2242JMed Genet 1994;31:224-233 Medical around the world J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from

Autosomal recessive disorders among Arabs: an overview from Kuwait

Ahmad S Teebi

Abstract which are the most common category of gen- Kuwait has a cosmopolitan population of etic disorders among Arabs in Kuwait. 1-7 million, mostly Arabs. This population is a mosaic of large and small minorities representing most Arab communities. In The country and population general, Kuwait's population is charac- Kuwait is a small Arab country situated in the terised by a rapid rate of growth, large north east of the Persian Gulf. It is bounded family size, high rates of consanguineous on the north and north east by Iraq and on the marriages within the Arab communities south by Saudi Arabia. The country's total with low frequency of intermarriage area (6880 square miles) is barren desert that is between them, and the presence of gen- rich in oil which is the source of Kuwaiti etic isolates and semi-isolates in some wealth. The population is cosmopolitan and extended families and Bedouin tribes. comprised of large and small minorities. Until Genetic services have been available in August 1990 (Iraqi invasion), its 1-7 million Kuwait for over a decade. During this people, according to a 1985 census,8 were made time it has become clear that Arabs have up of 40% Kuwaiti natives and Bedouin, and a high frequency of genetic disorders, 60% immigrants, the majority of whom were and in particular autosomal recessive Arabs. These immigrants were mostly from traits. Their pattern is unique and some Arabian Middle Eastern countries; however, disorders are relatively common. Ex- small minorities from North Africa are also amples are Bardet-Biedl and Meckel present. One of the large minorities before the syndromes, phenylketonuria, and fami- invasion of Kuwait were the Palestinians who lial Mediterranean fever. A relatively formed about 22% of the total population at http://jmg.bmj.com/ large number of new syndromes and var- that time. Those considered to be Kuwaiti iants have been delineated in Kuwait's natives are the early settlers of the urban population, many being the result of centres originating mostly from neighbouring homozygosity for autosomal recessive Arab countries, while the Bedouin are the that occurred because of inbreed- nomadic Arabs of the desert who live on the ing. Some of these syndromes have sub- fringes of the Arabian peninsula which in-

sequently been found in other parts of the cludes parts of Kuwait, Saudi Arabia, Qatar, on September 24, 2021 by guest. Protected copyright. world, negating the concept ofthe private United Arab Emirates, Oman, Iraq, Jordan, syndrome. This paper provides an over- and Syria as well as Negev and Sinai desert. view of autosomal recessive disorders Over the past three to four decades, they have among the Arabs in Kuwait from a per- settled in urban centres and have acquired the sonal perspective and published studies, citizenship of the countries that host them. and highlights the need for genetic ser- Those who lived in Kuwait have acquired vices in Arab countries with the goal of Kuwaiti nationality and some of them became prevention and treatment of genetic dis- indistinguishable from natives. However, orders. Bedouins form tribal communities which are quite isolated. It is very likely that individual (J Med Genet 1994;31:224-233) people from the same tribe or kindred have settled in different Arab countries and In contrast to the genetically well studied acquired their nationalities. populations of North America and Europe, Also, the Kuwaiti population has one of the Department of particularly commnunities such as the Amish,' highest growth rates in the world (approxim- Genetics, Yale and com- 50000 live and University School of French Canadians,2 Jews,3 many ately births/year) large family Medicine, New Haven, munities within the Arab world remained size with five children being an average num- Connecticut, USA unstudied. However, previous efforts have ber of offspring per family.8 The rate of con- A S Teebi been made to study genetic disorders in some sanguineous marriage is high, with high Correspondence to Arabian countries such as Lebanon,4 Saudi inbreeding coefficients not only within the Dr Teebi, Division of I here a , The Arabia,5 and Egypt.67 present geneti- Kuwaiti native population910 but also within Montreal Children's cist's experience in Kuwait and review per- other Arab communities, according to studies Hospital, 2300 Tupper, in order to an or in their Montreal, Quebec H3H 1P3, tinent published reports give conducted in Kuwaitl' countries of Canada. overview of autosomal recessive disorders, origin'116 (table 1). The most frequent form of Autosomal recessive disorders among Arabs: an overview from Kuwait 225

Table 1 Frequencies of consanguineous marriages among Arabs clinical, cytogenetic, and genetic counselling Population Frequency (%) Ref Comments services, to teach medical genetics to medical residents and other health professionals, and to Kuwaiti 54-3 9 Higher rates among Bedouin tribes J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from 37-8 10 conduct research directed towards under- Egyptian 23-3 10 Sample from Kuwait standing genetic problems in the community. 28-96 11 Higher rates in rural areas Iraqi 57-87 12 Higher rates in rural areas Genetic services have subsequently been Jordanian 36-2 10 Sample from Kuwait expanded to involve satellite clinics at the Al- 50-0 13 Lower rates among Christians Lebanese 26-0 14 Lower rates among Christians Amiri Hospital in Kuwait City and satellite Palestinian 39 0 15 Arabs in Israel community genetic programmes at three re- 38-7 16 Arab village in Israel gional hospitals in the governorates of Farwa- nia, Jahra, and Al-Ahmadi. Services in these consanguineous marriage is between first cou- regions were furnished on a weekly or twice sins, particularly paternal first cousins. Double weekly basis and on demand. The centre in first cousin marriages also exist. The fre- the years 1985 to 1990 was staffed by three quency of intermarriage between different trained at the consultant level, three Arab communities is low, which is also the case others at the registrar or senior registrar level, for some extended families and tribes within two nurses, and two social workers, and a the community. This has resulted in sustained reasonably equipped and staffed cytogenetics isolation particularly for the Bedouins and laboratory. some wealthy families. Genetic disorders in Kuwait Religion, culture, and genetic issues At birth, the incidence of major defects is Islam is the predominant religion among slightly higher than the 2 to 3% found in the Kuwaitis, the majority being Sunnite Muslims world's major surveys. However, if other dis- who are generally described as being modest orders that manifest later in life are included, with a strong faith in Islam. Despite the wes- the figure would be substantially higher than ternisation of a significant sector of the popula- in other parts of the world and the profile is tion, many still maintain their cultural ties and distinctive. In the virtual absence of prenatal religious principles. Although Islam, accord- diagnosis and termination of , and ing to many religious scholars, discourages the long reproductive period, patients with consanguineous marriages, such marriages chromosomal anomalies, particularly trisomy have been traditionally practised over many 21, constitute approximately 28% of patients generations because of social, economic, and seen at the genetic clinic (unpublished data on geographical factors. Because they are forbid- 1300 new patients seen at the Al-Amiri satel- den by Islam, uncle-niece/aunt-nephew mar- lite clinic and Farwania community genetic riages are virtually non-existent.'7 Prenatal programme over a seven year period from 1983

