Autosomal among Arabs: an · Autosomal recessive disorders amongArabs: anoverviewfromKuwait Table 1 Frequencies ofconsanguineous marriages amongArabs Population Frequency (%) Ref

2JMed Genet 1994;31:224-233

Medical genetics around the world

Autosomal recessive disorders among Arabs: anoverview from Kuwait

Ahmad S Teebi

AbstractKuwait has a cosmopolitan population of1-7 million, mostly Arabs. This populationis a mosaic of large and small minoritiesrepresenting most Arab communities. Ingeneral, Kuwait's population is charac-terised by a rapid rate of growth, largefamily size, high rates of consanguineousmarriages within the Arab communitieswith low frequency of intermarriagebetween them, and the presence of gen-etic isolates and semi-isolates in someextended families and Bedouin tribes.Genetic services have been available inKuwait for over a decade. During thistime it has become clear that Arabs havea high frequency of genetic disorders,and in particular autosomal recessivetraits. Their pattern is unique and somedisorders are relatively common. Ex-amples are Bardet-Biedl and Meckelsyndromes, phenylketonuria, and fami-lial Mediterranean fever. A relativelylarge number ofnew syndromes and var-iants have been delineated in Kuwait'spopulation, many being the result ofhomozygosity for autosomal recessivegenes that occurred because of inbreed-ing. Some of these syndromes have sub-sequently been found in other parts of theworld, negating the concept ofthe privatesyndrome. This paper provides an over-view of autosomal recessive disordersamong the Arabs in Kuwait from a per-sonal perspective and published studies,and highlights the need for genetic ser-vices in Arab countries with the goal ofprevention and treatment of genetic dis-orders.

(J Med Genet 1994;31:224-233)

Department ofGenetics, YaleUniversity School ofMedicine, New Haven,Connecticut, USAA S Teebi

Correspondence toDr Teebi, Division ofMedical Genetics, TheMontreal Children'sHospital, 2300 Tupper,Montreal, Quebec H3H 1P3,Canada.

In contrast to the genetically well studiedpopulations of North America and Europe,particularly commnunities such as the Amish,'French Canadians,2 and Jews,3 many com-

munities within the Arab world remainedunstudied. However, previous efforts havebeen made to study genetic disorders in someArabian countries such as Lebanon,4 SaudiArabia,5 and Egypt.67 I present here a geneti-cist's experience in Kuwait and review per-tinent published reports in order to give an

overview of autosomal recessive disorders,

which are the most common category of gen-etic disorders among Arabs in Kuwait.

The country and populationKuwait is a small Arab country situated in thenorth east of the Persian Gulf. It is boundedon the north and north east by Iraq and on thesouth by Saudi Arabia. The country's totalarea (6880 square miles) is barren desert that isrich in oil which is the source of Kuwaitiwealth. The population is cosmopolitan andcomprised of large and small minorities. UntilAugust 1990 (Iraqi invasion), its 1-7 millionpeople, according to a 1985 census,8 were madeup of 40% Kuwaiti natives and Bedouin, and60% immigrants, the majority of whom wereArabs. These immigrants were mostly fromArabian Middle Eastern countries; however,small minorities from North Africa are alsopresent. One of the large minorities before theinvasion of Kuwait were the Palestinians whoformed about 22% of the total population atthat time. Those considered to be Kuwaitinatives are the early settlers of the urbancentres originating mostly from neighbouringArab countries, while the Bedouin are thenomadic Arabs of the desert who live on thefringes of the Arabian peninsula which in-cludes parts of Kuwait, Saudi Arabia, Qatar,United Arab Emirates, Oman, Iraq, Jordan,and Syria as well as Negev and Sinai desert.Over the past three to four decades, they havesettled in urban centres and have acquired thecitizenship of the countries that host them.Those who lived in Kuwait have acquiredKuwaiti nationality and some of them becameindistinguishable from natives. However,Bedouins form tribal communities which arequite isolated. It is very likely that individualpeople from the same tribe or kindred havesettled in different Arab countries andacquired their nationalities.

Also, the Kuwaiti population has one of thehighest growth rates in the world (approxim-ately 50000 live births/year) and large familysize with five children being an average num-ber of offspring per family.8 The rate of con-sanguineous marriage is high, with highinbreeding coefficients not only within theKuwaiti native population910 but also withinother Arab communities, according to studiesconducted in Kuwaitl' or in their countries oforigin' 116 (table 1). The most frequent form of

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Autosomal recessive disorders among Arabs: an overview from Kuwait

Table 1 Frequencies of consanguineous marriages among Arabs

Population Frequency (%) Ref Comments

Kuwaiti 54-3 9 Higher rates among Bedouin tribes37-8 10

Egyptian 23-3 10 Sample from Kuwait28-96 11 Higher rates in rural areas

Iraqi 57-87 12 Higher rates in rural areasJordanian 36-2 10 Sample from Kuwait

50-0 13 Lower rates among ChristiansLebanese 26-0 14 Lower rates among ChristiansPalestinian 39 0 15 Arabs in Israel

38-7 16 Arab village in Israel

consanguineous marriage is between first cou-sins, particularly paternal first cousins. Doublefirst cousin marriages also exist. The fre-quency of intermarriage between differentArab communities is low, which is also the casefor some extended families and tribes withinthe community. This has resulted in sustainedisolation particularly for the Bedouins andsome wealthy families.

