epithelium located in the third and lateral T cerebral ventricles. It is responsible for the

production of CSF, which escapes the ventricular system and bathes the brain and spinal cord. The choroid plexus is highly echogenic and can be visualized easily with ultrasound in the fetus by the ninth week of gestation (7 weeks after conception). An extraordinary amount of controversy has been raised regarding the significance of choroid plexus cysts (CPCs) visualized in the fetal lateral cerebral ventricles in the second trimester of pregnancy. The cysts were first described by Chudleigh in 1984 as benign anatomical variants) The more recent recognition that CPCs appear to be more common in fetuses with aneuploidy, especially Trisomy t8, has raised concern over how parents should be counseled and what, if any, further diagnostic tests should be undertaken. 2-4 In this review we attempt to explain the histological basis for choroid cyst formation, the association with aneuploidy, and the management controversies that continue to be debated in the literature. CHOROID PLEXUS DEVELOPMENT

The histopathological development of the choroid plexus is described in four stages by Shuangshoti and Netsky. 5

Stage I (7 to 9 Gestational Weeks) The choroid plexus is characterized by a short club-shaped stalk covered by neuroepithelium. There is slight lobulation of the stalk by the end of this stage (Figs 1 and 2).

Stage H (9 to 17 Gestational Weeks) The choroid plexus is growing rapidly, now occupying half to two thirds of the lateral ventricle. The plexus becomes more lobulated and develops finger-like projections covered with secretory epithelium (primary villi) (Fig 3).

Stage III (17 to 28 Gestational Weeks) The relative size of the plexus diminishes compared with the size of the lateral ventricle. There is further lobulation and the primary villi become abundant. Many tubules develop in the interstitium formed by folding of the surface epithelium into the stroma during development of the plexus (neuroepithelial cysts). The number of tubules increases at a rate similar to the appearance of lobulations and villi, suggesting they are related to normal development of the plexus during this stage. Toward the end of this stage the loose stroma decreases in volume (Figs 4 and 5).

Stage IV (29 Weeks to Term) The villi become more delicate, with multiple branching fronds. There are numerous tubules present. Mesenchymal elements are replaced by large amounts of connective tissue (Figs 6 and

7). CYST FORMATION

CPCs have been reported most frequently by prenatal ultrasound during the mid to late second trimester when routine screening examinations for abnormalities and genetic studies are typically performed. This time period correlates with stage III. During this stage of development, the rapidly growing choroid plexus gives rise to cysts through the entanglement of villi. CSF is entrapped among the tangled villi, giving the appearance of a cyst on ultrasound examina-

From the Divisions of Maternal~Fetal Medicine, and Medical Genetics, lntermountain Health Care Perinatal Centers, University of Utah, Salt Lake City, UT. Address reprint requests to Kathleen A. Kennedy, hiD, Latter Day Saints Hospital, Department of Perinatology, 8th Ave and C St, Salt Lake City, UT84143. Copyright 9 1993 by W.B. Saunders Company 0887-2171/93/1401-0004505.00/0

Seminarsin Ultrasound, CT, andMRI, Vo! 14, No 1 (February), 1993: pp 23-30

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KENNEDY AND CAREY

Fig 3. Choroid plexus. Early stage II r plexus demonstrating increased Iobulations. (Reprinted with permission by Wistar Institute of Anatomy and Biology,) Fig 1. Choroid plexus. Stage I club-shaped choroid plexus in coronal section. (Reprinted with permission by Wistar Institute of Anatomy and Biology.)

tion. As the loose stroma decreases in amount, regression of previously formed fluid collections can occur, explaining the usual transient nature of these cysts. These cysts are a natural part of development of the choroid plexus and should be considered a normal anatomical finding. There is considerable epidemiological and pathological evidence that CPCs occur frequently in normal fetuses, children, and adults. 1,5-11 In the study by Shuangshoti and Netsky of fetuses and neonates, 33 of 40 speci-

Fig 2. Choroid plexus. Photomicrograph showing slight Iobulation of choroid plexus at the end of stage I. (Reprinted with permission by Wistar Institute of Anatomy and Biology.)

mens contained CPCs. Incidental CPCs have been found in over 50% of serial autopsy studies; these are present at all ages and are rarely of clinical significance. 12 The usual size ranges from 2 to 20 mm, with the mean being 6 to 7 mm (Fig 8). CPCS AND ANEUPLOIDY

CPCs are more common in fetuses with aneuploidy; Trisomy 18 is reported most often as well as a few cases of Trisomy 21. 2-4,6-1~ Triploidy has been reported rarely. 14,~3 In five unselected series in more than 30,000 pregnancies, the overall incidence of CPCs was 0.65 % in

Fig 4. Choroid plexus. Photomicrograph of choroid plexus in stage III infolding of epithelium forming primary villi. (Reprinted with permission by Wistar Institute of Anatomy and Biology.)

