American Journal of Medical Genetics 49:202-204 (1994)

Familial Hydrocephalus of Prenatal Onset Joel Zlotogora, Michal Sagi, and Tirza Cohen Department of Human Genetics, Hadassah Medical Center, Hebrew University, Jerusalem, Israel

Fourteen families in which more than one child was diagnosed with hydrocephalus of prenatal onset were seen in our genetic coun- seling clinic. In 7 families only males were affected: in 2 X-linked hydrocephalus was di- agnosed while X-linked inheritance was sus- pected in 3 other families. These 5 families were of Jewish origin. In the 8 families of Arab origin, the parents of the affected children were consanguineous. In 6 of these families at least one female was affected and the hydro- cephalus was most probably inherited as an autosomal recessive trait. This type of hydro- cephalus of prenatal onset appears to be fre- quent among Palestinian Arabs. 0 1994 Wiley-Liss, Inc.

KEY WORDS: autosomal recessive hydro- cephalus, X-linked hydro- cephalus

INTRODUCTION Hydrocephalus is a relatively common malformation

in stillborn and newborn infants; it is often secondary to a neural tube defect or as part of a syndrome. Isolated or nonsyndromal hydrocephalus is less frequent and most likely is heterogeneous.

Some of the cases of isolated hydrocephalus of prena- tal onset are due to monogenic defects, for instance X-linked hydrocephalus. However, the possible exis- tence of an autosomal recessive hydrocephalus is still doubted LMcKusick, 19921.

We report here on 14 families in which more than one patient with isolated hydrocephalus of prenatal onset was diagnosed.

METHODS AND CLINICAL RESULTS The 14 families (Fig. 1, Table I) included in this report

represent all the families referred to the genetic clinic in whom more than one child was diagnosed with hydro-

Received for publication March 18, 1993; revision received Au- gust 20, 1993.

Address reprint request to Joel Zlotogora, M.D., Department of Human Genetics, Hadassah Hospital, POB 12000, Jerusalem, Israel 91120.

0 1994 Wiley-Liss, Inc.

cephalus of prenatal onset without any other malforma- tion. In 4 families autopsies were performed at least in one case confirming that the hydrocephalus was isolated (families A, C, E, and N). In 3 families we examined one of the children who was living at the time of the consul- tation in our clinic. In the other families the data were obtained from the examination by the family physician, after the delivery or later. Data about the existence of hydrocephalus and/or neural tube defects were avail- able on all the first, second, and third degree relatives of the affected patients.

In 7 of the 14 families (Fig. la , Table I), only males were affected. The inheritance was X-linked in 2 of them (families A and B) since affected males were diagnosed in the offspring of at least 2 related women. In family A, enough informative individuals were available for link- age studies (family HSAS5 in Willems et al. [1992]). In 3 other families (families C, D, and E) the data suggest X-linked inheritance since the hydrocephalus was diag- nosed only in males and the parents of the patients were not consanguineous. All of these 5 families were of Jew- ish origin. In 2 Arab families (families F and G) only males were affected, however, it is difficult to determine the type of inheritance since the patients’ parents were related. In 7 families a t least one female was affected; in 6 of them the parents of the affected children were con- sanguineous (Fig. lb, Table I).

In all of the 8 Arab families (7 Muslim and 1 Chris- tian), the patients’ parents were consanguineous and in 6 of them at least 1 female was affected. The families were apparently unrelated. All of the Arab families were large; however, among the second and third degree relatives of the patients no case of hydrocephalus or neural tube defect has been diagnosed. These observa- tions suggest that the inheritance of the hydrocepha- lus is autosomal recessive in most or all of the Arab families.

In 4 families there were recurrent miscarriages; in 2 of these families (H and J) the chromosomes of the par- ents were examined and found to be normal. In one Muslim family (Family I), one child died of Niemann Pick disease type A; however, both offspring with hydro- cephalus were examined and found to have normal ac- tivity of sphingomyelinase.

DISCUSSION Hydrocephalus of prenatal onset is a relatively fre-

quent malformation, often due to a neural tube defect or associated with other malformations. Isolated hydro-

Familial Hydrocephalus 203

nd

F

Fig. 1. Familial cases of prenatal onset hydrocephalus. (a) Seven families in which only males were affected. (b) Families in which at least one female was affected. The affected cases affected are in black. Smaller black symbols are affected fetuses diagnosed during the pregnancy and aborted. Spontaneous miscarriages are represented by a black dot. sb, stillbirth; nd, neonatal death.

TABLE I. Data on the Patients and Relatives in 14 Families Children

Normal Relation Affected

Family Origin M F M F (F)* Jewish 2 - 2 - NC Jewish 2 - - - NC

A

Jewish 5 - NC B

1 Jewish 2 - - 2 NC

C

Jewish 3 - - - NC D

Muslim 2 - 1 2 1/16 E

G Muslim 3 - - - 1/16 F

Muslim 1 2 1 3 3 I64 I Muslim - 2 1 - >1/16 H

Christian 1 1 2 1 11256 K Muslim - 2 3 1 1/16 J

L Muslim 1 1 1 5 R Muslim 1 3 1 4 1/16

N Jewish 2 1 - - NC M

* F, coeficient of inbreeding; NC, nonconsanguineous; R, distantly related.

-

204 Zlotogora et al.

cephalus is rare at birth and may have various causes such as congenital infections or CNS malformation [Wil- liamson et al., 19841. In a large study of institutionalized severely retarded patients Opitz et al. found that 11 out of 57 patients with hydrocephaly were familial cases. Among those most had apparently X-linked hydro- cephalus and one family with a brother and sister af- fected was reported [Opitz et al., 19781. Among the 14 families from our clinic, X-linked hydrocephalus was diagnosed in 2 families; 3 additional families are sus- pected to be also affected with the same condition, how- ever, it is not possible a t the time to confirm this possi- bility. All these 5 families were of Jewish origin.

The existence of an autosomal recessive form of iso- lated hydrocephalus has been proposed in several case reports of families in which more than one affected child was born. However, some have doubted the existence of this type of inheritance and it was suggested that the cause may be multifactorial, which then explains the finding of multiple affected individuals in some families [Varadi et al., 19881. The observation that isolated hy- drocephalus and neural tube defects may be found with an increased incidence among the patients’ relatives [Cohen et al., 1979; Journel et al., 1989, Lorber 19841 is in favor of a multifactorial determination. Among the familial cases of nonsyndromal hydrocephalus seen in our clinic we did not observe any cases of hydrocephalus and/or neural tube defects in the second and third degree relatives of the patients. Most of our patients were Pal- estinian Arabs and originated from very inbred fami- lies. These observations are in favor of the existence of an autosomal recessive form of hydrocephalus of prena-

tal onset. Teebi and Naguib [19881 also reported a large Palestinian Arab family in which 2 boys and 2 girls were born with hydrocephalus to first cousin parents; there- fore, it seems that autosomal recessive hydrocephalus of prenatal onset is relatively frequent in this population.

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