Sickle Cell Anemia

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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Haemolytic anaemias

OMIM Number

603903

Mode of Inheritance

Autosomal recessive

Gene Map Locus

11p15.5

Description

Sickle cell disease refers to a collection of genetic blood disorders characterized by a hemoglobin variant called (HbS). Individuals who are affected with sickle cell anemia have two copies of this beta globin variant, and the primary hemoglobin present in their red blood cells is (HbS). This disease is particularly common among people whose ancestors come from sub-Saharan Africa; Spanish-speaking regions (South America, Cuba, Central America); Saudi Arabia; India; and Mediterranean countries such as Turkey, Greece, and Italy. Sickle cell anemia is an inherited autosomal recessive disorder characterized primarily by chronic anemia and periodic episodes of pain. The disorder produces abnormal hemoglobin, which causes the red blood cells to sickle or become crescent-shaped. These sickle shaped RBCs are much less deformable, and therefore obstruct microcirculation, and cause tissue infarction. This can result in hand-foot syndrome, fatigue, paleness, and shortness of breath, pain that occurs unpredictably in any body organ or joint, eye problems, yellowing of skin and eyes, delayed growth and puberty in children and often a slight build in adults. Other complications include infections, stroke, and acute chest pain.

Individuals who possess one copy of the normal beta globin gene (HbA) and one copy of the sickle variant (HbS) are referred to as having sickle cell trait (SCT), but these individuals do not express symptoms of sickle cell disease. Individuals affected with other types of sickle cell diseases are heterozygotes, with HbS and other beta-globin gene variants, like HbC and Hb beta-thalassemia. The prevalence of this disease in Africa, the Mediterranean and the Middle East is attributed to the increased protection to malaria infection in heterozygous carriers. Treatments, such as penicillin prophylaxis, have been developed that can significantly reduce the morbidity and mortality of sickle cell disease.

Molecular Genetics

Sickle cell anemia results from an A to T transversion at the sixth codon of the hemoglobin beta globin gene. The mutation of a single DNA base leads to the substitution of a valine for a glutamic acid in the beta globin polypeptide of sickle hemoglobin (HbS). Deoxygenation of the heme moiety of HbS leads to hydrophobic interactions between adjacent HbS molecules, which then aggregate into larger polymers, distorting the red blood cell (RBC) into the characteristic sickle shape. At least five different haplotypes are linked to the sickle gene, each of which can be identified based on mutation analysis in the promoter sequences of the G-gamma and A-gamma globin genes. These haplotypes are named following the geographical locations where they most occur. Namely, the Arabia-Indian haplotype is characterized by significantly higher levels of fetal hemoglobin (HbF) levels and a milder course of the disease. In contrast, patients with the African haplotypes, Bantu and Benin, express relatively lower levels of HbF with severe clinical presentations.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
166900.1ComorosMale Elliptocytosis; Retinal stroke... NM_000342.4:c.1199_1225delHeterozygousAutosomal, DominantFavale et al. 2009
603903.1United Arab EmiratesUnknown Anemia... NM_000518.5:c.17_18del, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 Patient with sickle ...
603903.2United Arab EmiratesUnknown Anemia... NM_000518.5:c.118C>T, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 Patient with sickle ...
603903.3United Arab EmiratesUnknown Anemia... HbS NM_000518.5:c.20A>T, NM_000518.4:c.114G>AHeterozygousBaysal, 2005 Patient with sickle ...
603903.4United Arab EmiratesUnknown Anemia... NM_000518.5:c.315+1G>A, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 Patient with sickle ...
603903.5United Arab EmiratesUnknown Anemia... Hb Monroe NM_000518.5:c.92G>C, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 Patient with sickle ...
141749.G.1.1Saudi ArabiaUnknown Persistence of hemoglobin F; Sickled ery... NM_000184.2:c.-211C>T, HbS NM_000518.5:c.20A>THomozygousAutosomal, DominantMiller et al. 1987 13 patients with sic...
141749.G.1.2Saudi ArabiaUnknown Persistence of hemoglobin F; Sickled ery... NM_000184.2:c.-211C>T, HbS NM_000518.5:c.20A>THeterozygous, HomozygousAutosomal, DominantMiller et al. 1987 3 patients with sick...
141749.G.1.3Saudi ArabiaUnknown Persistence of hemoglobin F (Mild); Sick... NM_000184.2:c.-211C>T, HbS NM_000518.5:c.20A>THeterozygous, HomozygousAutosomal, DominantMiller et al. 1987 4 individuals with s...
141749.G.1.4Saudi ArabiaUnknown Persistence of hemoglobin F (Mild); Sick... NM_000184.2:c.-211C>T, HbS NM_000518.5:c.20A>THeterozygousAutosomal, DominantMiller et al. 1987 9 individuals with s...
603903.G.1BahrainUnknown Anemia; Persistence of hemoglobin F... 3.7 kb del, NM_000518.5:c.-138C>A, HbS NM_000518.5:c.20A>THeterozygous, HomozygousJassim and Al Arrayed, 2006 Two patients from tw...
603903.G.2.1United Arab EmiratesUnknown Anemia... HbS NM_000518.5:c.20A>THomozygousBaysal, 2005 52 patients with sic...
603903.G.2.2United Arab EmiratesUnknown Anemia... NM_000518.5:c.92+5G>C, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 17 patients with sic...
603903.G.2.3United Arab EmiratesUnknown Anemia... NM_000518.5:c.93-21_96del, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 4 patients with sick...
603903.G.2.4United Arab EmiratesUnknown Anemia... HbS NM_000518.5:c.20A>T, Hb D-Punjab NM_000518.5:c.364G>CHeterozygousBaysal, 2005 3 patients with sick...
603903.G.2.5United Arab EmiratesUnknown Anemia... NM_000518.5:c.135del, HbS NM_000518.5:c.20A>THeterozygousBaysal, 2005 2 patients with sick...
603903.G.2.6United Arab EmiratesUnknown Anemia... HbS NM_000518.5:c.20A>T, NM_000518.5:c.251delHeterozygousBaysal, 2005 2 patients with sick...
603903.G.3.1Arab; United Arab Emir...Unknown Anemia... NM_000518.5:c.25_26del, NM_000518.5:c.92+5G>C, NM_000518.5:c.93-21_96del, NM_000518.5:c.135del, NM_000518.5:c.315+1G>A, NM_000518.5:c.27dup, HbS NM_000518.5:c.20A>T, NM_000518.5:c.251del, NM_000518.4:c.114G>AEl-Kalla and Baysal, 1998 Mutations identified...
603903.G.3.2United Arab EmiratesUnknown Anemia... HbS NM_000518.5:c.20A>T, Hb D-Punjab NM_000518.5:c.364G>CEl-Kalla and Baysal, 1998 Patients from three ...
603903.G.3.3Arab; United Arab Emir...Unknown Anemia Persistence of hemoglobin F... 3.7 kb del, HbS NM_000518.5:c.20A>THomozygousEl-Kalla and Baysal, 1998 25 patients with sic...
603903.G.3.4Arab; United Arab Emir...Unknown Anemia Persistence of hemoglobin F... HbS NM_000518.5:c.20A>THomozygousEl-Kalla and Baysal, 1998 Six patients with si...