CHOROID PLEXUS CYSTS

25

Fig 5. Choroid plexus. Photomicrograph of choroid plexus in stage III showing method of tubule formation, Arrow indicates folding of surface epithelium into stroma. (Reprinted with permission by Wistar Institute of Anatomy and Biology,)

normal fetuses; however, in those fetuses with CPCs the incidence of Trisomy 18 was 4.0%, which represents a significant increase over the general population (Table 1). Several groups have attempted to calculate the risk of Trisomy 18 in a fetus in whom a choroid plexus cyst is visualized prenatally. Fitzsimmons et a124 performed a study looking at postmortem ultrasound and pathological examination findings of the choroid plexus in 14 fetuses between 18 and 40 weeks' gestation with known Trisomy 18. They found CPCs in five of seven (71.4%) fetuses under 26 weeks with Trisomy 18. Interestingly, two of the five cases had no other abnormalities noted at the time of postmortem examination. The authors also made an estimation of the risk of Trisomy 18 in a second trimester fetus with a prenatally de-

Fig 7, Choroid plexus, Photomicrograph of choroid plexus. Stage IV showing delicate villi with multiple branches. (Reprinted with permission by Wistar Institute of Anatomy and Riolo-

gy.)

tected choroid plexus cyst. Given the following assumptions, (i) the prevalence of Trisomy 18 (1/6,000), (2) the frequency of CPCs in the second trimester fetus with Trisomy 18 (71.4%), and (3) the rate of CPCs in the general population of second trimester fetuses (1/150), Fitzsimmons et a124calculated the risk of Trisomy 18 in the second trimester fetus with a prenatally detected choroid plexus cyst as 1.78%. In a study from Israel, Achiron et al 7 determined that the incidence of CPCs in their population is approximately 0.6% and 2 of the 30 cases with CPCs had Trisomy 18. The authors estimate from the literature that the occurrence of CPCs

:9 %,,.

:

Fig 6, Choroid plexus. Photomicrograph of choroid plexus during stage IV tubule shown by arrow. (Reprinted with permission by Wistar Institute of Anatomy and Biology.)

'3

Fig 8. Choroid plexus. UItrasonographicevidence of a CPC.

KENNEDY AND CAREY

26 Table 1. Frequency of CPCs in Five Unselected Series: Incidence of Trisomy 18 in Pregnancies With CPCs Author and Reference Chitikara et aP (1988) Carnurri and Veniura ~~ (1989) Ostlere et alg (1990) Achiron et al7 (1991) Twinning et als (1991) Total

Pregnancies Examined By Ultrasound

CPCs

6,288

41 (0.5%)

3,000 11,700 5,400 4,541 30,929

10 (0.3%) 100 (0.8%) 30 (6.6%) 19 (0.42%) 200 (0.65%)

Fetusus With Trisomy18 1 1 3 2 1 8 (4.0%)

in the second trimester fetus with Trisomy 18 is 25 per 38 (66%). Taking this figure as well as the prevalence of Trisomy 18 in newborns and the frequency of CPCs in the general population, the authors calculate the risk of Trisomy 18 in a fetus with a CPC to be 3.3%. Assuming that 70% of fetuses with Trisomy 18 have other anomalies detectable on ultrasound examination, Achiron et al 7 estimate the risk of Trisomy 18 in a fetus with no other anomalies to be 1%. These risk estimates between 1% and 4% become important when counseling a particular patient regarding the risks and benefits of having further invasive genetic testing once a CPC is detected. Some authors have tried to modify the risk of aneuploidy based on the size, complexity, bilaterality, and persistence of the cysts. In most series, the majority of CPCs are small and solitary, rather than complex, and average 6 to 7 mm. Bilaterality is reported, often in association with Trisomy 18; however, several series have reported bilateral and unilateral cysts occurring with approximately equal frequency in normal f e t u s e s . 6A9 The natural history of CPCs diagnosed prenatally reveals that the majority resolve spontaneously by the 24th week of gestation. Chitkara et al 6 found the cysts were solitary in 80% of 41 cases. Unilateral and bilateral cysts occurred with equal frequency; however, multiple cysts and those larger than 11 mm in diameter were invariably bilateral; 80% diagnosed between 16 and 22 weeks resolved by the 24th week and 90% resolved by the 28th week when the choroid was completing stage III of development. Nicolaides et al4 reported four fetuses with bilateral CPCs diagnosed by ultrasound in the second trimester; three of the four cases had Trisomy 18. This was followed by