Religion, culture, and genetic issuesIslam is the predominant religion amongKuwaitis, the majority being Sunnite Muslimswho are generally described as being modestwith a strong faith in Islam. Despite the wes-ternisation of a significant sector of the popula-tion, many still maintain their cultural ties andreligious principles. Although Islam, accord-ing to many religious scholars, discouragesconsanguineous marriages, such marriageshave been traditionally practised over manygenerations because of social, economic, andgeographical factors. Because they are forbid-den by Islam, uncle-niece/aunt-nephew mar-

riages are virtually non-existent.'7 Prenataldiagnosis is acceptable for purposes of reassur-ance or of therapy. Termination of pregnancy,however, at any stage is absolutely forbidden(haram), unless the mother's life is endan-gered.'8 Under Islamic law, according to someinterpretations, termination of pregnancy isconsidered a crime. 9 However, couples mayavoid pregnancy if they are at an unacceptablyhigh risk of having a child with a certaingenetic defect. On the other hand, artificialinsemination using the husband's sperm(AIH) and in vitro fertilisation (IVF) using thehusband's sperm is acceptable, but usingdonor sperm is absolutely forbidden. Ingeneral, assisted reproduction using the hus-band's and wife's gametes is acceptable. Adop-tion has been practised since the early ages ofIslam. However, "legal" adoption is notallowed.

Genetic servicesGenetic services on a small scale began inKuwait in the late 1 960s but were discontinuedin the early 1970s because of the lack of quali-fied personnel. More sustained and extendedservices are relatively new and were initiated in1979 as a weekly clinic in the paediatric depart-ment of Al-Sabah Hospital, the main generalhospital at that time. In 1981, the medicalgenetics centre at the Maternity Hospital inthe Al-Sabah area near Kuwait City was offi-cially opened. The purpose was to provide

clinical, cytogenetic, and genetic counsellingservices, to teach medical genetics to medicalresidents and other health professionals, and toconduct research directed towards under-standing genetic problems in the community.Genetic services have subsequently beenexpanded to involve satellite clinics at the Al-Amiri Hospital in Kuwait City and satellitecommunity genetic programmes at three re-gional hospitals in the governorates of Farwa-nia, Jahra, and Al-Ahmadi. Services in theseregions were furnished on a weekly or twiceweekly basis and on demand. The centre inthe years 1985 to 1990 was staffed by threetrained geneticists at the consultant level, threeothers at the registrar or senior registrar level,two nurses, and two social workers, and areasonably equipped and staffed cytogeneticslaboratory.

Genetic disorders in KuwaitAt birth, the incidence of major defects isslightly higher than the 2 to 3% found in theworld's major surveys. However, if other dis-orders that manifest later in life are included,the figure would be substantially higher thanin other parts of the world and the profile isdistinctive. In the virtual absence of prenataldiagnosis and termination of pregnancy, andthe long reproductive period, patients withchromosomal anomalies, particularly trisomy21, constitute approximately 28% of patientsseen at the genetic clinic (unpublished data on1300 new patients seen at the Al-Amiri satel-lite clinic and Farwania community geneticprogramme over a seven year period from 1983to 1990). Although the incidence of aneuploi-dies among live births is higher than otherparts of the world,20 the pattern of chromoso-mal abnormalities in general does not appear tobe significantly different. On the other hand,birth defects as a result of known teratogensform only 1 to 2% of patients, partly becauseof restricted use of drugs and chemicals, prohi-bition of alcohol, and the fact that the vastmajority of females are naturally immune torubella before childbearing age. The remain-ing 70% of patients seen in genetic clinics canbe divided as follows. (1) Known autosomalrecessive (AR) disorders or unknown disorderswith a family pattern suggestive ofAR inherit-ance (approximately 45%). (2) Known multi-factorial and polygenic disorders (18%). (3)Known and unknown autosomal dominantdisorders (12%). (4) Unknown disorders with-out suggestive family pattern (22%). (5) Xlinked disorders (2 to 3%).

In addition to data from the survey (personalobservation), sources of information about ARphenotypes include personal communications,published studies, and case reports (generalreviews and abstracts are available).21-24 Apartfrom the extreme rarity of Huntington's dis-ease, the pattern and apparent frequencies ofautosomal dominant disorders in Kuwait arenot remarkably different from those in westerncountries. In contrast, several AR disordersare reported to be highly prevalent (table 2).Autosomal recessive disorders among Arabs in

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Table 2 Autosomal recessive disorders reported to be relatively common among Arabs in Kuwait

