American Journal of Medical Genetics 31:467-470 (1988)

Letter to the Editor

Autosomal Recessive Nonsyndromal Hydrocephalus

To the Editor:

The report of Willems et al. [1987] on a large kindred with an unusual form of X-linked hydrocephalus without aqueductal stenosis is very interesting and prompts us to describe a consanguineous Arab family with four hydrocephalic children (two males, and two females), one confirmed at autopsy to have the Arnold-Chiari malfor- mation. This family may indicate the existence of an autosomal recessive form, adding further evidence for genetic heterogeneity of familial hydrocephalus.

CLINICAL REPORTS Family Data (Fig. 1)

The father and mother (HI-7 and III-8) were phenotypically normal first cousins of Palestinian Arab origin. They were 35 and 27 years old, respectively, when evaluated in 1983. They have a normal daughter (IV-1) born in 1977 and another (IV- 2), who died in infancy from bronchopneumonia. The third child (IV-3) was a male stillborn at term by cesarean section (CS) with hydrocephalus documented from files, with occipitofrontal circumference (OFC) of 42 cm and weight of 3,400 g, with no other reported anomalies.

Patient 1 (IV-4) A female, the second affected hydrocephalic sib, was born in August 1983 at

term. The mother received daily folic acid supplements for 3 months in the precon- ception and early conception periods. Hydrocephaly was diagnosed prenatally by real-time ultrasound, which showed a progressive increase in the head circumference from the 19th week but, because of religious beliefs, the mother did not wish to terminate the pregnancy, which ended spontaneously at term. CS was done because of cephalopelvic disproportion and shoulder presentation. At birth, the infant showed an apparent hydrocephalus by transillumination with widely open sutures. OFC was 41 cm and weight was 3250 g.

Received for publication December 21, 1987; revision received April 25, 1988

Address reprint requests to Dr. A S . Teebi, P.O. Box 36660, Raas, 24757, Kuwait.

0 1988 Alan R. Liss, Inc.

468 Teebi and Naguib

I

I 1

I 1 1

1v

1

1 I 2 3 I 4 - 1 I

I

1 2 3 f 4 5 6

Fig. 1. Pedigree.

She had bilateral talipes equinovarus and single umbilical artery with no clinical evidence of congenital heart defect or any other apparent malformations. G-band chromosomes were normal. She died after 17 days, and autopsy examination showed thinning of vertex bones and a thinning of brain substance of both cerebral hemi- spheres, with excessive dilatation of both lateral ventricles. The third and fourth ventricles showed little dilatation. The lower part of the brain stem was herniated down through the foramen magnum, together with a piece of the cerebellum. The aqueduct of Sylvius was patent. Findings suggested a nonsyndromal Arnold-Chiari malformation.

PATIENT 2 (IV-5)

A male, the third affected sib, was born after 36 weeks’ gestation and delivered by CS. The mother received multivitamin supplementation before conception and in early pregnancy and she did not wish to have prenatal diagnosis done. The infant was hydrocephalic, with OFC 40.6 cm, weight 3,300 g with no spina bifida. He survived for 21 days; autopsy examination was refused by parents.

Patient 3 (IV-6) A female, the fourth affected sib, was born at 32 weeks’ gestation by elective

CS because of fetal distress. At birth the OFC was 34 cm and weight was 1,700 g. The infant had bilateral talipes equinovarus and no other abnormalities. Computed tomography (CT) scan of the head showed marked enlargement of lateral and third ventricles and an apparently normal fourth ventricle with high-density spots in the area of the basal ganglia. The baby died after 2 weeks; no autopsy examination was done.

Autosomal Recessive Nonsyndromal Hydrocephalus 469

DISCUSSION

Familial hydrocephalus presents considerable morphological and etiological heterogeneity. Both syndromal and nonsyndromal entities are known. Hydro- cephalus is a manifestation of several autosomal recessive syndromes, including the HARD E syndrome [Chemke et al., 1975; Warburg, 1978; AymC and Mattei, 19831, the hydrolethalus syndrome [Toriello and Bauserman, 1985; Aughton and Cassidy, 19871, and the severe form of Smith-Lemli-Opitz (RSH) syndrome [Lowry, 19831.

The nonsyndromal forms include the classical X-linked type of aqueductal stenosis [Bickers and Adams, 1949; Edwards, 1961; Halliday et al., 19861, the presumably X-linked type with cerebellar agenesis and absence of the foramina of Luschka and Magendie [Riccardi and Marcus, 1978; Renier et al., 19831, and the recently described X-linked type [Willems et al., 19871. A presumably autosomal recessive nonsyndromal form also exists. Schokaert and Janssens [ 19521 observed four sibs, including a female with hydrocephalus. Also, Abdul-Karim et al. [1964] reported two instances of consanguineous marriages, each resulting in three affected sibs. Another two instances of three affected male and female sibs were observed by Mehne [1961] and by McKusick [1986] in an Amish family. Lindenberg and Walker [ 197 11 described two successively born daughters of nonconsanguineous parents with hydrocephalus and lumbar meningocele. At autopsy, the Arnold-Chiari malformation was confirmed.

The presently described consanquineous family with four hydrocephalic sibs (two males, two females) not associated with spina bifida supports the existence of an autosomal recessive trait causing hydrocephalus. It is likely to be due to an isolated Arnold-Chiari malformation documented in one of our cases.

The Arnold-Chiari malformation is frequently observed in association with neural tube defects [Laurence, 19831 and appears to be multifactorially determined. Barry et al. [ 19571 think that this malformation results primarily from overgrowth of cerebellum and medulla, which results in a tonguelike projection of these structures herniating into the foramen magnum. The downward displacement of the hindbrain obstructs the flow of cerebrospinal fluid through the foramina of the fourth ventricle, causing hydrocephalus.

In one of our patients, the CT scan showed enormous enlargement of the lateral and third ventricles and an apparently normal fourth ventricle, which is compatible with Arnold-Chiari malformation. However, on the basis of this family and the suggestion of Barry et al. [1957], we think that the abnormal growth of cerebellum and medulla is controlled by a deleterious autosomal allele, which in a homozygous state causes isolated Arnold-Chiari malformation and progressive hydrocephalus during intrauterine and postnatal life.

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Ahmad S . Teebi Kamal K. Naguib Kuwait Medical Genetics Centre Maternity Hospital Kuwait

Edited by John M. Opitz and James F. Reynolds