genetic disorders among palestinian arabs. 2. hydrocephalus and neural tube defects
TRANSCRIPT
Genetic Disorders Among Palestinian Arabs.2. Hydrocephalus and Neural Tube Defects
Joel Zlotogora*The Rosa and David Orzen Human Genetic Clinic, Department of Human Genetics, Hadassah Medical Center,Hebrew University, Jerusalem, Israel
Congenital hydrocephalus and/or open neu-ral tube defect was present in at least oneindividual of 98 families out of the 2,000 Pal-estinian Arabic families who have visitedthe Genetic clinic at the Hadassah MedicalCenter. In 22 families the brain malforma-tion was part of a syndrome: Meckel syn-drome in 10, Warburg syndrome in another5, Carpenter in one, and undiagnosed in 6families.
In 76 of the families the neural tube defectand/or the hydrocephalus were non-syndromal. It seems that most of the cases ofisolated non-syndromal hydrocephalus rep-resented autosomal recessive traits and thatan abnormal allele is common among Pales-tinian Muslim Arabs. Am. J. Med. Genet. 71:33–35, 1997. © 1997 Wiley-Liss, Inc.
KEY WORDS: inbreeding; hydrocephalus;Meckel syndrome; neuraltube defects; Warburg syn-drome
INTRODUCTION
Congenital hydrocephalus is a relatively commonmalformation in the stillborn and newborn infant andits prevalence as a single congenital malformation isbetween 1:1,000 and 1:2,500 live births [Laurence,1993]. The etiology of congenital hydrocephalus is ex-tremely heterogeneous and for instance it may be sec-ondary to an open neural tube defect, a malformation ofthe brain, an intrauterine infection, or an intraven-tricular hemorrhage [Williamson et al., 1984]. Amongthe inherited forms of isolated congenital hydrocepha-lus, the X-linked recessive form is the most common inthe general population and accounts for between 2 to15% of primary idiopathic hydrocephalus in newbornmales [Kenwrick et al., 1996]. The existence of an au-
tosomal recessive form has been suggested which hasbeen reported to be frequent among the PalestinianArabs [Zlotogora et al., 1994].
Recently we completed a survey of all the PalestinianArabic families who have attended the genetic clinic atthe Hadassah Medical Center which confirmed thehigh frequency of an autosomal recessive form (orforms) of congenital hydrocephalus. Analysis of thedata showed that the disorder is genetically heteroge-neous in this population.
MATERIAL AND METHODS
The Population
The Palestinian Arab population, which I refer to inthis study, is the one living in the west bank of theJordan and includes the Arabs who are Israeli citizens.Most the population is rural living in villages or smalltowns and a part is living in larger cities like Jerusa-lem, Gaza, Nablus, Nazareth, or Hebron. Muslim rep-resent the largest group among the Palestinian Arabs,while Christian and Druze are much smaller commu-nities. An estimate of the number of Palestinian Arabsin the region is 3,000,000 including 1,000,000 IsraeliArab citizens [Central Bureau of Statistics, 1995].
The genetic clinic begun to operate at the HadassahHospital in 1965 and out 30 years more than 12,000families have visited the clinic (not including thosewhich came for routine prenatal diagnosis). This is theonly genetic clinic in Jerusalem and it serves the entirepopulation including a part of the west bank. In addi-tion, Haddassah Medical Center is a referral centerand therefore families come to the clinic from all theregion. As part of a study of genetic disorders amongPalestinian Arabs in Israel we collected 2,000 files rep-resenting all the Palestinian Arabic families who at-tended the genetic clinic. In this part of the study weanalyzed the data from all the families in which atleast one child was affected with hydrocephalus and/oran open neural tube defect. In some cases the data werefrom the family history only; however, almost all caseswere examined by the family physician, or when thechild was living, he was examined in our clinic. Inmany instances of intrauterine diagnosis and abortionan autopsy was performed.
*Correspondence to: Dr. Joel Zlotogora, Department of HumanGenetics, Hadassah Hospital POB 12000, Jerusalem, Israel91120.
Received 19 April 1996; Accepted 7 November 1996
American Journal of Medical Genetics 71:33–35 (1997)
© 1997 Wiley-Liss, Inc.