Other Reports

Algeria

Dahmane-Arbane et al. (1987) reported the comorbid case of Hb Boumerdes, an alpha chain variant alpha 2(37) (C2) Pro----Arg beta 2, with a benign homozygous sickle cell gene in an Algerian family. The abnormal hybrid hemoglobin had an electrophoretic mobility on cellulose acetate pH 8.7 electrophoresis between those of HbS and HbA2. Its expression was about 16%.

Bahrain

Buhazza et al. (1985) evaluated the hematological findings of 50 Bahraini patients with sickle cell disease (SCD). Family studies were done on both parents of 15 families and on seven other single parents. A control group of 21 newborns and 20 normal adults was also examined. HbF level of the 50 patients showed a range from normal to 54.2% which was lower than those encountered in surrounding countries. Of the 37 parents, 8.1% were homozygous for the disease, 8.1% were doubtfully beta-thalassemia heterozygotes, and 83.8% were HbS heterozygotes. Most of the parents were consanguineous. Three subjects (15%) in the control group were identified to be heterozygotes for the sickle gene, which indicates a high heterozygote frequency for the disease among Bahrainis.

Blair and Gregory (1986) studied the prevalence of hereditary anemias in two groups; 109 Bahraini girls of ages between seven and 18 years and 92 privileged Bahraini children attending the Salman Center. SCT showed an incidence of about 7% in both groups, however, the incidence of normochromic normocytic anemia which accompanied SCD was low. [Blair D, Gregory WB. Nutritional Vs hereditary anaemias appropriate screening procedures for Bahrain. Bahrain Med Bull. 1986; 8(3):124-7.]

El-Shafei et al. (1988) studied the complications during pregnancy of 100 consecutive unselected mothers and in a control group of 200 women. Thirty five of the mothers were SS, and 65 were AS. The incidence of vaso-occlusive crisis was significant in mothers with SCD related to low socio-economic groups. Also, the high level of HbF had no beneficial effect during the crisis episodes in sickle mothers. [Blair D, Gregory WB. Nutritional Vs hereditary anaemias appropriate screening procedures for Bahrain. Bahrain Med Bull. 1986; 8(3):124-7.]

Rasromani et al. (1990a) studied the prevalence of cholelithiasis in SCD and the relationship of its frequency to age and hematological parameters (hemoglobin and hemoglobin F values, microcytosis and reticulocyte count). Sixty-five patients with SCD attending Salmaniya Medical Center in Bahrain were included in the study. In 22 (34%) of the patients, abdominal ultrasound was abnormal; 19 of these (86.5 %) had multiple gallstones, while two had biliary sludge, and one had a solitary gallstone. Rasromani et al. (1990a) did not find any significant relationship between the frequency of cholelithiasis and age or hematological parameters. [Rasromani K, Jamsheer N, Mohammed AM, Al Mahroos S, Khan MI, Kamath KM. Prevalence of cholelithiasis in sickle cell disease. Med Principles Pract. 1990a; 91(2):182-184.]

Furthermore, Rasromani et al. (1990b) interviewed 50 SCD patients in Bahrain for history of priapism. Although priapism is a common complication in SCD patients (Black Americans-50%, Jamaicans-42%), Rasromani et al. (1990b) reported only one of the 50 patients to have suffered from it. The Bahraini patients were shown to have high HbF and low MCV values. The high HbF and microcytosis may play a protective role against the corpora cavernosa venous obstruction and priapism. [Rasromani KH, Mohammad AM, S al Mahroos, Khan IM. Priapism in sickle cell disease. Bahrain Med Bull. 1990b; 12(3):113-5.]

Mohammed et al. (1992) conducted a cord blood screening program to determine the frequency of SCD in Bahrain. A total of 10,327 cord blood samples, representing over 80% of all Bahraini neonates born in 1985 were analyzed in the study. Homozygous sickle cell disease was detected in 2.1%, while the sickle cell trait was found in 11.2% of the study population.

Al-Arrayed (1994a) conducted a study in order to ascertain the nature of SCD in the Bahraini population. The study involved getting SCD patients between the ages of 8 and 12 years to complete a questionnaire about common signs and symptoms, factors precipitating the crisis, and its relation to the food consumed. In addition, 70 SCD patients in the age group 15-50 years were retrospectively studied from the hospital case files to understand the severity of the clinical picture requiring hospital admissions, the common type of infections, and the treatment given. The most common sign of SCD presented by the children was fever (69%), followed by pain in hands (59%), limb (58%), abdomen (56%), knee (55%), and back (54%). Cold was the most common factor precipitating a crisis (45%), followed by fever (35%), and exhaustion (35%). Fava beans were found to aggravate the symptoms in these patients (55%), whereas fluids, fruits, and vegetables were found to relieve these symptoms in 25% of the cases. At least 2% of the students stopped schooling because of the severity of the disease, whereas 43% of the patients were irregular in school. In addition, 48% of the affected children reported the frequency of crisis to be once a month. Results from the study in the hospital indicated that the most common presenting sign in the hospitalized patients was anemia (92.9%), followed by pallor (90%), fever (85.7%), body aches (78.6%), headache (78.6%), and abdominal pain (77%).