Disorder McKusick No Community Ref

Adrenal hyperplasia, 21 hydroxylase deficiency 201910 Kuwaiti, Palestinian, Syrian, Egyptian, Yemeni, Sudanese 59, 60Argininosuccinic aciduria 207900 Palestinian, Jordanian, KuwaitiArthropathy, progressive pseudorheumatoid, of children 208230 Kuwaiti, Lebanese 50, 51Bardet-Biedl syndrome 209900 Bedouin, Kuwaiti, Palestinian, Syrian 30, 31, 34Chloride diarrhoea, familial 214700 Kuwaiti 57, 58Citrullinaemia 215700 Palestinian, Kuwaiti 54, 61Faciodigitogenital syndrome, Kuwait type 227330 Kuwaiti Bedouin tribeHomocystinuria 236200 Kuwaiti Bedouin, Palestinian 53, 54Hyperglycinaemia, non-ketotic 238300 Palestinian, Kuwaiti 54Laurence-Moon syndrome 245800 Kuwaiti 30Meckel syndrome 249000 Bedouin, Kuwaiti, Bedouin 35, 38, 39Mediterranean fever, familial (FMF) 249100 Palestinian, Egyptian, Lebanese, Syrian, Iraqi 26, 27Muscular dystrophy, Duchenne-like, autosomal recessive (SARCMD) 253700 Kuwaiti, Iraqi, Palestinian 47, 48Osteopetrosis, severe AR 259700 Kuwaiti, Saudi Arabian, Palestinian 63Osteopetrosis, renal tubular acidosis 259730 Kuwaiti, Saudi Arabian 65-67Phenylketonuria (PKU) 261600 Kuwaiti, Palestinian, Egyptian, Lebanese 52-67Pterygium syndrome, multiple 265000 Palestinian, Kuwaiti Bedouin, Bedouin 40-42Thalassaemias 273500 Kuwaiti, Saudi Arabian, Iraqi, Palestinian 70, 73Tyrosinaemia 276700 Kuwaiti, Palestinian 54

Kuwait will be discussed according to theirconspicuous features and McKusick's25 entrynumbers for the defined entities are included.

Relatively common autosomal recessivedisordersFAMILIAL MEDITERRANEAN FEVER (FMF) ORRECURRENT HEREDITARY POLYSEROSITISThis is a multisystem disease characterised byrecurrent, painful, self-limiting episodes ofperitonitis, pleuritis, arthritis, or erysipelas-like erythema usually accompanied by fever.26This condition was diagnosed in 88 children26and 151 adults27 from Kuwait. More than 70%of these patients were Palestinians or Jorda-nians. Accordingly, the prevalence of FMF inthis community is at least 1:2000. Similarobservations have been noted in Jordan (H AMajeed, personal communication). This dis-order is also common among Sephardic Jews25and Armenians21 and to a lesser degree inTurks, Greeks, Italians, and Arabs (other thanPalestinians). In earlier studies from Lebanon,FMF was found in most ethnic groups butparticularly in Armenians.4

BARDET-BIEDL SYNDROME (BBS) ANDLAURENCE-MOON SYNDROME (LMS)Laurence-Moon-Bardet-Biedl syndrome(LMBBS) was a common designation. How-ever, nosological splitting of LMBBS intoBBS and LMS has become widely accepted.As from 1986, 20 cases were diagnosed withBBS, including monozygotic twins, and sixwith LMS among a mixed Arab population inKuwait.303' The combined minimum preval-ence was 1 in 50 000 among the general popu-lation which is more than three times theprevalence in Switzerland. Many of these caseswere Palestinians, confirming the observationsamong Arabs from Israel.3233 Subsequentstudies documented more cases of BBS amongthe Bedouin with an estimated prevalence of1:13 500 which is three times higher than thatof the general population.34 The incidence ofBBS among the Bedouin in Jahra district wasestimated to be 1:6900 livebirths.34 Parentalconsanguinity was 87% among patients fromthe general population while it was 100%among Bedouin patients. BBS is also not rareamong Jews.32

MECKEL SYNDROME (MS)MS is a frequently diagnosed malformationsyndrome among neonates in Kuwait. Theincidence is unusually high for a malformationsyndrome (1:3530 livebirths)35 and most ascer-tained cases are of Bedouin ancestry. A similarlyhigh incidence is also seen among Tartars36 inthe former Soviet Union and among GujaratiIndians.37 A Bedouin family with five affectedsibs was reported to have a variant of MSlacking polydactyly.35 Other cases of MS wereascertained in a study of cleft lip with orwithout cleft palate.39

MULTIPLE PTERYGIUM SYNDROME (MPS)MPS was found in 13 cases in six sibshipsduring a genetic survey in the Farwania dis-trict (1/3 of Kuwait's Arab population). Theestimated minimum prevalence was 1 in 31 000in the general population.' A detailed reportof a Bedouin family with five affected sibs isavailable.4' A phenotypically similar but lethalcondition(s) has also been reported.42

FACIODIGITOGENITAL SYNDROME, KUWAIT TYPEThis condition, which closely resembles Aars-kog syndrome, has been described in fiveKuwaiti Bedouin sibs as a new syndrome.43Subsequently, nine patients in four sibshipsfrom the same tribe (approximately 8000people) have been found to have this disorderand all could be traced to a common ancestor.44The prevalence of this syndrome in this tribe isremarkably high and represents a foundereffect.