diagnosis is acceptable for purposes of reassur- to 1990). Although the incidence of aneuploi- http://jmg.bmj.com/ ance or of therapy. Termination of pregnancy, dies among live births is higher than other however, at any stage is absolutely forbidden parts of the world,20 the pattern of chromoso- (haram), unless the mother's life is endan- mal abnormalities in general does not appear to gered.'8 Under Islamic law, according to some be significantly different. On the other hand, interpretations, termination of pregnancy is birth defects as a result of known teratogens considered a crime. 9 However, couples may form only 1 to 2% of patients, partly because avoid pregnancy if they are at an unacceptably ofrestricted use of drugs and chemicals, prohi- high risk of having a child with a certain bition of alcohol, and the fact that the vast on September 24, 2021 by guest. Protected copyright. genetic defect. On the other hand, artificial majority of females are naturally immune to insemination using the husband's sperm rubella before childbearing age. The remain- (AIH) and in vitro fertilisation (IVF) using the ing 70% of patients seen in genetic clinics can husband's sperm is acceptable, but using be divided as follows. (1) Known autosomal donor sperm is absolutely forbidden. In recessive (AR) disorders or unknown disorders general, assisted reproduction using the hus- with a family pattern suggestive of AR inherit- band's and wife's gametes is acceptable. Adop- ance (approximately 45%). (2) Known multi- tion has been practised since the early ages of factorial and polygenic disorders (18%). (3) Islam. However, "legal" adoption is not Known and unknown autosomal dominant allowed. disorders (12%). (4) Unknown disorders with- out suggestive family pattern (22%). (5) X linked disorders (2 to 3%). Genetic services In addition to data from the survey (personal Genetic services on a small scale began in observation), sources of information about AR Kuwait in the late 1 960s but were discontinued phenotypes include personal communications, in the early 1970s because of the lack of quali- published studies, and case reports (general fied personnel. More sustained and extended reviews and abstracts are available).21-24 Apart services are relatively new and were initiated in from the extreme rarity of Huntington's dis- 1979 as a weekly clinic in the paediatric depart- ease, the pattern and apparent frequencies of ment of Al-Sabah Hospital, the main general autosomal dominant disorders in Kuwait are hospital at that time. In 1981, the medical not remarkably different from those in western genetics centre at the Maternity Hospital in countries. In contrast, several AR disorders the Al-Sabah area near Kuwait City was offi- are reported to be highly prevalent (table 2). cially opened. The purpose was to provide Autosomal recessive disorders among Arabs in 226 Teebi

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, 60 J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from Argininosuccinic aciduria 207900 Palestinian, Jordanian, Kuwaiti Arthropathy, progressive pseudorheumatoid, of children 208230 Kuwaiti, Lebanese 50, 51 Bardet-Biedl syndrome 209900 Bedouin, Kuwaiti, Palestinian, Syrian 30, 31, 34 Chloride diarrhoea, familial 214700 Kuwaiti 57, 58 Citrullinaemia 215700 Palestinian, Kuwaiti 54, 61 Faciodigitogenital syndrome, Kuwait type 227330 Kuwaiti Bedouin tribe Homocystinuria 236200 Kuwaiti Bedouin, Palestinian 53, 54 Hyperglycinaemia, non-ketotic 238300 Palestinian, Kuwaiti 54 Laurence-Moon syndrome 245800 Kuwaiti 30 Meckel syndrome 249000 Bedouin, Kuwaiti, Bedouin 35, 38, 39 Mediterranean fever, familial (FMF) 249100 Palestinian, Egyptian, Lebanese, Syrian, Iraqi 26, 27 Muscular dystrophy, Duchenne-like, autosomal recessive (SARCMD) 253700 Kuwaiti, Iraqi, Palestinian 47, 48 , severe AR 259700 Kuwaiti, Saudi Arabian, Palestinian 63 Osteopetrosis, renal tubular acidosis 259730 Kuwaiti, Saudi Arabian 65-67 Phenylketonuria (PKU) 261600 Kuwaiti, Palestinian, Egyptian, Lebanese 52-67 Pterygium syndrome, multiple 265000 Palestinian, Kuwaiti Bedouin, Bedouin 40-42 Thalassaemias 273500 Kuwaiti, Saudi Arabian, Iraqi, Palestinian 70, 73 Tyrosinaemia 276700 Kuwaiti, Palestinian 54