Additionally, Al Arrayed (1994b) studied 50 SCD patients retrospectively over a period of three months in order to find the hematological status for adult Bahraini SCD patients. The age the studied group ranged from 15 to 50 years. About 60% of the patients had Hb levels below 10 gm/dl and only 8.8% had Hb levels above 12 gm/dl. HCT levels were below 30 in 57% of SCD patients. Sixty four percent of the patients had MCH below 25pg and 62% showed MCV lower than 76 fl that were attributed partly to the presence of thalassemia gene and partly to iron deficiency anemia. MCHC was nearly normal as 57% had MCHC in the range of 32-34 g/dl. Patients displayed a high reticulocyte count as 76% had a count more than 3%.

One year later, Al Arrayed and Haites (1995) examined SCD among Bahrainis in four separate studies. In the first study, Al Arrayed and Haites (1995) observed the prevalence of SCD in the hospital population of Bahrain over six years. The study included 5,503 neonates and 50,695 non-neonates. Of the neonatal samples, 18.1% showed SCT, and 2.1% had SCD. The frequency of SCD in non-neonatal patients was found to be 10.44%, and 84% of the SCD patients had HbF. The second study examined the nature of SCD by sending a questionnaire to 100 school children with the disease. Al Arrayed and Haites (1995) found that the most common factors precipitating crisis in SCD children are cold, fever, and physical activity. Most of the SCD school children had pain in hands, limbs, abdomen, knee, and back. The mortality rate was low, only 10% of school patients had experienced the death of family members, due to SCD. This was attributed to their high level of HbF, and high prevalence of alpha-thalassemia gene. Al Arrayed and Haites (1995) also determined the hematological characteristics of Bahraini SCD patients. Most of the patients had low hemoglobin levels, low HCT, low MCH, and low MCV (microcytosis) levels. The later was thought to be due to the co-existence of alpha-thalassemia gene. Al Arrayed and Haites (1995) did the fourth study to detect the Beta-S gene haplotypes among Bahraini populations. Of 59 individuals form 19 families, 59% were carriers. The Asian haplotype was presented in all the 19 families, with a frequency of 90%. The second most common haplotype was S2 haplotype (5%) followed by the S1 African haplotype (2.5%).

Al-Arrayed (1995a) performed molecular genetic studies on 59 Bahraini individuals from 19 families in order to determine the haplotype of chromosomes carrying the sickle cell allele. The sickle gene was found to be linked to the Asian haplotype in 33 chromosomes (90%) and was present in all 19 families included in the study. SCD Patients were 27 homozygous with the Asian haplotype, five heterozygous (Asian, S2), two heterozygous (Asian, S1), and two heterozygous with (Asian, beta thalassemia). Additionally, Al-Arrayed et al. (1995b) undertook a survey of 200 Bahraini patients with sickle cell crisis presenting to the Accident and Emergency centre. Results revealed that 90% of the patients to be under 30-years of age. The male to female ratio was 3:1, indicating that females have a much milder course of the disease than males. The major presenting symptom was pain, which was seen in 86% of the patients (53% in the lower extremities, 30% in the upper extremities, 11% abdomen, and 6% generalized). The main factor precipitating crisis in the patients was exposure to cold (71%), followed by exposure to heat (21%). About 83% of the patients responded to treatment with hydration and non-narcotic analgesics or narcotic analgesics, and did not need to be admitted. [Al-Arrayed S, Hamza AY, Chandra S, Azem HA, Reza M. A survey of patients with sickle cell crisis presenting to accident and emergency department of Salmaniya Medical Centre, Bahrain. J Bahrain Med Soc. 1995b; 7(2):108-12.]

Dash (1995) reported the rare simultaneous occurrence of HbS and HbD in a Bahraini child for the first time. The patient was four months old when he was admitted to the emergency section with fever, cough, and pallor. His liver and spleen were enlarged. Peripheral blood smear showed severe anisopoikilocytosis, hypochromia, microcytes, target cells, and ligamented cells. Sickling test was positive and alkaline hemoglobin electrophoresis showed two major bands at positions HbS and HbF. By performing hemoglobin electrophoresis (alkaline and acid) for both parents, AD and AS patterns were detected in the father and mother, respectively. Sickling test was negative for the father and positive for the mother. The infant's hemoglobin was retested on acid agar gel which showed the presence of both HbD and HbS along with the natural hemoglobin (HbF), thus he was confirmed to be double-heterozygous for HbD and HbS.

During the study of the incidence of cystic fibrosis in Bahrain, Al Arrayed and Abdulla (1996) detected 27 patients with cystic fibrosis (25 were Bahrainis). Of those, four to six patients (19-22%) had SCT and one patient had sickle beta thalassemia.

Khan (1996) was the first to investigate the etiology of osteomyelitis and pyogenic arthritis in SCD children in Bahrain. During a period of six years, medical records of patients admitted to a medical center were reviewed. Seven patients (four females and three males) had eight episodes of osteoarticular infections. SS was observed in four patients and SF in three patients. About half of the patients had low grade fever and mild constitutional symptoms of osteomyelitis/pyogenic arthritis. Salmonella was found to be the etiologic agent of osteomyelitis and pyogenic arthritis in all patients. Two patients were admitted with septic arthritis and Salmonella was isolated in both cases, although Salmonella septic arthritis is reportedly rare in patient with SCD. Polymorphonuclear leukocytosis was detected in all five patients who had a positive blood culture. Khan (1996) suggested that an antibiotic specifically effective against Salmonella must be included in any treatment protocol for suspected osteoarticular infections in children with SCD.

Mohammad et al. (1998) studied the comorbidity of SCD with glucose-6-phosphate dehydrogenase (G6PD) deficiency in Bahrain. Blood samples from 310 Bahraini individuals (152 males and 158 females) attending four major health centers were collected and underwent hemoglobin and G6PD electrophoresis. The subjects were of ages ranged between 5-74 years. One-hundred-and-twenty-five individuals had either SCD or SCT. Severe G6PD deficiency (Gd-) was present in 47% of individuals with HbS, while only 19% of those with only HbA had such a deficiency, indicating a significant statistical difference between the two groups.