SEVERE AUTOSOMAL RECESSIVE CHILDHOODMUSCULAR DYSTROPHY (SARCMD)SARCMD, or Duchenne-like MD, is a rela-tively common disease among Arabs particu-larly in Sudan45 and Tunisia.46 In Kuwait, inFarwania and Jahra districts with highlyinbred populations, eight families were ascer-tained to have SARCMD.4748 This numberconstitutes more than one third of familieswith MD compared to 5% as estimated fromthe UK and North America and 6-8% asestimated from Brazil.49

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PROGRESSIVE PSEUDORHEUMATOIDARTHROPATHY OF CHILDHOOD, ORSPONDYLOEPIPHYSEAL DYSPLASIA TARDA WITHPROGRESSIVE ARTHROPATHY (SEDT-PA)This is a rare disorder that was diagnosed inthree families in Kuwait. Two of these familieswere reported in detail.505' A review of pub-lished reports has shown that seven out of 16cases were Arabs.51

PHENYLKETONURIA (PKU)PKU was found to have a frequency ofbetween 1-6% and 1-86% among institutiona-lised mentally retarded patients.5253 In addition, 13 cases were detected at the geneticclinic through evaluation for mental retard-ation.52 Other cases were published subse-quently.54 The majority of these patients haveconsanguineous parents. Five patients in threesibships have a common ancestry in a Kuwaitikindred. The incidence of classical PKU wasfound to be 1:6479 livebirths,55 as estimatedduring the course of a neonatal screeningproject, which is higher than the averagefigure from the USA and Europe (1:11 000).The combined incidence of PKU andhyperphenylalaninaemia (HPA) was 1:4860livebirths. PKU has also been ascertained in aBedouin mother with three children who hadPKU embryopathy.56

CONGENITAL CHLORIDE DIARRHOEA (CCD)In one study over a seven year period,57 16cases were ascertained, all of whom have con-sanguineous Kuwaiti parents. The estimatedminimum incidence was 7-6:100 000 live-births, similar to that in Finland.57 Twelveother children with suspected CCD died be-fore having a confirmed diagnosis. Other caseshave also been reported.58

CONGENITAL ADRENAL HYPERPLASIAOver a decade (1978-1988), at least 60 paedia-tric patients with congenital adrenal hyperpla-sia were diagnosed.59 The majority (90%) had21-hydroxylase deficiency while 10% hadeither 11 -B-hydroxylase deficiency or 3-B-hydroxysteroid dehydrogenase deficiency.The estimated overall incidence ranged from1:7000 to 1:9000 livebirths which is higherthan that in Europe and Canada. Other caseswere also ascertained in a study of true andpseudohermaphroditism.60

NON-KETOTIC HYPERGLYCINAEMIA (NKH) ANDHOMOCYSTINURIA (HC)Seven cases ofNKH and five cases ofHC wereascertained at Al-Sabah Hospital within athree year period.54 Several other cases ofNKH and HC were diagnosed in other hos-pitals to make these disorders relatively morecommon in Kuwait than in other parts of theworld.

UREA CYCLE DEFECTSCitrullinaemia is a commonly diagnosed dis-order.546' Cases of argininosuccinic aciduriaand carbamoyl phosphate synthase deficiency(CPS) are also common.

TYROSINAEMIASeveral cases of type I tyrosinaemia have beenfound in a laboratory survey.54 A Kuwaitifamily with several members with tyrosinae-mia type II was also reported.62

OSTEOPETROSIS, SEVERE AUTOSOMAL RECESSIVEData from Kuwait63 and Saudi Arabia64 indic-ate that this form of osteopetrosis is relativelycommon in the Arabian peninsula. The inci-dence, however, is not known. Osteopetrosiswith renal tubular acidosis and cerebral calcifi-cation has also been reported frequently fromKuwait657 and Saudi Arabia,666869 and itseems to be relatively common also.

HAEMOGLOBINOPATHIESThe genes for sickle cell haemoglobinopathiesand f0 thalassaemia are prevalent in Kuwait,and diseases resulting from homozygosity ordouble heterozygosity (sickle cell anaemia, °0thalassaemia, and Hb S ,B0 thalassaemia) arecommon.70 The prevalence of the sickle celltrait (McKusick no 141900-0243) may besimilar to or slightly lower than the 10 to 25%estimated in the Eastern Province of SaudiArabia.7'72 In a study from Kuwait involving110 patients with major f chain haemoglobi-nopathies, 47 patients had homozygous hae-moglobin S disease (Hb SS) and 21 had Hb 130thalassaemia.70 In contrast to African-Amer-ican patients with these diseases, most Kuwaitipatients have a less severe haemolytic anaemiaand fewer signs and symptoms of vaso-occlu-sive phenomena as a result of modifying effectsof high levels of Hb F. In another study,73 theincidence of a thalassaemia heterozygotes isestimated to be 4-6% by screening 345 con-secutive cord blood samples (16/345). All the16 samples contained a deletion in either oneor two a globin genes. The incidence is signi-ficantly lower than in the Eastern Province ofSaudi Arabia (56%).