numerous reports that are summarized and added to in the report by Ostlere et al. 9 In this report, 16 of 22 cases of Trisomy 18 exhibited bilaterality, the laterality was not stated in five cases in the original report, and one was reported as unilateral. This demonstrates a rate of bilaterality much greater than the 80% reported in the general population. There was also a tendency for the CPCs in the fetuses with Trisomy 18 to be large, most greater than 1 cm and some as large as 2 cm. Persistence of the cysts in affected pregnancies appears greater than expected in multiple small series reporting cases with Trisomy 18; however, small numbers and the frequency of pregnancy termination limits follow-up. Some authors have found frequent persistence beyond 24 to 26 weeks' gestation in normal fetuses, suggesting that this may not be a very good discriminator between karyotypically normal and abnormal fetuses. In addition, the fact that CPCs are frequently an incidental finding at autopsy at all ages suggests this is not necessarily a poor prognostic sign. 9 By far, the best discriminator between normal fetuses with CPCs and those with aneuploidy is the concurrent finding of other anomalies. No one disagrees with the recommendation that the visualization of CPCs is an indication for a careful targeted ultrasound examination. This examination should be conducted by someone who is familiar with the sonographic features of aneuploidy, and in particular with the features of Trisomy 18 as outlined in Table 2. In fact, 44 of the 55 (84%) reported cases of Trisomy 18 in association with CPCs had coexistent anomalies prompting genetic testing (Table 3). Unfortunately, Trisomy 21, which is the second most common abnormal karyotype associated with CPCs (14%), presents ultrasound clues only Table 2. Anomalies Common in Trisomy 18 Visualized by Ultrasound Heart Extremities Face Gastrointestinal/ renal Growth Fluid

Congenital heart defects Overlapping fingers, flexion deformities, rocker-bottom feet Micrognathia, cleft lip Esophogeal atresia, diaphragmatic hernia, omphalocele, horseshoe kidney, hydronephrosis Intrauterine growth retardation Polyhydramnios

CHOROID PLEXUS CYSTS

27

Table 3. Reported Aneuploidies in Second Trimester Fetuses With CPCs Aneuploidy with Author and Reference

Normal Ultrasound Karyotype Anomalies

Bundy et aF (1986)

Furness2~(1987) Ricketts et al z (1987) Farhood et a121 (1987) Chitkara et al e (1988) Fitzsimmons et a124 (1989) Hertzberg et a119 (1989) Gabrielli et al TM (1989) Camurri and Veniura TM (1989) Khouzam and Hooker TM (1989) Thorpe-Beeston et al TM (1990)

0

0

27

2t

4 2

0 1" 1* 3*,w

31

0

78

4*

1", large complex CPCs 0

9

1"

0

0

1"

0

97 19 28 37 67

Rotmensch et a122 (1992) Kennedy 1993 (current study) Total

1", large bilateral CPCs 1", large bilateral CPCs 1:1: 0

40 0

63

Ostlere et al 9 (1990) Twining et al s (1991) Achiron et al 7 (1991) Chinn et al 2z (1991) Platt et aUz (1991)

Normal Ultrasound

0 17 519

0 2*

16" 0 2$ 1 Trisomy 13 1 triploidy 3* 0 1" 1r 1" 1" 1 triploidy 0 3* 1r 0w 1r diminished but did not resolve 1" 1" 1:1: 44 (8.5%) 11 (2.1%)

*Trisomy 18. 1"Type not specified. r 21. w ultrasound examination.