Al-Mousawi (2004) studied a total of 41 replaced hips in 32 patients with SCD in Bahrain and recorded the complications and failures. The mean age of the patients was 28 years, with 17 women, and 15 men. Hemoglobin level was low in 13 patients, necessitating blood transfusion prior to the surgery. A total of 43 complications and 10 failures (indication of revision of arthroscopy) were recorded. Intra operative blood loss exceeded two liters in six patients. In two of these patients, operation was discontinued due to blood loss. Six patients developed sickle cell crisis and required special treatment. Other complications recorded were septic loosening (8), heterotopic ossification (7), acetabular perforation (7), clinical deep venous thrombosis (DVT), femoral shaft injury (5), wound hematoma (5), and aseptic loosening (1).

Al-Tantawi et al. (2005) described a 25-year-old SCT male patient who was admitted with the main complaint of right flank pain for three weeks. The patient had G6PD reduced activity. Urinalysis showed microscopic hematuria. Ureteroscopy and abdominal CT scan showed a mass in the right renal pelvis extending into the proximal 4-5 cm of the ureter and enlarged hilar renal lymph nodes. CT scan of the chest showed bilateral metastases. Postoperative histopatholigical report revealed grade III medullary carcinoma, which had invaded the renal parenchyma and perinephric fat with microscopic tumor nodules in the cortex, and marked vascular invasion. The patient was given then eight cycles of chemotherapy. Eight months later, his chest metastasis could not be seen on CT scan and the renal hilar lymph nodes had diminished in size from 12 cm to 1-2 cm only. Al-Tantawi et al. (2005) agreed that medullary renal carcinoma could be exclusive to patients with the SCT. [Al-Tantawi MA, Issa AA, Abdulla M, Samie MR. Medullary renal cell carcinoma: case report. Bahrain Med Bull. 2005; 27(4).]

Jassim and Al Arrayed (2006) studied the different molecular determinants that might cause an extremely mild form of sickle cell-beta thalassemia syndrome among Bahraini population. Blood samples of two Bahraini girls belonging to unrelated families were tested. Three different molecular determinants were found. The first one was the compound heterozygosity for the sickle cell mutation and nt-88 (C-A) mutation. The second determinant was the presence of HbS haplotype-associated high HbF expression. The third determinant was the coinheritance of alpha-thalassemia.

Al-Subaie et al. (2009) undertook a case-control study to investigate the distribution of HPA1, HPA2, HPA3, HPA4, and HPA5 alleles among vaso-occlusive crisis (VOC) and non-VOC control SCD patients. Study subjects comprised SCD patients with (VOC group; n = 127) or without (Steady-state group; n = 130) VOC events. Significantly higher frequencies of HPA-2b, HPA-3b, and HPA-5b alleles, and marked enrichment of HPA-3b/3b, HPA-5a/5b, and HPA-5b/5b genotypes, were seen in VOC than in control SCD patients. Taking homozygous wild-type genotypes as reference, univariate analysis identified HPA-3a/3b, HPA-3b/3b, and HPA-5b/5b to be associated with VOC. Multivariate analysis confirmed the independent association of only HPA-3a/3b and HPA-3b/3b genotypes with VOC. HPA-3 genotypes were found to be significantly correlated with VOC frequency, type, and medication, and requirement for hospitalization. While both HPA-3a/3b (P = 0.002; OR = 2.94; 95% CI = 1.49-5.77) and 3b/3b (P = 0.006; OR = 3.16; 95% CI = 1.40-7.17) genotypes were found to be associated with need for hospitalization, only HPA-3b/3b was associated with VOC frequency, type (localized vs. generalized), and medication (narcotics vs. NSAIDs). Al-Subaie et al. (2009) concluded that this study confirms the association of HPA polymorphisms with SCD VOC, of which HPA-3 appears to be independent genetic risk factors for SCD VOC.

Al Arrayed and Al Hajeri (2012) analyzed the results of the Bahraini Newborn Screening (NBS) program for sickle cell disease between 2007 and 2010. The total number of affected newborns born in 2010 was 47 out of a total birth of 11,317 neonates, giving an incidence of 0.41%. This is lower than incidences reported in previous years. In fact, the incidence was found to gradually, but persistently, decline from 2.1% in 1985 to 0.6% in 2009. Al Arrayed and Al Hajeri (2012) credit this reduction to increased awareness among the public due to educational and awareness campaigns launched more than 20 years ago.

Comoros

Badens et al. (2000) determined the frequency of hemoglobin S (HbS) in the Comorian community by performing neonatal screening in 467 (246 females and 221 males) Comorian newborns in Marseilles. Of those, 15 (3.2%) were carriers of HbS and one (0.2%) was affected by SCD (SS) resulting in a beta-S allele frequency of 1.8%. All 31 alleles carrying the beta-S mutation were found to have the Bantu haplotype suggesting that the beta-S gene was of exclusively African origin in the Comoros Islands.

Favale et al. (2009) reported a case of retinal stroke in a patient from the Comoros Islands with the comorbid association of the sickle cell trait and Southeast Asian ovalocytosis. They hypothesized that Southeast Asian ovalocytosis is possibly a risk factor for rare microvascular complications in sickle cell trait.

Kuwait

Adekile et al. (1994) characterized the beta-S chromosomes among Kuwaiti Arabs. Analysis of 18 beta-S chromosomes revealed haplotype 31 (Saudi Arabia/Indian) in 77.8% of the chromosomes and the Benin haplotype 19 in 16.7% of the chromosomes. Two years later, Adekile and Haider (1996a) used PCR and allele-specific oligonucleotide hybridization to study the genetic epidemiology of SCD in Kuwait. Data suggest that 76% of SS patients are homozygous for the Saudi Arabian/India haplotype, nevertheless various combinations of the Benin and Bantu haplotypes were seen. [Adekile AD, Haider MZ. Genetic epidemiology of sickle cell anemia and B-thalassemia in Kuwait. Kuwait Med J. 1996a; 28(2):104-10.]