DISORDERS FREQUENTLY DIAGNOSED IN KUWAITBUT UNCOMMON ELSEWHEREThese include cystinuria (220100), spinalmuscular atrophy or Werdnig-Hoffmann dis-ease (226600), GM1 gangliosidosis (230500),Gaucher disease type I (230300), micro-cephaly (251200), clinical anophthalmia(251600), mucolipidosis type II (252500),Hurler and Hurler-Scheie syndromes (252800),Maroteaux-Lamy syndrome (253200), Nie-man-Pick disease type B (257200), Sandhoffdisease (268800), multiple sulphatases (272200),Wilson's disease (277900), wrinkly skin syn-drome (278250), organic acidaemias, lethalchondrodystrophies, and undelineated neuro-degenerative brain disorders. The above

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information is not published and is based on

personal experience and personal communica-tions.

New autosomal recessive syndromesOut of 22 new syndromes and variants thatwere described in Kuwait in the period from1985 to 1992, three were autosomal domin-

78one was X linked,79 and 18 were auto-42448092somal recessive. of the 18 AR syn-

dromes and variants, 11 had new entries inMcKusick's catalogue25 which constitutes ap-proximately 5% of all new entries during thatperiod (11/211). The remaining seven dis-orders either had no entries,9294 or were in-cluded in existing AR81 87 95 96 or autosomaldominant'02 entries (table 3).

LIMB/PELVIS-HYPOPLASIA/APLASIA SYNDROME

This was the first new disorder to be describedfrom Kuwait.98 The patients were two Palesti-nian sibs (a male and a female) of consanguin-eous parents. They had severe limb deficiency,dysplastic hips, and minor facial anomalies.Subsequently, seven patients were describedfrom several countries including Brazil, Israel,Italy, and again from Kuwait in a Bedouinchild.99 Two of the five females hithertoreported had hypoplasia or aplasia of the uter-us.99100 Prenatal diagnosis by ultrasonographyhas been accomplished.'0'

HYPOGONADISM SYNDROMES

One syndrome was first described in three sibsof consanguineous Jordanian Christian parents.Anomalies included partial alopecia consistingof hair only in the centre of the scalp, primaryhypogonadism, and defective Mullerian de-velopment in the sisters.84 Their brother hadhormonal and histological findings consistentwith germinal cell aplasia. After this descrip-tion, two Kuwaiti sisters of consanguineousparents were found to have a similar condition(unpublished). Another hypogonadism syn-drome was reported in three sibs of first cousin

Palestinian parents." Anomalies includedhypogonadotrophic hypogonadism, mental re-

tardation, obesity, and minor skeletal anomal-ies. The two brothers also had gynaecomastia.This paper reviewed seven new autosomalrecessive disorders described from the MiddleEast, six of which were in Arabs and one was ina Yemenite Jewish family.

FACIODIGITOGENITAL SYNDROME, KUWAIT TYPEThis has been discussed under common dis-orders.43 44

CARDIOSKELETAL SYNDROME, KUWAIT TYPETwo male sibs of Kuwaiti first cousin parentswere found to have congenital heart malforma-tion and skeletal dysplasia including rhizome-lic limb shortness and coronal clefting of thevertebral bodies.80

BEDOUIN SPASTIC ATAXIA SYNDROMEThis condition was described in a highlyinbred Bedouin family with affected subjectsin several sibships.90 Anomalies included spas-tic ataxia, congenital cataracts, macular andcorneal dystrophy, and non-axial myopia, inthe absence of mental retardation. Immuno-logical abnormalities were common. The au-

thors concluded that this disorder was clinic-ally distinct from a similar disorder describedin Lebanon.'03

SPINOCEREBELLAR DEGENERATION WITH SLOWEYE MOVEMENTS (SDSEM)This condition was described in six subjects(three males and three females) in two sibshipsfrom a consanguineous Palestinian family.9'Associated manifestations included progres-sive intellectual impairment and extrapyrami-dal dysfunction as well as peripheral neuro-pathy and skeletal abnormalities. Musclebiopsy showed non-specific mitochondrialchanges.

Table 3 New genetic syndromes and variants reported from Kuwait

Disorder No of patients Family origin McKusick No Ref

Autosomal dominantGastric sneezing 11 Syrian 137130 74Hypertelorism-Teebi type (brachycephalofrontonasal dysplasia) 16 Iraqi 145420 75, 76Tibia, hypoplasia of, with polydactyly 2 Kuwaiti 188770 77, 78Autosomal recessiveGrebe-like chondrodysplasia 1 Palestinian 200700 81Cardioskeletal syndrome, Kuwaiti type 2 Kuwaiti 212135 80Cystic fibrosis with helicobacter gastritis, megaloblastic anaemia and subnormal mentality 2 Bedouin 219721 82Faciodigitogenital syndrome, Kuwait type 5+9 Kuwaiti, Bedouin 227330 43, 44Hypertelorism, hypospadias, polysyndactyly syndrome 3 Pakistani (non-Arab) 239710 88, 89Hypertelorism, hypospadias, tetralogy of Fallot syndrome 4 Palestinian 239711 83Hypogonadism, primary, and partial alopecia 3+2 Jordanian, Kuwaiti 241090 84Macrosomia with microphthalmia, lethal 5 Palestinian 248110 85, 86Microcephaly with normal intelligence 8 Palestinian 251260 87Bedouin spastic ataxia syndrome 22 Bedouin 271320 90Spinocerebellar degeneration with slow eye movements 6 Palestinian 271322 91Spondyloepimetaphyseal dysplasia, a new variant 3 Syrian, Bedouin 271640 95Trigonobrachycephaly, bulbous bifid nose, micrognathia, and abnormalities of the hands 2 Palestinian 275595 97

and feetLimb/pelvis-hypoplasia/aplasia syndrome 2+1 Palestinian 276820 98-101Weaver-like syndrome 2 Bedouin 277590 96Palmoplantar keratoderma, epidermolytic recessive form 2 Kuwaiti 144200* 102Craniofacial-hair-finger-caudal syndrome 1 Kuwaiti - 93, 94Hypogonadotrophic hypogonadism, obesity, MR, and skeletal anomalies 3 Palestinian - 92X linkedNephrosis, minimal charge 4 Syrian - 79