Kuwait will be discussed according to their MECKEL SYNDROME (MS) conspicuous features and McKusick's25 entry MS is a frequently diagnosed malformation numbers for the defined entities are included. syndrome among neonates in Kuwait. The incidence is unusually high for a malformation syndrome (1:3530 livebirths)35 and most ascer- Relatively common autosomal recessive tained cases are of Bedouin ancestry. A similarly disorders high incidence is also seen among Tartars36 in FAMILIAL MEDITERRANEAN FEVER (FMF) OR the former Soviet Union and among Gujarati RECURRENT HEREDITARY POLYSEROSITIS Indians.37 A Bedouin family with five affected This is a multisystem disease characterised by sibs was reported to have a variant of MS recurrent, painful, self-limiting episodes of lacking polydactyly.35 Other cases of MS were peritonitis, pleuritis, arthritis, or erysipelas- ascertained in a study of cleft lip with or like erythema usually accompanied by fever.26 without cleft palate.39 This condition was diagnosed in 88 children26 and 151 adults27 from Kuwait. More than 70% of these patients were Palestinians or Jorda- nians. Accordingly, the prevalence of FMF in MULTIPLE PTERYGIUM SYNDROME (MPS) this community is at least 1:2000. Similar MPS was found in 13 cases in six sibships observations have been noted in Jordan (H A during a genetic survey in the Farwania dis- Majeed, personal communication). This dis- trict (1/3 of Kuwait's Arab population). The order is also common among Sephardic Jews25 estimated minimum prevalence was 1 in 31 000 and Armenians21 and to a lesser degree in in the general population.' A detailed report http://jmg.bmj.com/ Turks, Greeks, Italians, and Arabs (other than of a Bedouin family with five affected sibs is Palestinians). In earlier studies from Lebanon, available.4' A phenotypically similar but lethal FMF was found in most ethnic groups but condition(s) has also been reported.42 particularly in Armenians.4

FACIODIGITOGENITAL SYNDROME, KUWAIT TYPE BARDET-BIEDL SYNDROME (BBS) AND This condition, which closely resembles Aars- on September 24, 2021 by guest. Protected copyright. LAURENCE-MOON SYNDROME (LMS) kog syndrome, has been described in five Laurence-Moon-Bardet-Biedl syndrome Kuwaiti Bedouin sibs as a new syndrome.43 (LMBBS) was a common designation. How- Subsequently, nine patients in four sibships ever, nosological splitting of LMBBS into from the same tribe (approximately 8000 BBS and LMS has become widely accepted. people) have been found to have this disorder As from 1986, 20 cases were diagnosed with and all could be traced to a common ancestor.44 BBS, including monozygotic twins, and six The prevalence ofthis syndrome in this tribe is with LMS among a mixed Arab population in remarkably high and represents a founder Kuwait.303' The combined minimum preval- effect. ence was 1 in 50 000 among the general popu- lation which is more than three times the prevalence in Switzerland. Many of these cases were Palestinians, confirming the observations SEVERE AUTOSOMAL RECESSIVE CHILDHOOD among Arabs from Israel.3233 Subsequent MUSCULAR DYSTROPHY (SARCMD) studies documented more cases of BBS among SARCMD, or Duchenne-like MD, is a rela- the Bedouin with an estimated prevalence of tively common disease among Arabs particu- 1:13 500 which is three times higher than that larly in Sudan45 and Tunisia.46 In Kuwait, in of the general population.34 The incidence of Farwania and Jahra districts with highly BBS among the Bedouin in Jahra district was inbred populations, eight families were ascer- estimated to be 1:6900 livebirths.34 Parental tained to have SARCMD.4748 This number consanguinity was 87% among patients from constitutes more than one third of families the general population while it was 100% with MD compared to 5% as estimated from among Bedouin patients. BBS is also not rare the UK and North America and 6-8% as among Jews.32 estimated from Brazil.49 Autosomal recessive disorders among Arabs: an overview from Kuwait 227

