The Journal of Maternal-Fetal Medicine 653-57 (1997)

Risk of Recurrence of Craniospinal Anomalies Csaba Papp, MD, Zsolt Adam, MD, Ern6 Toth-Pal, MD, Olga Torok, MD,

Valeria Varadi, MD, and Zoltan Papp, MD*

Department of Obstetrics and Gynecology, Semmelweis University Medical School, Budapest, Hungary

Abstract The authors analyzed 1,655 situations from their Genetic Counseling Service over a 15 year period where the reason for counseling was craniospinal anomaly (neural tube defects and/or hydrocephalus) in the family. Excluding the obviously nionogenically inherited cases, they investigated pregnancies under- taken after 1,285 isolated and 177 multiple forms of craniospinal abnormalities. The recurrence rate of craniospinal defects was found to be 3.66%, which is about ten times higher than the general population risk, supporting the theory of the multifactorial threshold model in the inheritance of these anomalies. The recurrence risks of neural tube defects and of hydrocephalus were 3.47% and 2.95%, respectively. The authors concluded that recurrence risk is mainly influenced by the pathoanatomic severity of the involved anomaly, the degree of relationship, and the number of affected relatives in the family. There is a positive correlation between the pathoanatomic severity of the anomaly in the proband and the offspring. A t least in one-half of the cases the same type of anomaly was observed again in the offspring as in the proband. Attention is drawn to the fact that hydrocephalus (ventriculomegaly) is often manifested only in the second half of gestation. Therefore, performing ultrasound examination is strongly recommended not only at the 18th but at the 24th week of gestation, as well in pregnancies with a positive history of neural tube defects and/or hydrocephalus. J. Matern.-Fetal Med. 6:53-57, 1997. o 1997 WiIey-Liss, Inc.

Key Words: neural tube defects; craniospinal anomalies; recurrence risk

INTRODUCTION Neural tube defects (NTDs: anencephaly/exenceph-

aly, spina bifida, and encephalocele) are usually incom- patible with human life. There is a parental demand to prevent these anomalies.

Some publications have documented the decreasing trend of NTDs in newborn infants over the past two decades [ 1,2]. Due to improvements in screening meth- ods and to their widespread use, the prevalence of NTDs at birth decreased from 3%0 to l%o [3-51.

The birth prevalence of isolated hydrocephalus ranges from 0.5%0 to 2.5%0 [5,6]. The most recent national data in Hungary demonstrate a l.6%0 birth prevalence of NTDs and a O.82%0 prevalence of iso- lated hydrocephalus [5].

It is evident that the etiology of hydrocephalus asso- ciated with NTDs is different from the other etiological forms of congenital hydrocephalus, but the same clini- cal outcome and a similar prognosis indicate that we

should observe and discuss these defects as craniospi- nal anomalies.

The higher incidence of isolated hydrocephalus in families affected by NTDs is well documented [6,7]. This observation supports efforts to analyze and discuss the risk ofrecurrence of these anomalies together, classifying these as craniospinal defects (CSPs), with regard to the severity of the anomaly and to the degree of relationship.

Although NTDs associated with other anomalies may be caused by chromosomal abnormalities, single gene disorders, and environmental agents, most iso- lated cases do not have an identifiable cause and are attributed to multifactorial inheritance. Therefore, the frequency of nonsyndromal NTDs should be higher among the families of probands.

*Correspondence to: Zoltan Papp, Department of Obstetrics and Gynecology, Semmelweis University Medical School, Baross u.27. Bu- dapest, Hungary, H-1088.

Received 15 October 1995; revised 5 July 1996; accepted 8 July 1996.

0 1997 Wiley-Liss. Inc.

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54 PAPP ET AL.

METHODS AND PATIENTS Nearly 30,000 genetic counselings were performed

in the Genetic Counseling Clinic of the Department of Obstetrics and Gynecology, University Medical School of Debrecen, between January 1, 1978, and June 30, 1990, and in the 1st Department of Obstetrics and Gynecology, Semmelweis University Medical School of Budapest, between July 1, 1990, and Decem- ber 31, 1992. Data of 1,655 situations where the reason for genetic counseling was one or more craniospinal anomalies in the medical history were collected from our genetic register. Those cases with hydrocephalus where the craniospinal anomalies were based on nonge- netic etiologies (perinatal hypoxia, cytomegalovirus [CMV], toxoplasmosis, etc.) were excluded from the study.

The grouping of probands depended on the presence of either isolated or multiple anomalies. From the iso- lated cases, eight hydrocephalus with monogenic inher- itance and eight with Meckel syndrome from the multi- ple group were excluded.

Genetic counseling was conducted in 1,441 isolated and 198 multiple cases where the etiology was unknown.