*Autosomal dominant entry in McKusick's catalogue.

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TRIGONOBRACHYCEPHALY SYNDROMEThis condition was described in a brother andsister, offspring of first cousin Palestinianparents.97 Other manifestations included a bul-bous nose which was slightly bifid at the tip,micrognathia, macrostomia, relatively broadfirst metatarsals and phalanges, and severe

psychomotor retardation.

MACROSOMIA-MICROPHTHALMIA SYNDROME

This condition was described in three femalesand two males from a sibship of 10 whoseparents were Palestinian first cousins.8586 Asso-ciated manifestations included median cleftpalate in three and recurrent infections in all,with early, rapid, or sudden death.

WEAVER-LIKE SYNDROMEA brother and sister, offspring of consanguin-eous Bedouin parents, were reported to havemanifestations resembling Weaver syn-drome.96 These included accelerated growth ofprenatal onset, hypotonia, variable psychomo-tor retardation, excess loose skin, dental dys-plasia, serrated gums, joint laxity, distinctivecraniofacial and digital anomalies, and a

hoarse, low pitched cry. One of them hadaccelerated harmonic skeletal maturation.

HYPERTELORISM-HYPOSPADIAS AND TETRALOGYOF FALLOT SYNDROMEThis combination was found in three brothersof Palestinian parents who were first cousinsonce removed.83 The father had hypertelorismand his brother, who is married to a secondcousin, had a daughter with hypertelorism andtetralogy of Fallot. The four affected relativeshad mild or borderline developmental delay.

HYPERTELORISM-HYPOSPADIAS ANDPOLYSYNDACTYLY SYNDROMEThis condition was described in two brothersand a sister of Pakistani consanguineous par-

ents (non-Arabs). Similar cases have also beenreported.89

MICROCEPHALY WITH NORMAL INTELLIGENCEA large inbred Palestinian kindred with eightcases in five sibships was found to have thiscombination in addition to a characteristicfacial appearance.87 This condition is probablydifferent from that associated with immuno-deficiency and increased risk of lymphoreticu-lar malignancies.

CYSTIC FIBROSIS WITH HELICOBACTER PYLORIGASTRITIS, MEGALOBLASTIC ANAEMIA, ANDSUBNORMAL MENTALITYA brother and a sister of consanguineousBedouin parents were found to have this asso-

ciation in addition to minor facial anomalies.

SPONDYLOEPIMETAPHYSEAL DYSPLASIA, A NEW

VARIANTA Syrian-Bedouin consanguineous family wasfound to have three children with this bonedysplasia (two males and a female).95 Theproband was a 6 year old boy with rhizomelicshortness of limbs, dwarfism, dish-like facies,cleft palate, deafness, and camptodactyly.Radiological changes were compatible withKniest disease. Two similarly affected sibsdied in early life.

CRANIOFACIAL-HAIR-FINGER-CAUDALSYNDROMEA Kuwaiti female of parents who were firstcousins once removed was described with cra-niofacial anomalies, abnormally slow growinghair, absence of primary teeth, camptodactyly,and a caudal appendage with sacrococcygealdimple.93 Intelligence was normal. A similarlyaffected female neonate was seen in the UnitedStates.94

GREBE-LIKE CHONDRODYSPLASIAThis non-lethal severe form of short limb bonedysplasia was found in two unrelatedpatients." One of these patients was the pro-duct of first cousin Palestinian parents.8"Features included peculiar facial appearancewith deafness, rib anomalies, and severe short-ness and distortion of long bones, notably thehumeri, tibiae, fibulae, metapodia, and pha-langes with marked irregularity and asym-metry.

AUTOSOMAL RECESSIVE EPIDERMOLYTICPALMOPLANTER KERATODERMATwo male sibs of first cousin Kuwaiti parentswere described as having this condition,'02which is known to be inherited as an autosomaldominant trait (144200). Parents presentedwith patchy eczematous skin lesions followedby palmoplanter keratoderma and raisedserum levels of IgE. Although gonadal mosai-cism cannot be excluded, it is more likely thatan autosomal recessive variant of the diseaseexists in this inbred population.