The same year, at Kuwait University, Adekile and Haider (1996b) determined the haplotypes of 92 beta/S chromosomes (from 39 SS, 11 AS, 2 S/beta-thal, and 1 SD subjects) and the alpha-globin gene status (27 SS and 33 AS) using a combination of polymerase chain reaction and AS methods. Hospitalization was found to originate due to vasooclusive crisis (60%) and infections (20%). Throughout the follow-up, some complications were observed in subjects such as splenomegaly (24%), hepatomegaly (15%), gallstones (15%), and aseptic necrosis of the femoral head (6%). The haplotypes presented in Kuwait included haplotype 31 (Saudi Arabia/India) in 80%, Benin haplotype 19 in 12% and Bantu haplotype 20 in 6% of the cases. Hb F in haplotype 31 homozygotes and heterozygotes varied between 11.4 and 35.1%, while the frequency of alpha-thal determinants was found to be 40%. The most common alpha-thal determinants included -alpha 3.7-kb deletion in 28%, the alpha 2 polyadenylation signal (AATAAA/AATAAG) mutation in 10%, and the IVS-I 5' end GAAGGT-GAGG/GAGG pentanucleotide (5 nt) deletion in 3% of the cases. Adekile and Haider (1996b) concluded that the high frequencies of alpha-thal trait and Saudi Arabia/India beta/S haplotype contribute to the mild nature of the SS disorder amongst Kuwaiti Arabs. On a separate track, Adekile et al. (1996) studied spleen function in a set of 20 Kuwaiti SCD patients aged 2 to 12 years through employing 99mTc-labeled tin colloid scintigraphy. The subjects underwent screening for the prevalent alpha-thalassemia determinants in the Arab peninsula including -alpha (3.7 kb) deletion, alpha2-globin gene polyadenylation signal (AATAAA -AATAAG) mutation, and 5' IVS-I splice junction pentanucleotide (GAGGTGAGG-GAGG) deletion through merging polymerase chain reaction and allele-specific oligonucleotide (ASO) hybridization methods. The SS patients were segregated into three groups based on the outcome of their colloid uptake. Group I composed of 7 subjects (35%) having normally visualized spleens, Group II comprised of 5 patients (25%) with partial visualization, and Group III contained 8 persons (40%) with blind visualization of the spleen. The significant differentiated marks amongst those within Group I and III were found to be mean corpuscular volumes (MCVs) of 74.1 +/- 5.1 and 90.1 +/- 6.6 fl (P<0.0001) and mean corpuscular hemoglobins (MCHs) of 22.4 +/- -2.7 and 27.5 +/- 4.0 pg (P<0.05), respectively. The frequency of alpha-thalassemia determinants were found to be 57% within Group I, 30% within Group II, and 19% within Group III, meanwhile the overall frequency was 35%. Adekile et al. (1996) demonstrated that alpha-thalassemia trait seems to correlate with normal splenic performance within the SS studied patients.

Haider et al. (1998) carried out a combined prospective and retrospective study to explore the influence of coexistent alpha-thalassemia feature on the prevalence of gallstones in 45 SS patients from Kuwait. The cohort consisted of 30 males and 15 females with a mean age of 7.2 +/- 3.1, with the majority of subjects being homozygous for the Saudi Arabia/India (SAI) haplotype (87%) and the remaining were SAI/Benin compound heterozygote (11%). Seven patients (4 males and 3 females) with a mean age of 10.5 +/- 5.5 years, were found to suffer from gallstones and a lower Hb (8.4 +/- 0.8 g/dl) when compared to the group of lower mean age (6.8 +/- 3.2 years) lacking gall stones (9.5 +/- 1.3 g/dl). Moreover, gallstones were not present in the 4 alpha-thalassemia homozygotes, but occurred in 2 out of 13 heterozygotes and 5 out of 23 subjects without coexistent alpha-thalassemia, revealing a statistically significant difference with a chi2 value of 20.4. Haider et al. (1998) proposed that coexistent alpha-thalassemia might play a role in reducing the possibility of developing gall stones and hemolysis in Arab SS subjects. Later, Haider et al. (2000) employed the ELISA method on 24 age-matched Hb AA controls and 28 steady-state SCD patients at Kuwait University, to estimate plasma levels of GM-CSF. Throughout the study, controls included 14 healthy subjects and 10 ill subjects and 5 SS cases who suffered from 6 episodes of painful crisis. Amongst the SCD cases, 82% were found to be homozygous for the Saudi Arabia/India (SAI) haplotype with Hb varying from 15 to 35% and total Hb commencing from 8.5 to 11 g/dl. Three siblings were found to be heterozygous for SAI/Benin compound with Hb F starting from 9 to 23% and total Hb of >10 g/dl. Every single subject was found to be homozygous for the Benin or Bantu haplotype possessing Hb F <2% with total Hb of 6.6 and 7.2 g/dl, respectively. Four steady-state SS subjects experienced evident levels of plasma GM-CSF varying from 75 to 1, 817.6 pg/ml and out of those, 2 patients had Hb F <2.0% and 2 subjects were heterozygotes for the SAI/Benin compound possessing Hb F of 11 and 9%, respectively. Sensible plasma GM-CSF was found in 4 SS cases, 6 healthy controls, and 6 ill controls. A correlation of GM-CSF with Hb F level or degree of anemia in steady-state SS cases could not determined, but Haider et al. (2000) proposed the likelihood of other factors affecting the generation of this cytokine in the examined patients.

Adekile et al. (1999) studied a cohort of patients with hemoglobin SS disease. The cohort consisted of 23 Saudi Arabia/India (SAI) homozygotes and six SAI/Benin compound heterozygotes. Parameters such as serum immunoglobulin fractions [IgG, IgA and IgM], IgG subclasses and spleen function were compared between the patients group and controls. Adekile et al. (1999) observed that in the patients group increased serum IgG is linked with poor splenic function and recurrent infections, while increased IgM is noted mainly in those with relatively normal splenic function.