RESULTS
In 98 families there was at least one individual withcongenital hydrocephalus and/or an open neural tubedefect (Table I). Among these families, 42 had congen-ital hydrocephalus without open neural tube defects; itwas non-syndromal in 34 families and syndromal inthe other 8 (Meckel in 4, Warburg in 2, and an undi-agnosed syndrome in each of the other 2 families). In 47families at least one individual was affected with anopen neural tube defect; 42 were isolated and non-syndromal and 5 were part of a syndrome (Meckel in 4,and Carpenter in one). In the last 9 families there wasat least one sib affected with isolated hydrocephalusand another with an open neural tube defect (Meckelsyndrome in 2, Warburg syndrome in 3, and an undi-agnosed syndrome in the other 4 families).
Non-syndromal open neural tube defects were pres-ent in individuals from 42 families. Among 26 familieswith myelomeningocele, there were five with two af-fected sibs. Among the 14 families with an anence-phalic child there was an additional child with myelo-meningocele in 2 of them. In two families with a childwith an occipital encephalocele there was a sib with amyelomeningocele.
Non-syndromal hydrocephalus was diagnosed in 34families. There were three Christian families; in onetwo children were affected and in the other two fami-lies there was only one affected child. In the 31 Muslimfamilies the parents were consanguineous in 30(96.5%), 21 of them as first cousins (67.5%). There wasa total of 55 affected individuals: one in 12 families, twoin 15 families, three in three in families, and four inone family. Eight affected individuals were diagnosedin utero; seven were stillborn, sixteen died neonatally,and twelve died later (almost all during their firstyear). The other 12 affected children were alive whenthe family came to the clinic. This variability in thetime of survival was inter and intra-familial.
Meckel syndrome was diagnosed in ten Muslim fami-lies. In nine the parents were consanguineous and insix as first cousins. Seventeen individuals were af-fected in these families: five with hydrocephalus alone,six with an occipital cephalocele, and six who died athome without exact description of the cranial defect.Other typical signs of the syndrome were present indifferent combinations among the affected individuals.In five families, one case only was diagnosed, in fourthere were two cases and in the last family four cases.
Warburg syndrome was diagnosed in five Muslimsfamilies. The parents were first cousins in four of thefamilies. The diagnosis of Warburg syndrome wasbased on typical eye and central nervous system mal-formations. In these families, 13 individuals were af-fected: ten with hydrocephalus and three with occipitalcephalocele. In two families three children had hydro-cephalus, in one family two individuals had hydroceph-alus and one cephalocele, and in the last two familiesone child had hydrocephalus the other occipital cepha-locele.
Carpenter syndrome was diagnosed in one family.One child was stillborn with anencephaly and polydac-tyly, another child was diagnosed in utero, and the au-topsy demonstrated craniosynostosis and preaxialpolysyndactyly. The parents were related as first cous-ins and had three other normal children.
Undiagnosed syndromes were found in six families.In four Muslims families more than one individual wasaffected with a brain malformation; in all cases theparents were consanguineous. In two families, two in-dividuals were affected with hydrocephalus and onewith anencephaly. In the one family there was onechild born with hydrocephalus and two fetuses diag-nosed in utero with anencephaly. In the last familythere were two children born with hydrocephalus andthree fetuses diagnosed in utero (two with occipitalcephalocele and one with hydrocephalus). All caseswith an open defect were diagnosed in utero andaborted). Since in most cases no pathological examina-tion was done, other malformations, in particular eyedefects, were not excluded. In two other Muslim fami-lies there was only one affected child. In one case thechild had congenital hydrocephalus and cleft lip andpalate; he died at 6 months. In the other case the childwas affected with congenital hydrocephalus, bilateralcoloboma of the optic disk and mental retardation.
It may be that some of these cases with undiagnosedsyndromes represent incomplete or atypical forms ofMeckel or Warburg syndrome.
DISCUSSION
Consanguineous matings are very prevalent amongArabs in the Middle East; in different countries fromthe region the rate of consanguineous marriagesranges from 23 to 58% [Khoury and Massad, 1992;Teebi, 1994]. In Israel, it is estimated that both amongMuslim and Christian Arabs, approximately 45% of themarriages are between relatives and almost 25% be-tween first cousins [Jaber et al., 1994]. In such a popu-lation it is expected to find a relatively high frequencyof autosomal recessive disorders and multifactorialcongenital malformations.
