Chapter 11:         Associated Abnormalities


 

In the previous chapters I have endeavored to prove that reliance on the criteria of cyst size, number, bilaterality or persistence is not sufficient to make a judgement on the benignity of choroid plexus cysts.  In this chapter I will assert that it is the presence of other anatomical abnormalities that is the key to detecting T18, and hence the key to the puzzle of choroid plexus cysts, provided a suitable level of expertise and knowledge is utilized in the performance of the scan.  In the data and discussion which follow I have concentrated on those abnormalities seen with T18 rather than those more commonly associated with T21 or the other chromosomal aberrations for several reasons.  Firstly, T18 is evidently the major concern when CPC are seen. Secondly, the reliability of ultrasound detectable markers for Down syndrome is still under intense debate and would require another major study to unravel.

 

Only rarely do investigators fail to recommend a search for other fetal abnormalities.  Ostlere146, bolstered by his trust in size as a reliable criteria, advocated a detailed scan only in those fetuses whose CPC were greater than 5mm.  If others do not recommend checking for abnormalities to triage for karyotyping, it is because they recommend karyotyping in all cases. 

 

Additional abnormal findings serve to strengthen the “soft” signs of CPC, and this was borne out by Nicolaides133.  He showed that combinations of soft signs increase the risk for aneuploidy dramatically (in his high risk population), from 2% for a single abnormality to 16% if two are present, to 86% of there are eight or more. 

11.1         Trisomy18 Reviews, CPC and/or Other Abnormalities

How many fetuses with T18 have CPC and/or other abnormalities?  Several reviews of the ultrasound findings in all chromosomal abnormalities or specifically in T18, have been performed which may help to put this argument into some perspective. 

 

In 1986 Bundy33 reported on 12 fetuses with T18.  10 had abnormalities detected on ultrasound, and the other two had clinically evident malformations.  One had CPC as the only ultrasound abnormality but no further clinical information was available concerning missed abnormalities in this fetus.  Fitzsimmons79 performed post-autopsy ultrasound on 14 abortuses with T18.  Five demonstrated CPC; in two cases this was the only evident abnormality.  All other fetuses had abnormalities noted.  Eydoux73 found 33 cases of T18 in association with amniotic fluid disorders, growth retardation or other malformations (mainly heart and limb malformations), but none with CPC.  Benacerraf12 reported on 26 cases of T18, six of which had no ultrasound identified abnormalities.  CPC were present in five cases, one of which had no other detected abnormalities.  In Nicolaides’133 series of 83 cases of T18, all had at least two ultrasound-detected abnormalities.  30 had CPC.   Nyberg136 reported a series of 47 cases of T18, 42 of which had no abnormalities detected on ultrasound.  There were 12 cases of CPC, 2 as isolated findings.  Twining188 described 7 cases of T18, only one of which had CPC, but all had multiple abnormalities.  Stoll181 found 26 cases of T18, 13 of which had abnormalities detected on ultrasound, but no CPC.  All had other abnormalities detected clinically.  Only one of 16 heart defects was found.  In Claussen’s51 study, 25 cases of T18 were found, “of which nearly half showed omphalocele and/or IUGR and heart defects” on ultrasound examination.

 

 

Author

Cases of T18

U/S abnormalities

CPC

Isolated CPC

Bundy33

12

10

1

1

Fitzsimmons7

14

14

7

2

Eydoux73

33

33

0

0

Benacerraf12

26

20

6

1

Nicolaides133

83

83

30

0

Twining188

7

7

1

0

Nyberg47

47

42

12

2

Stoll181

26

13

0

0

Claussen51

25

12

0

0

Total

273

 234 (86%)

57 (21%)

6 (2%)

Table 17:  From surveys of trisomic fetuses: T18 fetuses with U/S detected abnormalities.

 

Structural, growth or amniotic fluid abnormalities, or combinations of these were detected in 86% of fetuses with T18.  CPC were seen in 21% of cases, and 10% of these, or 2% overall, had no other detected abnormality. 