trimester ultrasound examination (Table 3). If reliance on the presence of anomalies had been used to recommend or not recommend genetic testing in reported cases, 16% of Trisomy 18 fetuses and almost two thirds of the Trisomy 21 fetuses would have been missed! The experience of one of the authors (Kennedy), demonstrates the difficulty in making generalizations regarding the karyotype and the associated features of CPCs. During a 16-month period from May 1991 to September 1992, 22 fetuses with CPCs were evaluated in the second trimester. Fifty percent (11/22) of these were bilateral. The cysts were larger than 1 cm in only four cases and all of these were bilateral. Almost half (9/22) of the patients declined amniocentesis. The pregnancy outcome was known in 91% (20/22). There were karyotype abnormalities in 15% (3/20) of cases. Two had Trisomy 18 and one had Trisomy 21 (Table 4). All of the patients who returned for a follow-up ultrasound study at approximately 25 weeks' gestation had resolution of the cysts. There were no other anomalies noted in two of the three cases with a karyotype abnormality, including one with Trisomy 18. This same case had resolution of the cysts at 25 weeks' gestation. The population included three patients of advanced maternal age and a second trimester fetus with a choroid plexus cyst. Two of these three fetuses had a karyotype abnormality. Neither size, laterality, resolution, or the presence of other anomalies was helpful in this population in discriminating between karyotypically normal and abnormal fetuses. MANAGEMENT

one third of the time. 25 In the reported cases of aneuploidy associated with CPCs, 4 of the 7 (57%) Trisomy 21 cases had no additional abnormalities noted at the time of the second

There is great controversy over whether every fetus with an isolated choroid plexus cyst should have invasive genetic testing with its inherent risk of pregnancy loss (Table 5).

Table 4. CPCs and Abnormal Karyotype at IHC Perinatal Centers (May 1991 to September 1992) Karyotype

Maternal Age

Laterality

Trisomy 21

39

Unilateral

5 mm at 16.5 wks

Trisomy 18

37

Bilateral

8 mm at 16.6 wks

Trisomy 18

31

Bilateral

> 10 mm at 17 wks

Largest Cyst

Findings No other anomalies, declined amniocentesis and follow-up ultrasound, diagnosis at birth Repeat ultrasound at 25 wks revealed resolution of cysts, no other anomalies, declined amniocentesis, stillbirth at 34 wks, postmortem karyotype Ventricular septal defect, omphalocele, amniocentesis performed, stillbirth 33 wks

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Table 5. Summary of Opinion in the Literature Regarding Amniocemesis in Fetuses With CPCs Amniocentesis Recommended

Author and Reference Farhood et a121(1987) Furness 2~(1987) Chitkara et als (1988)

Routinely

Only if Large or Other Anomalies

No No No

Yes

Unsu re Yes Yes No No Yes No No No Yes

Yes No No

Yes Yes

Camurri and Veniura TM

(1989) Fitzsimmons et a124(1989) Gabrielli et al is (1989) Hertzberg et al TM (1989) Ostlere et a117(1989) Achiron et al 7 (1991) Benaccerraf et aP5 (1990) Chinn et al zs (1991) Ostlere et al 9 (1990) Platt et a113(1991) Thorpe-Beeson et al TM (1990) Twining et al s (1991)

Unsure No

Yes Yes

No Yes Yes Yes No

Yes Yes

The controversy centers around two questions: (1) how many fetuses with CPCs and an otherwise normal ultrasound examination will have aneuploidy; and (2) is the risk of aneuploidy greater than the risk of losing a normal fetus as a result of the procedure? Table 3 lists all the reported cases of aneuploidy in association with CPCs. As stated previously, 16% of fetuses with Trisomy 18 and 57% with Trisomy 21 had no associated anomalies. This fact would be alarming to some patients considering genetic testing for CPCs. However, one must realize that these figures are skewed because many come from the concentrated experience of referral centers or from individual case reports; the tendency of authors to report more positive than negative results causes both selection bias and publication bias. Theoretical and empirical risk estimates of aneuploidy have been attempted in the setting of a fetus with a CPC in the second trimester. Table 1 reviews five prospective and relatively unselected investigations reported in the literature that involve over 30,000 pregnancies with 200 CPCs (incidence, 0.65%). 7-10Eight of these 200 fetuses with CPCs had Trisomy 18, which is an empiric risk estimate of 4.0%. The theoreti-