PROGRESSIVE PSEUDORHEUMATOID UREA CYCLE DEFECTS ARTHROPATHY OF CHILDHOOD, OR Citrullinaemia is a commonly diagnosed dis- SPONDYLOEPIPHYSEAL DYSPLASIA TARDA WITH order.546' Cases of argininosuccinic aciduria PROGRESSIVE ARTHROPATHY (SEDT-PA) and carbamoyl phosphate synthase deficiency J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from This is a rare disorder that was diagnosed in (CPS) are also common. three families in Kuwait. Two of these families were reported in detail.505' A review of pub- lished reports has shown that seven out of 16 TYROSINAEMIA cases were Arabs.51 Several cases of type I tyrosinaemia have been found in a laboratory survey.54 A Kuwaiti family with several members with tyrosinae- mia type II was also reported.62 PHENYLKETONURIA (PKU) PKU was found to have a frequency of between 1-6% and 1-86% among institutiona- OSTEOPETROSIS, SEVERE AUTOSOMAL RECESSIVE lised mentally retarded patients.5253 In addi Data from Kuwait63 and Saudi Arabia64 indic- tion, 13 cases were detected at the genetic ate that this form of osteopetrosis is relatively clinic through evaluation for mental retard- common in the Arabian peninsula. The inci- ation.52 Other cases were published subse- dence, however, is not known. Osteopetrosis quently.54 The majority of these patients have with renal tubular acidosis and cerebral calcifi- consanguineous parents. Five patients in three cation has also been reported frequently from sibships have a common ancestry in a Kuwaiti Kuwait657 and Saudi Arabia,666869 and it kindred. The incidence of classical PKU was seems to be relatively common also. found to be 1:6479 livebirths,55 as estimated during the course of a neonatal screening project, which is higher than the average HAEMOGLOBINOPATHIES figure from the USA and Europe (1:11 000). The genes for sickle cell haemoglobinopathies The combined incidence of PKU and and f0 thalassaemia are prevalent in Kuwait, hyperphenylalaninaemia (HPA) was 1:4860 and diseases resulting from homozygosity or livebirths. PKU has also been ascertained in a double heterozygosity (sickle cell anaemia, °0 Bedouin mother with three children who had thalassaemia, and Hb S ,B0 thalassaemia) are PKU embryopathy.56 common.70 The prevalence of the sickle cell trait (McKusick no 141900-0243) may be similar to or slightly lower than the 10 to 25% estimated in the Eastern Province of Saudi CONGENITAL CHLORIDE DIARRHOEA (CCD) Arabia.7'72 In a study from Kuwait involving In one study over a seven year period,57 16 110 patients with major f chain haemoglobi- cases were ascertained, all of whom have con- nopathies, 47 patients had homozygous hae- sanguineous Kuwaiti parents. The estimated S http://jmg.bmj.com/ minimum incidence was 7-6:100 000 live- moglobin disease (Hb SS) and 21 had Hb 130 births, similar to that in Finland.57 Twelve thalassaemia.70 In contrast to African-Amer- other children with suspected CCD died be- ican patients with these diseases, most Kuwaiti fore having a confirmed diagnosis. Other cases patients have a less severe haemolytic anaemia have also been and fewer signs and symptoms of vaso-occlu- reported.58 sive phenomena as a result of modifying effects of high levels of Hb F. In another study,73 the incidence of a thalassaemia heterozygotes is on September 24, 2021 by guest. Protected copyright. CONGENITAL ADRENAL HYPERPLASIA estimated to be 4-6% by screening 345 con- Over a decade (1978-1988), at least 60 paedia- secutive cord blood samples (16/345). All the tric patients with congenital adrenal hyperpla- 16 samples contained a deletion in either one sia were diagnosed.59 The majority (90%) had or two a globin genes. The incidence is signi- 21-hydroxylase deficiency while 10% had ficantly lower than in the Eastern Province of either 11 -B-hydroxylase deficiency or 3-B- Saudi Arabia (56%). hydroxysteroid dehydrogenase deficiency. The estimated overall incidence ranged from 1:7000 to 1:9000 livebirths which is higher DISORDERS FREQUENTLY DIAGNOSED IN KUWAIT than that in Europe and Canada. Other cases BUT UNCOMMON ELSEWHERE were also ascertained in a study of true and These include cystinuria (220100), spinal pseudohermaphroditism.60 muscular atrophy or Werdnig-Hoffmann dis- ease (226600), GM1 gangliosidosis (230500), Gaucher disease type I (230300), micro- cephaly (251200), clinical anophthalmia NON-KETOTIC HYPERGLYCINAEMIA (NKH) AND (251600), mucolipidosis type II (252500), HOMOCYSTINURIA (HC) Hurler and Hurler-Scheie syndromes (252800), Seven cases of NKH and five cases of HC were Maroteaux-Lamy syndrome (253200), Nie- ascertained at Al-Sabah Hospital within a man-Pick disease type B (257200), Sandhoff three year period.54 Several other cases of disease (268800), multiple sulphatases (272200), NKH and HC were diagnosed in other hos- Wilson's disease (277900), wrinkly skin syn- pitals to make these disorders relatively more drome (278250), organic acidaemias, lethal common in Kuwait than in other parts of the chondrodystrophies, and undelineated neuro- world. degenerative brain disorders. The above 228 Teebi

information is not published and is based on Palestinian parents." Anomalies included personal experience and personal communica- hypogonadotrophic hypogonadism, mental re- tions. tardation, obesity, and minor skeletal anomal- ies. The two brothers also had gynaecomastia. J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from New autosomal recessive syndromes This paper reviewed seven new autosomal recessive disorders described from the Middle Out of 22 new syndromes and variants that East, six of which were in Arabs and one was in were described in Kuwait in the period from a Yemenite Jewish family. 1985 to 1992, three were autosomal domin- 78one was X linked,79 and 18 were auto- somal recessive. 42 44 8092 of the 18 AR syn- FACIODIGITOGENITAL SYNDROME, KUWAIT TYPE dromes and variants, 11 had new entries in This has been discussed under common dis- McKusick's catalogue25 which constitutes ap- orders.43 44 proximately 5% of all new entries during that period (11/211). The remaining seven dis- orders either had no entries,9294 or were in- CARDIOSKELETAL SYNDROME, KUWAIT TYPE cluded in existing AR81 87 95 96 or autosomal dominant'02 entries (table 3). Two male sibs of Kuwaiti first cousin parents were found to have congenital heart malforma- tion and skeletal dysplasia including rhizome- LIMB/PELVIS-HYPOPLASIA/APLASIA SYNDROME lic limb shortness and coronal clefting of the This was the first new disorder to be described vertebral bodies.80 from Kuwait.98 The patients were two Palesti- nian sibs (a male and a female) of consanguin- eous parents. They had severe limb deficiency, BEDOUIN SPASTIC ATAXIA SYNDROME dysplastic hips, and minor facial anomalies. This condition was described in a highly Subsequently, seven patients were described inbred Bedouin family with affected subjects from several countries including Brazil, Israel, in several sibships.90 Anomalies included spas- Italy, and again from Kuwait in a Bedouin tic ataxia, congenital cataracts, macular and child.99 Two of the five females hitherto corneal dystrophy, and non-axial myopia, in reported had hypoplasia or aplasia of the uter- the absence of mental retardation. Immuno- us.99100 Prenatal diagnosis by ultrasonography logical abnormalities were common. The au- has been accomplished.'0' thors concluded that this disorder was clinic- ally distinct from a similar disorder described in Lebanon.'03 HYPOGONADISM SYNDROMES One syndrome was first described in three sibs of consanguineous Jordanian Christian parents. SPINOCEREBELLAR DEGENERATION WITH SLOW Anomalies included partial alopecia consisting EYE MOVEMENTS (SDSEM) http://jmg.bmj.com/ of hair only in the centre of the scalp, primary This condition was described in six subjects hypogonadism, and defective Mullerian de- (three males and three females) in two sibships velopment in the sisters.84 Their brother had from a consanguineous Palestinian family.9' hormonal and histological findings consistent Associated manifestations included progres- with germinal cell aplasia. After this descrip- sive intellectual impairment and extrapyrami- tion, two Kuwaiti sisters of consanguineous dal dysfunction as well as peripheral neuro- parents were found to have a similar condition pathy and skeletal abnormalities. Muscle (unpublished). Another hypogonadism syn- biopsy showed non-specific mitochondrial on September 24, 2021 by guest. Protected copyright. drome was reported in three sibs of first cousin changes.