11.2         CPC, Abnormalities and T18

How many fetuses with CPC have abnormalities and T18, and how many without abnormalities have T18?  What are these abnormalities?  These are crucial questions.

 

From the literature survey those articles that discussed abnormalities found in association with CPC were detailed and summarized.  Out of a total of 1378 patients, 94 fetuses (7.3%) with both CPC and T18 were counted.  Table 17 and Fig 15 show the regions of the abnormalities. 

 

 

Extremity

40

42.6%

Cardiac

38

40.4%

Abdominal

28

29.8%

Growth

23

24.5%

Cranial

17

18.1%

Face

13

13.8%

Hygroma

7

7.4%

Cord/Placenta

6

6.4%

Renal

6

6.4%

Amniotic fluid

4

4.3%

Spinal

3

3.2%

Isolated

12

12.8%

Total

94

 

Table 18: Regions of abnormality in fetuses with T18 and CPC  

 

Fig 15:  From series of CPC:  Percentage of regions of abnormality detected in T18 fetuses.

 

A wide range of abnormalities has been reported in conjunction with T18, and it has proved difficult to detect a consistent pattern, as fetuses seem to adopt a different grouping of anomalies each time.  The characteristic newborn morphological appearances however correspond to the reported ultrasound findings overall.  It can be seen that the extremities (42.6%) and the heart (40.4%) are the most frequently abnormal body regions in T18 fetuses.  As these are the regions where most abnormalities are missed by ultrasound, 136 it stands to reason that they are the areas that hold the key to detection of T18.  Improvements in cardiac scanning have been dramatic in recent years with the introduction higher detail scanners and of colour Doppler, and the burgeoning of education for sonographers in this area.  DeVore65 was able to increase his detection rate of T21 from 29% to 87% and of T18 from 50% to 100% with the addition of high quality colour scanning of the fetal heart.  Unfortunately improvements in detecting extremity anomalies may not have quite so dramatic. 

11.3         Risk of “isolated” CPC in fetuses with T18

From Table 18 it can be seen that only 12 fetuses (12.8%) with T18 had no detected abnormalities other than CPC.  This agrees closely with the data presented in Table 17, that 14% of all T18 fetuses have no detected abnormality and that 2% have “isolated” CPC (or 10% of those with CPC).  However, several of these “isolated” cases did had structural defects found on autopsy, which were potentially detectable by a thorough ultrasound examination.  For example, Furness has stated “… our reported case was before we were looking at hands, and the baby did indeed have camptodactyly [and a VSD]; i.e., it would not now be a case of ‘choroid cysts as an isolated finding*.’”  This statement echoes the conclusions of Nyberg136 who found that when abnormalities were missed with ultrasound they were generally of the extremities or of the heart. (Table 19

 

It is likely that Dr Furness is not alone and that several of the “isolated cases” were in fact complicated by other abnormalities that would not be missed on a thorough scan performed by an aware sonographer, on a modern machine, using today’s protocols.   Two of Walkinshaw’s193 three “isolated” cases had either talipes or camptodactyly and a VSD; the third had no autopsy.  The small cardiac defects that were noted in Nyberg’s series and missed by ultrasound were all in fetuses with other abnormalities, including one where CPC was an “isolated” finding. 

 

 

Abnormality

Total

Detected by Sonography

Percent Detected

Cystic hygroma or nuchal thickening

10

9

90

Omphalocele

11

10

91

Large cisterna magna

9

9

100

Cardiac defects

29†

18

62

Clenched hands

20

9

45

Clubfeet or rocker bottom feet

15

10

67

Other extremity abnormalities*

5

1

20

Single umbilical artery

9

6

67

Meningomyelocele

8

8

100

Renal anomaly

8

7

88

IUGR

25

24

96

*includes phocomelia (1 case), absent thumb (2 cases), radial aplasia (2 cases).  Excludes shortened humerus alone or syndactyly. 

† includes four small ventricular septal defects

IUGR, intrauterine growth retardation.

 

Table 19: From Nyberg136.  Abnormalities missed on U/S among 47 T18 fetuses.