This study is based on families that came to the ge-netic clinic at Hadassah Medical Center and includesmainly residents from the region of direct referral in-cluding Jerusalem and its surroundings, as well as apart of the territories in the west bank of the Jordan.Therefore from these data, we cannot calculate the trueincidence of hydrocephalus and or neural tube defectsor even their relative frequency in the population. Inaddition, statistical data on the frequency of birth de-
TABLE I. Hydrocephalus and or Open Neural Tube Defects(NTD) in Palestinian Arabic Families*
NTDHydro-
cephalusNTD and
hydrocephalus Total
Isolated 42 34 — 76Meckel syndrome 4 4 2 10Warburg syndrome — 2 3 5Carpenter syndrome 1 — — 1Others — 2 4 6Total 47 42 9 98
*Each family was classified according to the individuals affected: NTDonly, hydrocephalus only, and NTD in at least one individual and hydro-cephalus in another.
34 Zlotogora
fects are not available since many of the families in-cluded in this study were not Israeli citizens.
Among individuals with open neural tube defectswho came to our clinic there was a relatively largenumber with occipital cephalocele. Analysis of the as-sociated malformations and of the family data demon-strated that many cases with occipital cephalocele werein fact affected with Meckel or Warburg syndrome. Ithas been suggested that there is an increased risk forhydrocephalus in families with a propositus affectedwith an open neural tube defect [Cohen et al., 1979].However, while we observed several families in whichone sib had hydrocephalus and another had an en-cephalocele or anencephaly, we never observed one sibwith hydrocephalus and another with an open myelo-meningocele. It is probable that those families includ-ing siblings affected with open and closed neural tubedefects were in fact examples of complex syndromesand that the relation between the malformations is thevariability of single gene disorders.
The Warburg syndrome is relatively rare and in aseries of 18 typical patients [Dobyns et al., 1985] con-genital hydrocephalus was present in ten cases andposterior encephalocele in the other eight cases. An-other anomaly which is diagnosed easily in the syn-drome is a developmental defect of the eyes such ascorneal opacities, cataracts, and/or microphthalmia.According to these criteria Warburg syndrome was di-agnosed in five of the families reported here and wasprobable in another one. Only after further examina-tions which were not done in most of our patients, othertypical findings of Warburg syndrome may be found,including retinal abnormalities and type II lissen-cephaly (CT scan or autopsy).
Meckel syndrome is relatively easy to diagnose sincepolydactyly is an evident symptom. The syndrome wastypical in at least one case in each of the 10 Muslimfamilies reported here. Since anencephaly may be pres-ent in children with Meckel syndrome it is possible thatthis was the diagnosis in the three families with anundiagnosed syndrome in which at least one child wasborn with hydrocephalus and another with anen-cephaly.
As already mentioned, the data presented here donot allow a determination of the frequency of congeni-tal hydrocephalus; however, it has been our impressionthat it must be relatively frequent among the Palestin-ian Arabs. We could demonstrate that congenital hy-drocephalus is genetically heterogeneous and thatamong Muslim Arabs it may occur in three relativelyfrequent autosomal recessive syndromes. Since in theWarburg and Meckel syndromes affected individuals
may present with congenital hydrocephalus without anopen neural tube defect, some of the cases classifiedhere as isolated hydrocephalus may have been incom-plete forms of these syndromes. Isolated congenital hy-drocephalus was particularly frequent among the Mus-lims Arabs since it was diagnosed in 31 families. Theobservations that, in this community, the parents ofthe affected individuals were consanguineous in 30 of31 cases (in 21 of them as first cousins) and that therewere 19 families with multiple cases suggest an auto-somal recessive inheritance for congenital hydroceph-alus. We have shown in this same Arab populationthat, among autosomal recessive disorders, the parentsof children affected were consanguineous in most of thecases when the disease was rare, while in relativelyfrequent disorders consanguineous marriages wereless frequent [Zlotogora, 1997]. The consanguinity rateof 96.5% among the parents of non-syndromal isolatedcongenital hydrocephalus is much higher than ex-pected for a relatively frequent autosomal recessivedisorder. This may be an indication of more than onegene is involved and of further genetic heterogeneity inthis condition.
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