Table 3 New genetic syndromes and variants reported from Kuwait Disorder No of patients Family origin McKusick No Ref Autosomal dominant Gastric sneezing 11 Syrian 137130 74 Hypertelorism-Teebi type (brachycephalofrontonasal dysplasia) 16 Iraqi 145420 75, 76 Tibia, hypoplasia of, with polydactyly 2 Kuwaiti 188770 77, 78 Autosomal recessive Grebe-like chondrodysplasia 1 Palestinian 200700 81 Cardioskeletal syndrome, Kuwaiti type 2 Kuwaiti 212135 80 Cystic fibrosis with helicobacter gastritis, megaloblastic anaemia and subnormal mentality 2 Bedouin 219721 82 Faciodigitogenital syndrome, Kuwait type 5+9 Kuwaiti, Bedouin 227330 43, 44 Hypertelorism, , polysyndactyly syndrome 3 Pakistani (non-Arab) 239710 88, 89 Hypertelorism, hypospadias, tetralogy of Fallot syndrome 4 Palestinian 239711 83 Hypogonadism, primary, and partial alopecia 3+2 Jordanian, Kuwaiti 241090 84 Macrosomia with microphthalmia, lethal 5 Palestinian 248110 85, 86 Microcephaly with normal intelligence 8 Palestinian 251260 87 Bedouin spastic ataxia syndrome 22 Bedouin 271320 90 Spinocerebellar degeneration with slow eye movements 6 Palestinian 271322 91 Spondyloepimetaphyseal dysplasia, a new variant 3 Syrian, Bedouin 271640 95 Trigonobrachycephaly, bulbous bifid nose, micrognathia, and abnormalities of the hands 2 Palestinian 275595 97 and feet Limb/pelvis-hypoplasia/aplasia syndrome 2+1 Palestinian 276820 98-101 Weaver-like syndrome 2 Bedouin 277590 96 Palmoplantar keratoderma, epidermolytic recessive form 2 Kuwaiti 144200* 102 Craniofacial-hair-finger-caudal syndrome 1 Kuwaiti - 93, 94 Hypogonadotrophic hypogonadism, obesity, MR, and skeletal anomalies 3 Palestinian - 92 X linked Nephrosis, minimal charge 4 Syrian - 79 *Autosomal dominant entry in McKusick's catalogue. Autosomal recessive disorders among Arabs: an overview from Kuwait 229