Detection of small VSDs and other signs in the extremities play a significant role in determining the rates of risk.  Platt152 was concerned that we might be expecting an unreasonable degree of excellence, as some patients are not ideal candidates for ultrasound.  One of the three fetuses in his study had a small VSD as the only other abnormality. 

“Ultrasonography is not a perfect science.  We all make mistakes, and even the most experienced will not be able to identify all abnormalities.  Therefore if we identify one of these clues [CPC] to the detection of malformation, I think we need to give it careful attention.”152

 

In contrast, both Nadel123 and Gross91 in their studies of isolated CPC come to the conclusion that karyotyping should not be offered.  It is difficult for the sonographer to find a a consistent message in the literature.

11.4         Malformation Rate

Data gathered during the Geelong Hospital survey indicated that 3.6% of obstetrical examinations exhibited a structural or growth problem with the fetus or cord.  This is in close agreement with the PDCU report for 1993 that indicated a malformation rate of 3.96% in Victoria.  As mentioned earlier, the PDCU indicated a T18 rate of 1/2311 (0.0433%) for 1991-1993. 

13.5         Statistical Analysis

It is difficult in this instance to calculate Bayes Theorem as there is no 2x2 table.  However the likelihood ratio for isolated CPC can be approximated by using 12.8% of isolated CPC in Table 18 as the specificity of the test.  The 3.6% ultrasound detection rate of anomalies in a low risk population such as Geelong’s can be equated to 1 minus the specificity.  These numbers are then factored into Bayes Theorem and the risk of trisomy when CPC are an isolated finding can be calculated.

 

 

 

Odds (Risk) with isolated CPC = 

12.8%  x 0.0433% / 3.6% = 0.153% or 1 in 652. 

 

We can compare this to the risk when any other abnormality is seen with CPC.  In this instance the 87.2%  of T18 fetuses with CPC and other anomalies can be approximated to the sensitivity.  The equation then becomes:

 

 

Odds (Risk) with abnormalities & CPC = 

87.2% x 0.0433% / 3.6% = 1.049% or 1 in 95. 

 

This technique provides a method of attaining the relative risk of T18 in the median age group. 

 

When CPC and other abnormalities are present the risk of T18 is higher than the risk for amniocentesis, and therefore the detection of such other provides the only useful criterion for the triaging of cases for further investigation.

11.6         Conclusion:

Other abnormalities are frequently detected in fetuses with trisomy 18, but occasionally none are seen, even with good equipment and detailed investigations.  However as CPC are not all that common in T18, their presence or absence does not actually provide that much help.  Over 80% of T18 fetuses will present with abnormalities other than CPC.  Nevertheless, CPC in combination with other abnormalities increases the risk dramatically. 

 

 

“Isolated” CPC is not a useful criterion because:

·        only 21% of fetuses with T18 have CPC, 

·        CPC are very common in the normal fetal population

·        T18 is relatively uncommon.

·        the risk for T18 in “isolated” CPC is only 1 in 652.

 

The combination of CPC and other abnormalities is useful in the selection of patients for further investigation because:

 

·        86 - 88% of T18 fetuses have had structural, growth or amniotic fluid abnormalities detected with ultrasound.

·        the greater the number of abnormalities, the greater the risk. 

·        improved scanning techniques of the extremities and the heart will increase  the detection of T18 (and other aneuploidies) further.

·        the risk for T18 in fetus with CPC and other problems is 1 in 95. 

 

The presence of other abnormalities on the ultrasound examination is the only criterion that will increase the patient’s risk of a chromosomal abnormality beyond that of the risk for amniocentesis.  After discussion with the mother, if termination is an acceptable option, karyotyping may therefore be offered. 

 

 As discussed, the range of abnormalities found in T18 is rather wide and random.  In order to assist sonographers in the detection of concurrent abnormalities in fetuses with CPC, and to determine if any another abnormality might indicate T18 independently, a detailed analysis of malformations commonly seen with T18 is given in the following chapter.