The risk of recurrence was assessed on the basis of the empiric observations of Carter et al. [8], depending on the number of affected member(s) of the family

Independently of the risk of recurrence, we proposed parents to undertake consecutive pregnancy (ies) since the prenatal diagnosis of craniospinal anomalies is given by ultrasound scanning.

In spite of our advice, 156 of the 1,441 isolated and 21 of the 198 couples with multiple anomalies decided against pregnancy. Therefore, we could follow-up the outcome of 1,285 pregnancies in the first group and 177 in the second.

In cases of more than one affected member in the family with different craniospinal anomalies, the data of the closer relative provided the basis for classification.

[8,9l.

RESULTS The number of congenital anomalies among the

1,285 pregnancies was 58 (47 craniospinal and 11 other), with a total frequency of 4.5 1% and a frequency of 3.66% for craniospinal anomalies (Table 1). Pregnan- cies terminated at parental request occurred in cases where anomalies were detected in the second trimester. Among the craniospinal anomalies, one case with spina bifida, one with encephalocele, and four with hydro-

cephalus were not detected prenatally. Of the 11 non- craniospinal anomalies, three were detected prenatally, one hygroma colli, one ADAM (amniotic deformity, adhesion, mutilation) complex, and one nonimmune hydrops. In these cases the pregnancies were terrni- nated; other anomalies were detected only postnatally. There were three cases of congenital heart disease, two cases with isolated cleft lip, one isolated cleft palate, one isolated cleft lip and palate, and one trisomy 21.

If the total risk of recurrence of craniospinal anoma- lies (3.66%) is analyzed with respect to the individual defects of the probands, the risk of recurrence of cranio- spinal malformations in cases of NTDs is 3.77% (37/ 980), while it is 3.28% (10/305) in cases of isolated hydrocephalus. The true risk of recurrence of NTDs is 3.47% (34/980), while the risk of recurrence of isolated hydrocephalus is 9/305 (2.95%).

The risk of recurrence of the different types of anom- aly is detailed in Table 2.

The recurrence risk is more frequent in combined NTDs (anencephaly + spina bifida or spina bifida + hydrocephalus) than it is in single anatomic defects (isolated anencephaly, spina bifida, or hydrocephalus). The risk of recurrence in isolated spina bifida is 2.96%, while if it is connected with hydrocephalus, the risk is twice as great: 6.85%. We also observed a close connection between the anatomic type of the malfor- mation of the proband and of the offspring.

We did not find any recurrence in the group of multiple anomalies. These cases most probably oc- curred on the basis of environmental noxas (Table 3).

The role of the degree of relationship of the pro- band(s) and the number of affected relatives is summa- rized in Table 4.

DISCUSSION The higher than average recurrence risk of NTDs

is well known from Carter’s clinical experiences and original works which explain multifactorial inheritance and constitute the basis of genetic counseling in daily practice [4,8-lo]. Other observations demonstrate the accumulation of cases with hydrocephalus in certain families, supporting the theory of a similar etiology of NTDs and some isolated forms of hydrocephalus [6,7,111-

The prevalence of hydrocephalus is higher in families affected with NTDs [ 1 11 and in pregnancies with a previ- ous history of isolated hydrocephalus; the incidence of NTD is also higher [6]. The similar etiology indicated that we observed and discussed our cases together with

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RISK OF RECURRENCE OF CRANIOSPINAL ANOMALIES 55

TABLE 1. Risk of Recurrence of Fetal Craniospinal Defects in High-Risk Families: Summary of the Data (Excluding Multiple Cases)

Familv historv Total

The pregnant woman or the 134

78

196

partner is affected

is affected One sibling o r one parent

One distant relative is affected

One child is affected 93 9

One child + one relative are 29

Two relatives are affected 22 affected

Three o r more inemhers of 1 3 the family are affected

Two children are affected 30

Pregnancies decided Pregnancies Induced against undertaken terminations

13 121 CSP (3) Non-CSP (0)

8 70 CSP (2) Non-CSP (0)

11 185 CSP (6) Non-CSP (0)

112 827 CSP (24) Non-CSP (3)

5 24 CSP (1) Non-CSP (0)

2 20 CSP (0) Non-CSP (0)

2 11 CSP ( I ) Non-CSP (0)

3 27 CSP (4) Non-CSF (0)

Spontaneous abortions Births

10 108

4 64

13 166 (Non-CSP: 1)

(Non-CSP: 2) 57 743 (CSP: 5)

(Non-CSP: 4) 2 2 1

2 18 (CSP: 1)

1 9

4 19 (Non-CSP: 1)

Risk of recurrence of CSP defects

?h

31121 (2.5)

2170 (2.9)