TRIGONOBRACHYCEPHALY SYNDROME SPONDYLOEPIMETAPHYSEAL DYSPLASIA, A NEW This condition was described in a brother and VARIANT sister, offspring of first cousin Palestinian A Syrian-Bedouin consanguineous family was parents.97 Other manifestations included a bul- found to have three children with this bone J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from bous nose which was slightly bifid at the tip, dysplasia (two males and a female).95 The micrognathia, macrostomia, relatively broad proband was a 6 year old boy with rhizomelic first metatarsals and phalanges, and severe shortness of limbs, , dish-like facies, psychomotor retardation. cleft palate, deafness, and camptodactyly. Radiological changes were compatible with Kniest disease. Two similarly affected sibs died in early life. MACROSOMIA-MICROPHTHALMIA SYNDROME This condition was described in three females two from a of 10 whose and males sibship CRANIOFACIAL-HAIR-FINGER-CAUDAL parents were first cousins.8586 Asso- Palestinian SYNDROME ciated manifestations included median cleft A Kuwaiti female of parents who were first palate in three and recurrent infections in all, cousins once removed was described with cra- with early, rapid, or sudden death. niofacial anomalies, abnormally slow growing hair, absence of primary teeth, camptodactyly, and a caudal appendage with sacrococcygeal WEAVER-LIKE SYNDROME dimple.93 Intelligence was normal. A similarly A brother and sister, offspring of consanguin- affected female neonate was seen in the United eous Bedouin parents, were reported to have States.94 manifestations resembling Weaver syn- drome.96 These included accelerated growth of prenatal onset, , variable psychomo- GREBE-LIKE CHONDRODYSPLASIA tor retardation, excess loose skin, dental dys- This non-lethal severe form of short limb bone plasia, serrated gums, joint laxity, distinctive dysplasia was found in two unrelated craniofacial and digital anomalies, and a patients." One of these patients was the pro- hoarse, low pitched cry. One of them had duct of first cousin Palestinian parents.8" accelerated harmonic skeletal maturation. Features included peculiar facial appearance with deafness, rib anomalies, and severe short- ness and distortion of long bones, notably the humeri, tibiae, fibulae, metapodia, and pha- HYPERTELORISM-HYPOSPADIAS AND TETRALOGY langes with marked irregularity and asym- OF FALLOT SYNDROME metry. This combination was found in three brothers of Palestinian parents who were first cousins once removed.83 The father had hypertelorism http://jmg.bmj.com/ AUTOSOMAL RECESSIVE EPIDERMOLYTIC and his brother, who is married to a second PALMOPLANTER KERATODERMA cousin, had a daughter with hypertelorism and Two male sibs of first cousin Kuwaiti parents tetralogy of Fallot. The four affected relatives were described as having this condition,'02 had mild or borderline developmental delay. which is known to be inherited as an autosomal dominant trait (144200). Parents presented with patchy eczematous skin lesions followed HYPERTELORISM-HYPOSPADIAS AND by palmoplanter keratoderma and raised on September 24, 2021 by guest. Protected copyright. POLYSYNDACTYLY SYNDROME serum levels of IgE. Although gonadal mosai- This condition was described in two brothers cism cannot be excluded, it is more likely that and a sister of Pakistani consanguineous par- an autosomal recessive variant of the disease ents (non-Arabs). Similar cases have also been exists in this inbred population. reported.89 Disorders with unknown frequencies CYSTIC FIBROSIS (CF) MICROCEPHALY WITH NORMAL INTELLIGENCE A eight CF (219700), a well known and studied dis- large inbred Palestinian kindred with ease in Europe and North America, was not cases in five sibships was found to have this reported in Kuwait until 1981 when two combination in addition to a characteristic patients (Kuwaiti and Syrian) presented with facial appearance.87 This condition is probably meconuim ileus.'0 One of them died postoper- different from that associated with immuno- atively and the other had recurrent respiratory deficiency and increased risk of lymphoreticu- infections and died at the age of 1 year. At lar malignancies. necropsy, clinical findings of CF were noted. Subsequently, CF was reported in several Kuwaiti and Palestinian patients.'05'07 A ques- CYSTIC FIBROSIS WITH HELICOBACTER PYLORI tionnaire survey showed that 40 patients were GASTRITIS, MEGALOBLASTIC ANAEMIA, AND diagnosed with CF in all hospitals in Kuwait SUBNORMAL MENTALITY from 1979 to 1979 (approximately 500 000 A brother and a sister of consanguineous livebirths).'08 Manifestations were variable and Bedouin parents were found to have this asso- occasionally atypical. Several infants pre- ciation in addition to minor facial anomalies. sented initially with hyponatraemia, hypo- 230 Teebi