cal risk estimates of Trisomy 18 in second trimester fetuses with CPCs by Achiron et al7 of 66% and of Benacerraf et a115of 28.6% are very discrepant and are based on different assumptions. Benacerraf et a115 used the estimated incidence of CPCs in the normal population of second trimester fetuses (1%), the incidence of CPCs in fetuses with Trisomy 18 (30%, her study), the known incidence of Trisomy 18 (3/10,000), and the rate of identification of anomalies in their cases of Trisomy 18 (77%) to compute the risk of Trisomy 18 in a second trimester fetus with CPCs and no other anomalies15; given these assumptions they calculated that 477 amniocenteses would be necessary in order to identify one additional case of Trisomy 18. Since the fetal loss as a result of the amniocentesis is expected to be 1 in 200, if Benacerraf's assumptions are correct, two normal fetuses would be lost for each additional diagnosis of aneuploidy; therefore, Benacerraf et al7 are opposed to offering amniocentesis routinely unless other anomalies are detected. Achiron et al 7 used slightly different assumptions to calculate the risk of a fetus with no other ultrasound abnormalities and CPCs in the second trimester to be 3.3%; if 70% of these fetuses had other anomalies visualized the theoretical risk of the fetus having Trisomy 18 with an otherwise normal ultrasound study is approximately 1%. This figure of 1% is higher than the age-related risk of a chromosomal abnormality in the offspring of a 35-year-old woman to whom we routinely offer genetic testing; this justifies the opinion of Achiron et al 7 that all women who have a second trimester fetus with a CPC should be offered amniocentesis routinely. Platt et aP 3 agree that all second trimester fetuses with CPCs are at sufficient risk for a karyotype abnormality that genetic testing should be offered. Their cohort is a referral population, which therefore, is more selected. They detected three cases of Trisomy 18 out of 62 that had amniocentesis. Platt et a113bring up several important points in their discussion: (1) all ultrasonologists are not well versed in the subtle features of aneuploidy; (2) certain features of aneuploidy such as congenital heart disease can be missed in the second trimester;

29

CHOROID PLEXUS CYSTS

(3) the fetal head undergoes closer scrutiny than almost any other structure; therefore, CPCs may be evident when other anomalies are not visible; and (4) the sensitivity and specificity of ultrasonic diagnosis of malformations have not been determined prospectively. Therefore, estimating risk dependent on detection of anomalies is fraught with error.

THE AUTHORS' APPROACH

The exact risk of aneuploidy in a particular fetus with CPCs in the second trimester is difficult to determine with confidence. In spite of the problems associated with selection and publication bias and small numbers in highly selected cohorts, the authors of this review lean toward the estimated risk near 1%. Given this estimate, it is reasonable to provide genetic counseling and to offer amniocentesis, as the risk of aneuploidy is higher than the age-related risk of a 35-year-old woman to whom we routinely offer genetic testing.

SUMMARY AND CONCLUSIONS

There is little disagreement in the literature on the following points: 1. CPCs are common and found in normal fetuses in the second trimester, reflecting normal development of this tissue. 2. CPCs appear to be more common in aneuploid fetuses, especially Trisomy 18. 3. The presence of CPCs in the second trimester fetus is an indication for a targeted ultrasound looking for signs associated with aneuploidy. 4. CPCs in Trisomy 18 fetuses tend to be larger ( > 1 cm) and are more often bilateral; persistence is a less reliable finding. 5. The majority of reported cases with CPCs and Trisomy 18 (84%) as well as approximately one third of the cases of Trisomy 21 have associated structural anomalies. 6. Authorities disagree as to the need for routine amniocentesis in the absence of other anomalies. However, the risk is probably close to 1% and these authors believe amniocentesis should be offered with proper informed consent.