61185 (3.2)

291827 (3.5)

1124 (4.2)

1120 (5.0)

1/11 (9.1)

4127 (14.8)

Total 1,441 156 1,285 CSP (41) 93 1,148 (CSP: 6) 4711,285 (3.66) Non-CSP (3) (Non-CSP: 8)

TABLE 2. Risk of Recurrence of Craniospinal Defects Depending on the Anatomic Type of Anomaly of the Proband (%)’

Recurrence risk of Anatomic type A C E X A C E X + SB SB SB + HC HC Occ. Enc. Total

ACEX 312 16 11216 01216 11216 01216 11216 612 16 (1.39) (0.46) (0.46) - (0.46) (2.77)

ACEX + SB 1/91 219 1 019 1 019 1 019 1 019 1 319 I (3.3) (1.10) (2.20) - - -

SB 11472 11472 71472 31472 11472 11472 141472 (0.21) (0.21) (1.47) (0.63) 0.21 (0.21) (2.96)

SB + HC 01146 11146 01146 71146 21146 01146 101146 - (0.68) - (4.79) (1.37) - (6.65)

HC 11305 01305 01305 01305 91305 01305 101305 - (2.95) - (3.27)

Occ. Enc. 0128 2128 0128 0128 0128 2128 4/28 - (7.14) - (7.14) (14.28)

’ AC, anencephaly; EX, rxencephaly; SB, spina hifida; HC, hydrocephalus; Occ. Enc., occipital encephalocele.

-

-

- (0.32) -

- -

the designation of “craniospinal” anomalies. This desig- nation included all NTDs and such cases of isolated hy- drocephalus where the etiology was uncertain.

Two decades ago, when the opportunities for prena- tal diagnosis were absent, a large number of parents refused to undertake consecutive pregnancies. The in- troduction of second trimester ultrasound screening changed the reproductive behavior of parents: backed by the protection of prenatal diagnosis, more and more mothers undertook consecutive pregnancies [4,12].

Our genetic counseling, which we have based on empiric experience strongly supported by prenatal screening, was introduced 15 years ago. In the past 15 years (1978-1992), more and more parents have accepted our genetic policy: in all 1,639 cases where the indication of genetic counseling was one or more craniospinal anomalies in the family history, the major- ity of parents accepted a new pregnancy (1,462/ 1,639 = 89.20%). Thus, a large number of parents were involved in our study, and we have had the opportunity

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56 PAPP ET AL.

TABLE 3. Risk of Recurrence of Fetal Craniospinal Defects in High-Risk Families: CSP as a Part of Multiple Anomalies

Pregnancies Risk of decided Pregnancies Induced Spontaneous recurrence of

Family history Total against undertaken terminations ahortions Births CSP defects (%)

The pregnant woman or the 2 1 1 0 1 0 01 1

One sibling is affectecl 4 1 3 0 1 2 013 One distant relative is affected 23 4 19 0 3 16 0119 One child is affected 165 13 152 0 7 145 01152 One child + one relative are affected 4 2 2 0 0 2 012 Total 198 21 177 0 12 165 01177

partner is affected

TABLE 4. Risk of Recurrence of Craniospinal Defects Depending on the Family History

Family history Recurrence risk (YO)

The pregnant woman o r the partner 2.48 (31121)

One sihling or one parent is affected 2.86 (2170) One distant relative is affected 3.24 (61185) One child is affected 3.30 (101305) One child and one relative 4.17 (1124)

Two relatives are affected 5.00 (1120) Three or niore members of the 9.09 (1111)

Two children are affected 14.82 (4127)

is affected

are affected

family are affected

to detect the exact recurrence rate in Hungary during this period.

The risk of recurrence of all craniospinal anomalies was 3.66%, while the risk of recurrence of CSP in cases of NTDs was 3.77% and that in cases of hydrocephalus 3.28%. These numbers are about ten times greater than the average incidence in Hungary between 1988 and 1990: the midtrimester prevalence of craniospinal anomalies at the 16th week of gestation is 2.94 per 1,000. The midtrimester prevalence of NTDs is 1.64% and that of isolated hydrocephalus 0.91%0 [5].

Our data support the role of similar genetic factors in the development ofcases with NTDs and with hydro- cephalus. The nearly equal risk of recurrence of the two anomalies and the fact that the siblings of the probands with NTDs have a significantly higher risk of hydrocephalus (and vice versa) support the hypothe- sis of similar etiology. In pregnancies with a positive history of NTDs, the occurrence of isolated hydroceph- alus was 3/980 (0.31%). This incidence is four times higher than the average for the whole population, which is O.82O/oO. Where isolated hydrocephalus was in

the medical history the rate of NTDs was twice as high (1/305 = 0.33%) than in the general population (1.67%0) [5]. These data show that the presence of NTDs in the family history increases the risk of isolated hydrocephalus and vice versa.