chloraemia, and metabolic alkalosis owing to the people of the Palestinian village whose excessive sweating in Kuwait's very hot and affected members live in several countries humid weather.'07 These patients had minimal including the West Bank, Jordan, and Kuwait. manifestations of pulmonary and pancreatic The population of this village tends to in- J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from exocrine deficiency. CF among Arabs from breeding even outside their homeland. Lebanon, Iraq, and Israel has been reported.'09 It has been suggested that the incidence is high among Arabs of Israel, in the Bedouin as well Genetic predisposition to as in the city dwellers. This was supported by a non-disjunction (257300) recent study from Jordan."0 Our experience Following the suggestion of Penrose"2 that a from Kuwait suggests that the frequency of recessive in man may cause non-disjunc- CF may be less than that in western countries tion of chromosome 21 in the ova of homozy- with mild allelic variants prevailing. gous females, similar to the gene in Drosophila Melanogaster, a study from Kuwait"3 showed that Down's syndrome (DS) was four times CONGENITAL DEAFNESS, TYPE 1 (220700) more frequent among the children of closely In a large inbred Palestinian family, 13 sub- related parents than among those of unrelated jects in several sibships were reported to have parents (p <0-005). Another study"4 also sug- uncomplicated profound deafness from early gested an association between consanguinity infancy."' The family originated from a small and the occurrence of non-disjunction after village (El-Sawiah) on the West bank near correcting for maternal and paternal ages, but Nablus. Eight cases in three other families a single gene effect was not observed. Recent from the same village (apparently not related data from a community genetic survey at Far- to each other or the reported family) were wania and Jahra districts containing 15% and ascertained to have a clinically similar disorder 80% Bedouin respectively have shown an inci- (unpublished data). At the Farwania genetic dence of DS of 1 7 and 4 5/1000 livebirths clinic, at least nine more patients from four respectively."5 The incidence of DS correlates Kuwaiti or Syrian families were found. It is very well with the inbreeding coefficient. A difficult, however, to conclude that this dis- remarkably higher incidence of DS was noted order is highly prevalent in Kuwait because of in the higher inbreeding coefficient group with the remarkable genetic heterogeneity of deaf- almost similar mean maternal ages, which ness. Certainly, it has a very high frequency in suggests the existence of some recessive ele- ments controlling non-disjunction. A similarly Table 4 Other autosomal recessive disorders reported among Arabs in Kuwait high frequency of consanguinity was noted Disorder McKusick No Ref among the grandparents of DS patients. In the highly inbred Bedouin community ofthe Jahra Acrodermatitis enteropathica 201100 116 3-B-hydroxysteroid dehydrogenase deficiency 201810 59 district, two families had sibs with recurrent 3-B-hydroxysteroid deficiency 202010 59 aneuploidies, one of these families had two sibs Congenital hypoplastic anaemia of Blackfan and Diamond 205900 117 http://jmg.bmj.com/ Anencephaly, AR 206500 118 with trisomy 21 and the other had sibs with Costello syndrome 218040 119 trisomy 21 and trisomy 18. Comparable high Cystathioninuria 219500 53 Cystinuria 220100 54 frequencies of DS were also reported from Dyserythropoietic anaemia, type I 224120 120 West Jerusalem and among the Negev Torsion dystonia, AR 224500 121 Ehlers-Danlos syndrome type VI 225400 122 Bedouin.' '5 Fucosidosis 230000 123 Galactosaemia 230400 21, 39 Hallermann-Streiff syndrome 234100 124 Histidinaemia 235800 21 Other disorders reported from Kuwait on September 24, 2021 by guest. Protected copyright. Hydrocephalus, AR 236600 125 Urofacial syndrome 236730 126, 127 In addition to the aforementioned, there are a Hyperlysinuria 238750 53 number of AR disorders that have been Hyperprolinaemia 239500 54 Intestinal atresia, multiple 243150 128 reported among Arabs from this country (table Apple peel syndrome (jejunal atresia) 243600 129, 130 4). Although it may not be an exhaustive list, it Primary hypomagnesaemia 248250 131 Mandibuloacral dysplasia 248370 132 includes a number of case reports of unusual Maple syrup urine disease (MSUD) 248600 54 associations, case series studies, and informat- Metaphyseal chondrodysplasia, Spahr type 250400 133 Clinical anophthalmia 251600 134 ive pedigrees. Some of the case reports served Multiple pterygium syndrome, lethal 253290 42 as early delineation of disorders. Examples Schwartz-Jampel syndrome 255800 135 Osteoporosis-pseudoglioma syndrome 259770 136 are the urofacial syndrome (Ochoa syn- Persistent Mullerian duct syndrome 261550 60, 137 drome),'26 127 metaphyseal chondrodysplasia, Congenital hepatic fibrosis 263200 138 Porphyria, congenital erythropoietic 263700 139 Spahr type,'33 and the Costello syndrome."9 Pseudohermaphroditism, male, with gynaecomastia 264300 60 A number of unusual associations have also Pseudovaginal perineoscrotal hypospadias 264600 60 not be fortuitous if Vitamin D dependent rickets type I 264700 140 been reported which may Renal tubular acidosis with nerve deafness 267300 141 found in several members of the family, such Erythrophagocytic lymphohistiocytosis, familial 267700 142 Robinow syndrome 268310 143 as the association of osteoporosis-pseudo- Russell-Silver syndrome 270050 144 glioma syndrome and ventricular septal defect Skin peeling, familial, continuous 270300 145 and Spastic paraplegia 270800 146 in three sibs of consanguineous parents,'36 Thyroid hormonogenesis, genetic defect 274300 147 the association of the AR congenital dyseryth- Tyrosinaemia type II 276600 62 recurrent multi- Spondylothoracic dysplasia 277300 39 ropoietic anaemia (CDA) with Wilson's disease 277900 148 focal osteomyelitis and Sweet syndrome Xanthinuria 278300 149 two XX male syndrome 278850 150 (unknown aetiology) in male sibs of first Brachmann-de Lange syndrome, AR 122470* 151 cousin Palestinian parents and the occurrence Central Coppock-like cataract 123470* 152 of CDA and Sweet syndrome in their female *Autosomal dominant entry in McKusick's catalogue. cousin. 120 Autosomal recessive disorders among Arabs: an overview from Kuwait 231