Disorders with unknown frequenciesCYSTIC FIBROSIS (CF)CF (219700), a well known and studied dis-ease in Europe and North America, was notreported in Kuwait until 1981 when twopatients (Kuwaiti and Syrian) presented withmeconuim ileus.'0 One of them died postoper-atively and the other had recurrent respiratoryinfections and died at the age of 1 year. Atnecropsy, clinical findings of CF were noted.Subsequently, CF was reported in severalKuwaiti and Palestinian patients.'05'07 A ques-tionnaire survey showed that 40 patients werediagnosed with CF in all hospitals in Kuwaitfrom 1979 to 1979 (approximately 500 000livebirths).'08 Manifestations were variable andoccasionally atypical. Several infants pre-sented initially with hyponatraemia, hypo-

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chloraemia, and metabolic alkalosis owing toexcessive sweating in Kuwait's very hot andhumid weather.'07 These patients had minimalmanifestations of pulmonary and pancreaticexocrine deficiency. CF among Arabs fromLebanon, Iraq, and Israel has been reported.'09It has been suggested that the incidence is highamong Arabs of Israel, in the Bedouin as wellas in the city dwellers. This was supported by arecent study from Jordan."0 Our experiencefrom Kuwait suggests that the frequency ofCF may be less than that in western countrieswith mild allelic variants prevailing.

CONGENITAL DEAFNESS, TYPE 1 (220700)In a large inbred Palestinian family, 13 sub-jects in several sibships were reported to haveuncomplicated profound deafness from earlyinfancy."' The family originated from a smallvillage (El-Sawiah) on the West bank nearNablus. Eight cases in three other familiesfrom the same village (apparently not relatedto each other or the reported family) wereascertained to have a clinically similar disorder(unpublished data). At the Farwania geneticclinic, at least nine more patients from fourKuwaiti or Syrian families were found. It isdifficult, however, to conclude that this dis-order is highly prevalent in Kuwait because ofthe remarkable genetic heterogeneity of deaf-ness. Certainly, it has a very high frequency in

Table 4 Other autosomal recessive disorders reported among Arabs in Kuwait

Disorder McKusick No Ref

Acrodermatitis enteropathica 201100 1163-B-hydroxysteroid dehydrogenase deficiency 201810 593-B-hydroxysteroid deficiency 202010 59Congenital hypoplastic anaemia of Blackfan and Diamond 205900 117Anencephaly, AR 206500 118Costello syndrome 218040 119Cystathioninuria 219500 53Cystinuria 220100 54Dyserythropoietic anaemia, type I 224120 120Torsion dystonia, AR 224500 121Ehlers-Danlos syndrome type VI 225400 122Fucosidosis 230000 123Galactosaemia 230400 21, 39Hallermann-Streiff syndrome 234100 124Histidinaemia 235800 21Hydrocephalus, AR 236600 125Urofacial syndrome 236730 126, 127Hyperlysinuria 238750 53Hyperprolinaemia 239500 54Intestinal atresia, multiple 243150 128Apple peel syndrome (jejunal atresia) 243600 129, 130Primary hypomagnesaemia 248250 131Mandibuloacral dysplasia 248370 132Maple syrup urine disease (MSUD) 248600 54Metaphyseal chondrodysplasia, Spahr type 250400 133Clinical anophthalmia 251600 134Multiple pterygium syndrome, lethal 253290 42Schwartz-Jampel syndrome 255800 135Osteoporosis-pseudoglioma syndrome 259770 136Persistent Mullerian duct syndrome 261550 60, 137Congenital hepatic fibrosis 263200 138Porphyria, congenital erythropoietic 263700 139Pseudohermaphroditism, male, with gynaecomastia 264300 60Pseudovaginal perineoscrotal hypospadias 264600 60Vitamin D dependent rickets type I 264700 140Renal tubular acidosis with nerve deafness 267300 141Erythrophagocytic lymphohistiocytosis, familial 267700 142Robinow syndrome 268310 143Russell-Silver syndrome 270050 144Skin peeling, familial, continuous 270300 145Spastic paraplegia 270800 146Thyroid hormonogenesis, genetic defect 274300 147Tyrosinaemia type II 276600 62Spondylothoracic dysplasia 277300 39Wilson's disease 277900 148Xanthinuria 278300 149XX male syndrome 278850 150Brachmann-de Lange syndrome, AR 122470* 151Central Coppock-like cataract 123470* 152

*Autosomal dominant entry in McKusick's catalogue.

the people of the Palestinian village whoseaffected members live in several countriesincluding the West Bank, Jordan, and Kuwait.The population of this village tends to in-breeding even outside their homeland.

Genetic predisposition tonon-disjunction (257300)Following the suggestion of Penrose"2 that arecessive gene in man may cause non-disjunc-tion of chromosome 21 in the ova of homozy-gous females, similar to the gene in DrosophilaMelanogaster, a study from Kuwait"3 showedthat Down's syndrome (DS) was four timesmore frequent among the children of closelyrelated parents than among those of unrelatedparents (p <0-005). Another study"4 also sug-gested an association between consanguinityand the occurrence of non-disjunction aftercorrecting for maternal and paternal ages, buta single gene effect was not observed. Recentdata from a community genetic survey at Far-wania and Jahra districts containing 15% and80% Bedouin respectively have shown an inci-dence of DS of 1 7 and 4 5/1000 livebirthsrespectively."5 The incidence of DS correlatesvery well with the inbreeding coefficient. Aremarkably higher incidence of DS was notedin the higher inbreeding coefficient group withalmost similar mean maternal ages, whichsuggests the existence of some recessive ele-ments controlling non-disjunction. A similarlyhigh frequency of consanguinity was notedamong the grandparents of DS patients. In thehighly inbred Bedouin community of the Jahradistrict, two families had sibs with recurrentaneuploidies, one of these families had two sibswith trisomy 21 and the other had sibs withtrisomy 21 and trisomy 18. Comparable highfrequencies of DS were also reported fromWest Jerusalem and among the NegevBedouin.' '5