Our data support the previous observation that in NTD associated with other anomalies-if we exclude single gene disorders-the recurrence risk is practically zero. In these cases, the NTDs are caused by environ- mental (teratogenic) agents (Table 3).

The grouping of the probands into isolated and mul- tiple NTDs is important because without this classifica- tion the risk of recurrence would be calculated lower. In our study, it would have been 47/1,462 = 3.21% instead of 47/1,285 = 3.66%.

It is interesting that cleft lip and/or palate was ob- served more frequently (4/1,285 = 0.31%) in pregnan- cies with a positive history of CSPs than in the general population (0.92%0) [5]. This phenomenon has also been described by other authors; the cause of this might be that the development of these anomalies also de- pends on the disturbance of the closure [ 131.

It is important to determine the risk of recurrence in the practice of genetic counseling so that, even with prenatal diagnosis, the parents are able to determine the probability of an affected fetus or make the decision against pregnancy. It is well known that in NTDs and cases with hydrocephalus the risk of recurrence is higher, corresponding to niultifactorial inheritance. The risk of recurrence is also influenced by the severity of the previous craniospinal anomaly, by the number of the affected members of the family, and by the de- gree of relationship. Without a large number of observa- tions the precise risk of recurrence remained uncertain. Our study contributes valuable information.

When investigating the severity of CSPs it can be

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RISK OF RECURRENCE OF CRANIOSPINAL ANOMALIES 57

concluded that the risk of recurrence of the severe forms is much higher than that in less severe cases (Table 2). The risk of recurrence of a proband with anencephaly/exencephaly and spina bifida is higher , 3.30%, than it is in cases with anencephaly/exencephaly only (2.77%); the risk of recurrence of spina bifida combined with hydrocephalus is 6.85%, which is signifi- cantly higher than it is in isolated spina bifida (2.96%) or hydrocephalus (3.27%). Among our patients, the highest risk of recurrence was found in cases with occip- ital encephalocele (14.28%).

We also observed that severe cases were followed by severe cases. In other words, in less severe cases the risk of recurrence of the same pathoanatomical defect was 50%, while in severe cases it was 70% or more. For example, with an anencephaly/exencephaly + spina bifida combination, the chance of the same pathoanatomical lesion is 2/3 and 7/10 in the combina- tion of spina bifida + hydrocephalus. In isolated spina bifida or anencephaly cases the chances of the same pathoanatomical lesion are 7/14 and 3/6, respectively.

There is a correlation between the risk of recurrence and the degree of relationship and between the risk of recurrence and the number of affected members of the family (Table 4). The risk of recurrence is lowest (2.48%) in cases where either the mother or her partner are affected. This low recurrence risk is perhaps due to the fact that in these cases the anomalies of the parents are mild-for example, a closed low spina bi- fida-and even with these anomalies they could live until the reproductive age. The risk of recurrence is higher in the presence of one (3.24%) or two (5.00%) affected distant relatives, and it is also higher if one child (3.50%) or a further relative (4.17%) or more relatives (9.09%) are affected. Two affected children provide the highest risk of recurrence (14.82%).

If we analyze the severity of anomaly together with the family history, the highest risk of recurrence was found in cases where the parents have had a child with spina bifida and hydrocephalus (the number of occipital encephalocele cases is not enough for any conclusion). Our observations emphasize the importance of the pathoanatomical examination of the affected chil- dren/fetus(es) since without this result we could not calculate the exact risk of occurrence. The risk of recur- rence in isolated spina bifida is 2.96%, but it is 6.85% when it is associated with hydrocephalus.

Our results provide valuable data for genetic counsel- ing: if we know the severity of the defect(s) of the

proband(s) and the degree of relationship, we can cal- culate the risk of recurrence more exactly. This might be higher or lower than the average value (3.66%) but always higher than the total prevalence of CSPs in the general population (expressed per thousand).

Prenatal ultrasound diagnosis of NTDs is possible at the 18th week of gestation, but at this time the presence of ventriculomegaly is not always detectable. A second prenatal scanning at the 22-24th week of gestation is necessary among patients who had relatives with NTDs or hydrocephalus. Now the main trend is to split nosolog- ical entities in the research because the main goal is to delineate as many homogenous entities as possible from the etiological aspect. In NTDs, six zippers are known innormal neural tube fusion [ 141. According to this con- cept, experts recently attempted to differentiate these subgroups: preoccipital, cervical, thoracic, lumbar, and sacral [ 151. We intend to analyze our data further by the level of the lesion and potential closure sites.

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