Homozygosity for two AR syndromes in the are optimal for the expression of AR disorders, same sibship is not rare. In an inbred Palesti- as seen by the large number of newly recog- nian family, three out of eight sibs had AR nised AR disorders. A number of new syn- microcephaly with typical facial appearance dromes described from Kuwait have now been J Med Genet: first published as 10.1136/jmg.31.3.224 on 1 March 1994. Downloaded from and mental retardation. Two of these also had recognised in other countries, suggesting that glycogen storage disease type I, and another the private syndrome does not exist. sib had only glycogen storage disease (unpub- The frequencies of AR disorders in Kuwait lished data). A Kuwaiti brother and sister with may reflect those of the Arabs at large since the consanguineous parents had the phenotype of population is mixed with significant repres- Ehlers-Danlos syndrome with aortic regurgi- entation from most Arab nations. It may tation and mitral valve prolapse in addition to not be mere chance that Arabs, particularly peripheral polyneuropathy. 122 Although this Palestinians, share with Jews several common may be a new form of Ehlers-Danlos syn- recessive genes. Being hitherto unstudied drome, it is more likely that the sibs had populations, the Arab countries will continue inherited different recessive traits. to be a source of new information about gen- Although some case series studies provide etic disorders for the whole world. For these no incidence data, the number of cases in- communities with special religious and cul- cluded indicates that certain disorders are tural backgrounds, more work should be done probably not rare, such as congenital hypo- in planning and implementing ways of preven- plastic anaemia of Blackfan and Diamond"7 tion and treatment of genetic disorders. and vitamin dependent rickets type I.'40 Among cases diagnosed in Kuwait's popula- The author is grateful to Professor W Roy Breg and Mrs Miriam Schoenfield-DiMaio for reading this manuscript and to tion, a number are commonly encountered Saeed Teebi for typing it. The author is the winner of the among Jews.3153154 Examples are the Pales- Kuwait Prize in Basic Science (Genetics) at the level of the Arab World for 1989, given by Kuwait Foundation for the tinian family with erythrophagocytic lym- Advancement of Science (KFAS). phohistiocytosis,142 another with torsion dystonia,"25 and two Kuwaiti families with 1 McKusick VA, ed. Medical genetic studies of the Amish. Baltimore: Johns Hopkins University Press, 1978. Tay-Sachs disease (unpublished data). 2 Andermann E, Scriver CR, Wolfe LS, Dansky L, Ander- A number of informative pedigrees for other mann F. Genetic variants of Tay-Sachs disease. Tay- Sachs disease and Sandhoffs disease in French-Cana- diseases have been found. Examples are the dians, juvenile Tay-Sachs disease in Lebanese-Cana- Robinow syndrome pedigree,'43 Russell-Silver dians, and Tay-Sachs screening program in the French- Canadian population. Prog Clin Biol Res 1977;18:161-8. syndrome with six affected sibs and normal 3 Goodman RM. Genetic disorders among the Jewish people. consanguineous parents,'" AR hydroceph- Baltimore: Johns Hopkins University Press, 1979. 4 Der Kaloustian VM, Naffah J, Loiselet J. Genetic diseases alus,'25 apple peel syndrome,'29130 and the in Lebanon. AmJ Med Genet 1980;7:187-203. extended pedigrees suggestive of an autosomal 5 Nyhan WL, Sakati NO. Diagnostic recognition of genetic disease. Philadelphia: Lea and Febiger, 1987. recessive form of anencephaly."18 Since then, 6 Hashem N, ed. Preventable aspects of genetic morbidity. AR inheritance of anencephaly in some fami- Proceedings of the First International Conference. Cairo: Ain Shams University, 1982. lies has been accepted by McKusick.'5 In an 7 Temtamy S, McKusick V. The genetics of hand malforma- inbred Syrian-Bedouin family, three sibs were tions. Birth Defects 1978;XIV:3. New York: The National http://jmg.bmj.com/ Foundation-March of Dimes, Alan R Liss, 1978. found to have cyclops or alobar holoprosence- 8 Al-Qudsi S. The dynamics of domestic labour participation phaly (unpublished data). and migrant labour dependent: the case of Kuwait. In: Eckus R, ed. The economics oflabour mobility in the Middle The paucity of neurodegenerative disorders East. Boston: MIT Press (in press). and other metabolic disorders may not reflect a 9 Al-Awadi, Moussa MA, Naguib KK, et al. Consanguinity among the Kuwaiti population. Clin Genet 1985;27:483- low frequency among Arabs but rather the 6. underlying difficulties in establishing or con- 10 Al-Nassar KE, Kelly CL, EL-Kazimi A. Patterns of con- sanguinity in the population of Kuwait. Am 7 Hum Genet firming the diagnosis of such disorders. How- 1989;45(suppl 4): A0915. on September 24, 2021 by guest. Protected copyright. ever, their pattern is somewhat similar to that 11 Hafez M, El-Tahan H, Awadalla M, et al. Consanguineous matings in the Egyptian population. J Med Genet reported from Saudi Arabia.'55 1983;20:58-60. 12 Al-Hamamy H, Al Bayati N, Al-Kubaisy W. Consanguin- eous marriages in the Iraqi urban population and the effect on pregnancy outcome and infant mortality. Iraqi Comments Med J 1986;34:76-80. 13 Khoury SA, Massad D. Consanguineous marriage in Jor- In McKusick's 1992 edition,25 the number of dan. Am J Med Genet 1992;43:769-75. asterisked and non-asterisked autosomal dom- 14 Klat M, Khudr A. Cousin marriages in Beirut, Lebanon: is the pattern changing. J Biosoc Sci 1984;16:369-73. inant entries is more than twice the number of 15 Freundlich E, Hino N. Consanguineous marriage among AR entries (3711 versus 1631). While the auto- rural Arabs in Israel. Isr J Med Sci 1984;20:1035-8. 16 Jaber L, Merlob P, Bu X, Rotter JI, Shohat M. Marked somal dominant phenotype manifests as a re- parental consanguinity as a case for increased major sult of a single dose of an autosomal allele, malformations in an Israeli Arab community. Am J Med Genet 1992;44:1-6. either inherited or freshly mutated, the AR 17 Teebi AS, Marafie MJ. Uncle-niece/aunt-nephew mar- phenotype manifests as a result of a double riages are not existing among Arab Muslims. Am J Med Genet 1988;30:981. dose of an autosomal allele which requires 18 Hathout H. Abortion and Islam. Leb Medj 1972;25:237-9. both parents to be heterozygotes and to have a 19 Shaltut M. Al-Fatwa. Cairo: General Culture Administra- tion at Al-Ashan, 1959. 25% chance of both transmitting the allele(s) 20 Farag TI, Al-Awadi SA, Al Othman SA, et al. Down to their offspring in each The syndrome and trisomy 18 in the Bedouins. Am J Med pregnancy. Genet 1988;29:943-4. chance of having an affected homozygous child 21 Al-Awadi SA, Teebi AS, Farag TI, Naguib KK. Inherited in a is increased the metabolic disease in Kuwait: the need for a nationwide family by increasing neonatal screening. In: Therrell BL Jr, ed. Advances in number of children. In a family with four or neonatal screening. Amsterdam: Elsevier Science Pub- five children, one of them would be lishers, 1987: 479-80. expected 22 Teebi AS. Neonatal screening for inherited metabolic dis- to be affected. In Kuwait and other Arab ease: the need for introducing a new service in Kuwait. 7 countries, to the rates of consan- Kuwait Med Assoc 1988;22:197-9. owing high 23 Teebi AS, Farag TI. New monogenic disorders in a mixed guinity and the large family size, conditions Arab population. AmJ Hum Genet 1989;45(suppl 2):A66. 232 Teebi

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