Other disorders reported from KuwaitIn addition to the aforementioned, there are anumber of AR disorders that have beenreported among Arabs from this country (table4). Although it may not be an exhaustive list, itincludes a number of case reports of unusualassociations, case series studies, and informat-ive pedigrees. Some of the case reports servedas early delineation of disorders. Examplesare the urofacial syndrome (Ochoa syn-drome),'26 127 metaphyseal chondrodysplasia,Spahr type,'33 and the Costello syndrome."9A number of unusual associations have also

been reported which may not be fortuitous iffound in several members of the family, suchas the association of osteoporosis-pseudo-glioma syndrome and ventricular septal defectin three sibs of consanguineous parents,'36 andthe association of the AR congenital dyseryth-ropoietic anaemia (CDA) with recurrent multi-focal osteomyelitis and Sweet syndrome(unknown aetiology) in two male sibs of firstcousin Palestinian parents and the occurrenceof CDA and Sweet syndrome in their femalecousin. 120

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Homozygosity for two AR syndromes in thesame sibship is not rare. In an inbred Palesti-nian family, three out of eight sibs had ARmicrocephaly with typical facial appearanceand mental retardation. Two of these also hadglycogen storage disease type I, and anothersib had only glycogen storage disease (unpub-lished data). A Kuwaiti brother and sister withconsanguineous parents had the phenotype ofEhlers-Danlos syndrome with aortic regurgi-tation and mitral valve prolapse in addition toperipheral polyneuropathy. 122 Although thismay be a new form of Ehlers-Danlos syn-drome, it is more likely that the sibs hadinherited different recessive traits.Although some case series studies provide

no incidence data, the number of cases in-cluded indicates that certain disorders areprobably not rare, such as congenital hypo-plastic anaemia of Blackfan and Diamond"7and vitamin dependent rickets type I.'40Among cases diagnosed in Kuwait's popula-

tion, a number are commonly encounteredamong Jews.3153154 Examples are the Pales-tinian family with erythrophagocytic lym-phohistiocytosis,142 another with torsiondystonia,"25 and two Kuwaiti families withTay-Sachs disease (unpublished data).A number of informative pedigrees for other

diseases have been found. Examples are theRobinow syndrome pedigree,'43 Russell-Silversyndrome with six affected sibs and normalconsanguineous parents,'" AR hydroceph-alus,'25 apple peel syndrome,'29130 and theextended pedigrees suggestive of an autosomalrecessive form of anencephaly."18 Since then,AR inheritance of anencephaly in some fami-lies has been accepted by McKusick.'5 In aninbred Syrian-Bedouin family, three sibs werefound to have cyclops or alobar holoprosence-phaly (unpublished data).The paucity of neurodegenerative disorders

and other metabolic disorders may not reflect alow frequency among Arabs but rather theunderlying difficulties in establishing or con-firming the diagnosis of such disorders. How-ever, their pattern is somewhat similar to thatreported from Saudi Arabia.'55

CommentsIn McKusick's 1992 edition,25 the number ofasterisked and non-asterisked autosomal dom-inant entries is more than twice the number ofAR entries (3711 versus 1631). While the auto-somal dominant phenotype manifests as a re-sult of a single dose of an autosomal allele,either inherited or freshly mutated, the ARphenotype manifests as a result of a doubledose of an autosomal allele which requiresboth parents to be heterozygotes and to have a25% chance of both transmitting the allele(s)to their offspring in each pregnancy. Thechance of having an affected homozygous childin a family is increased by increasing thenumber of children. In a family with four orfive children, one of them would be expectedto be affected. In Kuwait and other Arabcountries, owing to the high rates of consan-guinity and the large family size, conditions

are optimal for the expression ofAR disorders,as seen by the large number of newly recog-nised AR disorders. A number of new syn-dromes described from Kuwait have now beenrecognised in other countries, suggesting thatthe private syndrome does not exist.The frequencies of AR disorders in Kuwait

may reflect those of the Arabs at large since thepopulation is mixed with significant repres-entation from most Arab nations. It maynot be mere chance that Arabs, particularlyPalestinians, share with Jews several commonrecessive genes. Being hitherto unstudiedpopulations, the Arab countries will continueto be a source of new information about gen-etic disorders for the whole world. For thesecommunities with special religious and cul-tural backgrounds, more work should be donein planning and implementing ways of preven-tion and treatment of genetic disorders.

The author is grateful to Professor W Roy Breg and MrsMiriam Schoenfield-DiMaio for reading this manuscript and toSaeed Teebi for typing it. The author is the winner of theKuwait Prize in Basic Science (Genetics) at the level of theArab World for 1989, given by Kuwait Foundation for theAdvancement of Science (KFAS).

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