At Kuwait University, Raghupathy et al. (2000) examined 39 patients with SCD for the amount of Th1 (IL-2 and IFN-gamma) and Th2 (IL-4) cytokines within the plasma and supernatants subsequent to peripheral blood mononuclear cell culture and mitogen stimulation. SCD patients consisted of 29 SS patients (5 experienced 7 episodes of vaso-occlusive crisis), 8 S/beta-thal cases and 2 Hb SD subjects in a stable condition. In addition, 24 controls (3 Hb AS and 21 Hb AA) were examined, however, throughout the study 10 of those were ill and 14 were healthy. The examination revealed similar levels of plasma IL-2 and IFN-gamma within the cases and controls, higher level of plasma IL-4 in SS cases with a stable condition, no significant distinction was noticed within the various groups following mitogen stimulation, ratios of plasma IL-2 to IL-4 and IFN-gamma to IL-4 were found to be significantly lower amongst the stable-state SS cases, and subjects with decent splenic function demonstrated a virtual Th1 bias. Raghupathy et al. (2000) pointed out the possibility of Th2 bias in the SS subjects proposing the tendency of SCD patients to bacterial infections and the protection that exists in these patients against the bacterial infection.

In a study conducted in 2007, Adekile et al. investigated Hb F levels in 149 patients with SCD, ranging from 3-months to 60-years in age. All, except four patients, were homozygous for the SAI (Saudi Arabia/India) haplotype; the four exceptions being heterozygous SAI/Benin. As expected, SCD patients in this study showed elevated Hb F levels. These levels, however, were highest in those in the age group < 5 years of age. In fact, in patients < 2 years of age, the mean Hb F level was elevated as much as 30%. Adekile et al. (2007) conjectured that this elevation of Hb F levels in patients with the SAI haplotype could be responsible for the observation of Kuwaiti SCD patients not developing the early vasculopathy or bacterial infections that are characteristic of the disease. One year later, Akar and Adekile (2008) studied the common causes and patterns of hospitalizations among 50 children with SCD in Kuwait. The 351 hospital admissions of these patients during a 10-year period (1995-2004) accounted for 0.6% of all admissions. Common causes for admission were vaso-occlusive crisis (63%), acute splenic sequestration crisis (9%), hemolytic crisis (9%), and acute chest syndrome (7%).

Oman

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of SCD in Oman to be 3.8%.

In two members of an Arabian family from Oman, Ramachandran et al. (1992) discovered a leu-to-val replacement at position beta-32. In one person, it occurred with HbS and in the other with HbA.

White et al. (1993) estimated the frequency of sickle trait in Oman by studying 1,000 Omani subjects. The frequency this condition was found to be 0.061 in this population. The results of the study also indicated in this population with SCD, homozygosity of the alpha+ gene significantly modified the clinical picture.

Jacob et al. (1995) reported a case of spontaneous subarachnoid hemorrhage in a 30-year old female patient of SCD (HbS-beta thalassemia on electrophoresis). She presented with severe headache and vomiting. Clinically, she was found to be febrile, pale, drowsy, disoriented, with mild left facial paresis, neck stiffness and positive kerning's sign. Lumbar puncture revealed blood stained CSF (2400 RBCs), with xanthrochromic supernatant. Other investigations (CT brain, cerebral angiogram, chest X-ray and echocardiogram) were normal. Within three weeks, her condition improved gradually. Jacob et al. (1995) assumed that occlusion of the vasa vasorum led to localized pathology of the large vessels explaining the pathology in this patient, as the angiogram was normal, excluding aneurysm or arteriovenous malformation. Jacob et al. (1995) advised the maintenance of HbS level <20% in these patients by regular blood transfusions, in order to minimize the recurrence of cerebrovascular complications. [Jacob PC, Chand P, Tharakan J. Non-aneurysmal subarachnoid haemorrhage in sickle cell disease. Oman Med J. 1995; 12(2):28.]

Nagel et al. (1998) studied a pedigree of heterozygous carriers of HbS (Oman) that segregated into 2 types of patients: those expressing about 20% HbS (Oman) and concomitant -alpha/alpha-alpha thalassemia and those with about 14% of HbS (Oman) and concomitant -alpha/-alpha thalassemia. The higher expressors of HbS (Oman) had SCD of moderate intensity, whereas the lower expressors had no clinical syndrome and were comparable to the solitary case first described in Oman. In addition, the higher expressors exhibited a unique form of irreversibly sickled cell reminiscent of a 'yarn and knitting needle' shape, in addition to folded and target cells. Purified HbS (Oman) has a C(SAT) (solubility of the deoxy polymer) of 11 g/dL, much lower than HbS alone (17.8 g/dL). Another double mutant, HbS (Antilles), has a similarly low C(SAT) and much higher expression (40 to 50%) in the trait form, but has a phenotype that is similar in intensity to the trait form of HbS (Oman). Nagel et al. (1998) concluded that the pathology of heterozygous HbS (Oman) is the product of recipient properties of the classic mutation which are enhanced by the second mutation at beta-121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the beta-121 mutation. They speculated that the hemolytic anemia results from the abnormal association of the highly positively charged HbS (Oman) (3 charges different from normal hemoglobin) with the RBC membrane.

Suresh et al. (1999) reported the accidental detection of HbS Oman in a nine year old Omani boy who presented to the Ear, Nose and Throat department with two years history of snoring and mouth breathing, and was diagnosed with adenoid hyperplasia by X-ray of the post nasal space. Preoperative investigations as adenoidectomy revealed normal G6PD activity, positive sickling test, Hb of 11.4 g/dl with low MCH (20.4 pg) and MCV (59.4 fl) with normal MCHC and RDW, as well as normal white blood cell and platelet counts. On the blood film, there were many Napoleon hat shaped red cells along with microcytosis, hypochromia, anisopoiklocytosis and occasional target cells. A diagnosis of HbS Oman trait was made which was confirmed by hemoglobin electrophoresis as it showed HbS Oman of 17%, HbA was 76.7%, HbA2 was 4.3%, and HbF was 2%. This patient had no history of painful crisis or any hematological problems. Upon studying the parents by hemoglobin electrophoresis, it turned out that the mother, who had no history of painful crisis or other hematological problems, was also a carrier of this Hb variant, as she had 18% of HbS Oman, HbA was 76%, HbA2 was 4.3% and HbF was 1.7%, while the father had normal hemoglobin. The father and mother were from different tribes. [Suresh V, Asila NS, Nafisa MZ, Laitha MN, Susamma M. Haemoglobin S Oman trait- A sickling variant. Oman Med J. 1999; 16(1):23-4. Suresh V, Asila NS, Nafisa MZ, Laitha MN, Susamma M. Haemoglobin S Oman trait- A sickling variant. Oman Med J. 1999; 16(1):23-4.]