REFERENCES I. Chudleigh P, Malcolm PJ, Campbell S: The prenatal diagnosis of transient cysts of the fetal choroid plexus. Prenat Diagn 4:135-137, 1984 2. Bundy AL, Saltzman DH, Pober B, et al: Antenatal sonographic findings in Trisomy 18. J Ultrasound Med 5:361-364, 1986 3. Ricketts NEM, Lowe EM, Patel NB: Prenatal diagnosis of choroid plexus cysts. Lancet 1:213-214, 1987 4. Nicolaides KH, Rodeck CH, Gosden CM: Rapid karyotyping in non-lethal fetal malformations. Lancet 1:283286, 1986 5. Shuangshoti S, Netsky MG: Histogenesis of choroid plexus in man. Am J Anat 118:283-316, 1966 6. Chitkara U, Cogswell C, Norton K, et al: Choroid plexus cysts in the fetus: A benign anatomic variant or pathologic entity? Report of 4l cases and review of the literature. Obstet Gynecol 72:185-189, 1988 7. Achiron R, Barkai G, Katznelson B-M, et al: Fetal lateral ventricle choroid plexus cysts: The dilemma of amniocentesis. Obstet Gyneco178:815-818, 1991 8. Twining P, Zuccollo J, Clewes J, et al: Fetal choroid plexus cysts: A prospective study and review of the literature. Br J Radiology 64:98-102, 1991 9. Ostlere SJ, Irving HC, Lilford RJ: Fetal choroid plexus cysts: A report of 100 cases. Radiology 175(3):753-55, 1990 10. Camurri L, Veniura A: Prospective study on Trisomy 18 and fetal choroid plexus cysts. Prenat Diagn 9:742, 1989

11. Clark SL, DeVore GR, Sabey PL: Prenatal diagnosis of cysts of the fetal choroid plexus. Obstet Gynecol 72:585587, 1988 12. Fakhry J, Schechter A, Tenner MS, et al: Cysts of the choroid plexus in neonates: Documentation and review of the literature. J Ultrasound Med 4:561-563, 1985 13. Platt LD, Carlson DE, Medearis AL, et al: Fetal choroid plexus cysts in the second trimester of pregnancy: A cause for concern. Am J Obstet Gynecol 164:1652-1656, 1991 14. Thorpe-Beeston JG, Gosden M, Nicolaides KH: Choroid plexus cysts and chromosomal defects. Br J Radiology 63:783-786, 1990 15. Benacerraf BR, Harlow B, Frigoletto FD Jr: Are choroid plexus cysts an indication for second-trimester amniocentesis? Am J Obstet Gynecol 162:1001-1006, 1990 16. Gabrielli S, Reece A, Pilu G, et al: The clinical significance of prenatally diagnosed choroid plexus cysts. Am J Obstet Gynecol 160:1207-1210, 1989 17. Ostlere SJ, Irving HC, Lilford RJ: A prospective study of the incidence and significance of fetal choroid plexus cysts. Prenat Diagn 9:205-211, 1989 l 8. Khouzam MN, Hooker JG: The significance of prenatal diagnosis of choroid plexus cysts. Prenat Diagn 9:213216, 1989 19. Hertzberg BS, Kay HH, Bowie JD: Fetal choroid plexus lesions: Relationship of antenatal sonographic ap-

30 pearance to clinical outcome. J Ultrasound Med 8:77-82, 1989 20. Furness ME: Choroid plexus cysts and Trisomy 18. Lancet 1:693, 1987 21. Farhood AI, Morris JH, Bieber FR: Transient cysts of the fetal choroid plexus: Morphology and histogenesis. Am J Med Genet 27:977-982, 1987 22. Rotmensch S, Luo J-S, Nores JA, et al: Bilateral choroid plexus cysts in Trisomy 21. Am J Obstet Gynecol 166:591-592, 1992 23. Chinn DH, Miller EI, Worthy LM, et al: Sonographically detected fetal choroid plexus cysts: Frequency and association with aneuploidy. J Ultrasound Med 10:255-258, 1991

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24, Fitzsimmons J, Wilson D, Pascoe-Mason J, et al: Choroid plexus cysts in fetuses with Trisomy 18. Obstet Gyneco173:257-260, 1989 25. Nyberg DA, Resta RG, Luthy DA, et al: Prenatal sonographic findings of down syndrome: Review of 94 cases. Obstet Gynecol 76:370-377, 1990 26. Eydoux P, Cholset A, LaParrier N, et al: Chromosomal prenatal diagnosis: Study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diag 9:255-269, 1989 27. Donnefield AE, Mennuti MD: Sonographic findings in fetuses with common chromosomal abnormalities. Clin Obstet Gyneco131:80-96, March 1988