Sejekan et al. (1999) conducted a retrospective study to assess the pregnancy outcome in Omani women with SCT who delivered during years 1995-1997. Out of 1866 pregnant women enrolled in this study, 91 (5%) had sickle cell trait and 1775 had normal hemoglobin (control group), and in both groups, the total number of pregnancies per patient were similar (four pregnancies). Among the previous pregnancies, the incidence of intrauterine fetal deaths and neonatal deaths were significantly higher in those with sickle cell trait (1% versus 0.4%, and 2% versus 0.25%, respectively), who also showed increased incidence of anemia (9% versus 4 %) during the antenatal period. But, the difference in other antenatal complications (pregnancy induced hypertension, chronic hypertension, diabetes, intrauterine growth retardation, oligo- and poly-hydramnios, urinary tract infection, and systemic lupus erythematosis) was not statistically significant. Regarding the current delivery outcome, the gestational age at delivery, incidence of intrauterine fetal death and neonatal deaths were not different between the two groups, but those with sickle cell trait had higher rates of Cesarian section (11% versus 4%) and increased incidence of abruptio placenta (2% versus 0.34%). [Sejekan PB, Kaur S, Vaclavinkova V, Krilikowiski A. Pregnancy outcome in Omani women with sickle cell trait. Oman Med J. 1999; 16(2):10-2]

Daar et al. (2000) used beta-gene cluster haplotypes to identify the uni-or multi-centric origin of the sickle mutation, its genetic flow and its influence on hematological parameters. Out 117 beta S chromosomes the majority (48.7%) had the typical Benin haplotype and four had the atypical Benin type (with a difference in the 5' region) making up a total of 52.1% with Benin haplotype. Thirty chromosomes had typical Arab-India haplotype with one atypical Arab-India haplotype (total of 26.7% with Arab-India haplotype), and 24 chromosomes exhibited the typical Bantu haplotype with one atypical Bantu haplotype (total of 21.4% with Bantu haplotype). When the level of HbF was studied in 52 subjects with SS genotype, higher levels of HbF were detected in the Arab-India haplotype in the homozygous form, when compared to the Bantu and Benin haplotypes, and this level decreased in the heterozygous form of this haplotype (even in its atypical form). There was a gender effect on the homozygous form of Arab-India haplotype as the average of HbF in males was 14.5% while in females was 23.3%. On the other hand, such a difference was not evident in the heterozygous form. On determining the HbF levels in S/thalassemia and SC disease, similar level and range was found among the Benin, Bantu and Arab-India haplotypes combined with beta-thalassemia chromosomes, and in SC disease in which the haplotypes were Benin and Bantu. Out of 23 normal Omani chromosomes, one haplotype predominated (56.6%) while the rest (seven haplotypes) had lower frequencies of 4.4-13%. Daar et al. (2000) explained the five atypical haplotypes (Benin A1-A3, Bantu A1, and Arab-India A1) as a combination of typical Benin, Bantu or Arab-India haplotype with an Omani normal haplotype (one of eight). They also linked the different haplotypes to different historical origins. The Arab-India haplotype linkage to beta S gene was explained by the contact between Oman and Iraq, Iran, Indus Valley and India, and its presence in the Arabian Peninsula strengthened the hypothesis that this Indo-European form of beta S gene originated in the Harappa culture or nearby population and migrated during the Sassanian Persian Empire to the eastern portions of the Arabian Peninsula. On the other hand, the Benin haplotype linked to beta S gene in Oman was explained as due to the historical contact between Oman and the Sub-Saharan Africa, and the presence of Bantu haplotype as due to the contact between Oman and Tanzania and Mombassa. Daar et al. (2000), thus, confirmed the multi-centric origin of sickle mutation in Oman with detection of three major haplotypes.

Rajab et al. (2000) conducted a study to determine the birth prevalence of symptomatic hemoglobinopathies (with exclusion of alpha-thalassemia) in Oman through a national register which was obtained by gathering information (demographic and course of the disease) about the patients from hospital-based registers of all 17 regional hospitals and two tertiary care centers. In total, 3105 SCD cases were included, but 1474 cases (47%) were excluded after sorting out the duplicates and excluding those with wrong diagnosis. By December 1995, 1757 SCD patients (1620 retrospectively from hospital records and 137 from one year prospective registration) were identified in 23 tribes. All cases were under the age of 20 years. The birth prevalence of symptomatic beta-globin disorders in Oman was 1 in 323 live births or 3.1 per 1000 live births in 1989-1992 which included 2.7 per 1000 live births of homozygous SCD. Each year, it was calculated that 118 new cases of SCD were expected to be born. Heterozygote HbS carrier frequency was calculated as 10%. Upon analysis of the prevalence by tribal names, it was found that SCD was prevalent in 40% of Omani tribes with uneven distribution among the sub-tribal groups as only one third of the tribal population had affected members with one or two affected sibships in almost half of these. The regional distribution of SCD revealed that it was more prevalent (more than 70% of cases) in regions with smear-positive rates of malaria of 1% to more than 5% (parts of Dhahira, Dakhliya, North and South Shargiya). The molecular studies revealed 40 Benin, eight Bantu, six Bantu A4, and three Arab-Indian RFLP haplotypes associated with SCD in Oman.

In a study on the hemoglobinopathies in the United Arab Emirates, Baysal (2001) examined the HbS gene in 50 Omani SCD patients. Haplotype homozygosity was prevalent in the population (80%). The Benin haplotype was the most common in the population (34%), followed by the Bantu haplotype (24%), and the Saudi Arabian/Indian haplotype (22%); suggestive of an East African influence on the Arabian Peninsula and on Oman in particular.

Al-Riyami et al. (2001) estimated the prevalence of hemoglobinopathies in Oman by interviewing members of households (6600 with response rate of 92.5%) randomly selected from a list prepared from a sample of 264 units chosen from all Oman districts. The 1993 national population census was used as a frame for the two-stage stratified probability sampling. Blood was withdrawn from 6342 children (aged 0-5 years) and analyzed by way of complete blood count and blood indices, levels of HbS, HbA2 (values more than 3.5% confirmatory of beta-thalassemia trait in the absence of any hemoglobin abnormality) and HbF. The prevalence of SCT was 6% and the mean level of HbS was 29% in 219 children with ages of 2 to 5 years (no regional variation). SCT showed significant regional variation, being more common in North Sharqiya (10%) and Al Dakhiliyah (9%), and least common in Dhofar (0.2%), but no association with age, gender, level of hemoglobin, or history of blood transfusion (during one year before the study) was detected. The prevalence of first cousin consanguinity was determined as 34%, and it was associated significantly with homozygous blood disorders. Upon comparison of the prevalence with that of other countries of the Gulf Cooperation Council (GCC), Oman had a higher prevalence than United Arab Emirates (2%) and Saudi Arabia (1%). On combining these results with the 1993 census, it was calculated that in Oman, 14,314 children under the age of five years had SCT, and according to the authors' results and the Hardy-Weinberg equation, the number of children born yearly with a major hemoglobinopathy was 2 per 1000 live births which increased to 3 per 1000 live births upon correction for consanguinity. Therefore, with a birth rate of 42,000/year, 125 children with a major hemoglobinopathy would be born yearly in Oman. As these numbers would increase the burden on health services, Al-Riyami et al. (2001) suggested that future health planning for Oman should be undertaken by improving and strengthening the national programs for detection, genetic counseling and health education.

Hamdi et al. (2002) conducted a retrospective study on 3,501 pregnant Omani ladies in Nizwa region, to determine the incidence of SCT as well as to assess their pregnancy complications and neonatal outcome. A total of 319 pregnant ladies (9.1%) were found to have SCT and 3,182 had normal hemoglobin. The average age in both groups was 27 years, while 51% of women in both groups were primigravida. SCT ladies had the highest incidences of previous abortions and neonatal deaths (4.6% and 1.6% versus 2.6% and 0.7% in the control group, respectively). As regarding antenatal complications, the incidence of anemia (41.4%) was higher among the SCT group than the control group (25.2%), but the other complications (pregnancy induced hypertension, intrauterine growth retardation, diabetes, oligohydramnios and polyhydramnios) were similar in both groups. No difference in the gestational age at delivery (>38-40 weeks in 55.7% of SCT and 48% of control) and the birth weights (>2.5 kg-3 kg in 37.9% in SCT and 38.8% of control) was found between the groups. Nearly, 90.5% of women with SCT and 89.5% of the control group delivered via normal vaginal delivery and there was no statistical difference in the incidences of abruption placenta or Cesarean section between the two groups. Hamdi et al. (2002) described SCT as a benign condition, but recommended that stressful situations in pregnancy like dehydration, anoxia, and infection be avoided to prevent complications.

Al-Jahdhamy et al (2002) reported a case of compound heterozygosity for HbS and HbS Oman in a one-year old female who presented with fever and anemia. Investigations showed Hb of 7 g/dl and the blood film showed both sickle cells and Napoleon hat cells. Hb electrophoresis on alkali and acid gels confirmed the presence of HbF, HbS, and HbS Oman. The patient's mother was found to be heterozygous for HbS Oman, while the father was heterozygous for HbS upon HPLC analysis.

Jaiyesimi et al. (2002) reported the morbidities associated with SCD by reviewing hospital records of 97 affected Omani children (53 boys, and 44 girls; median age 7 years) admitted to the hospital in years 1999-2000. On the NCHS reference curves, 66 children with SCD (68%) were below the fifth percentile when compared to 27 of the 97 control children (28%) and this difference was statistically significant. Ninety children had SCD, while the other seven had sickle cell-thalassemia. G6PD activity was normal in 55 children, deficient in 24 and was unknown in 18 children. In 95 children, the mean steady state Hb was 7.9 SD 1.2 g/dl (range of 6-10 g/dl), and there was no statistically significant difference in the mean Hb between the age groups less than one year, 1-5, 6-10 and 11-12 years. Blood transfusion was required in 30 patients with varying frequencies, but the majority (13 patients) received transfusions three times or more. The 97 patients were admitted 316 times during the one year of study period with a mean of 3.3 times per child while the majority of patients (54%) were admitted three times or more. Out of the 316 admissions, 262 (83%) were for VOC, 38 (12%) were for severe anemia, 13 for infection and the other three were for acute chest syndrome, severe epistaxis and osteonecrosis of the femoral head. The mean duration of hospital stay per child was 10.4 days, and the 97 patients had used 1009 bed-days during one year. During the study period, out of all pediatric medical admissions, the mean of SCD-related admissions was 10.7%, with no significant seasonal variation. No association was detected between age, total hemoglobin and the VOC incidence. The extremities were the mostly affected sites by VOC with concurrent involvement of the chest and contagious areas (arms, abdomen and spine) in 9% of the episodes. Other complications noted in these patients were dactylitis (4), hypersplenism (4), epistaxis (3), ischemic necrosis of femoral head (2), and one case each of pathological fracture of lumbar vertebra, acute chest syndrome, acute splenic sequestration, and cholelithiasis. According to the disease severity parameters, 28 patients out of the 97 had mild disease, 26 had moderately severe disease and 43 had very severe disease. The patients with sickle-thalassemia disease had similar pattern with mild (3), moderately severe (2), and severe (2) types.

Osman et al. (2005) reported an eight year old boy with SCD who had pagophagia and a history of craving for ice which was noticed over a period of four months. The parents noticed that he had no painful attacks over two months with a drop in his hemoglobin level, which was explained by Osman et al. (2005) as due to the hemodilution with the decrease of hemoglobin concentration. The patient had a history of passing fresh blood in stool. Clinically, he was pale and per rectum, and he had a rectal polyp. Investigations revealed hemoglobin of 5.9 g/dl (his baseline was 8-9 g/dl) and ferritin of 1 ng/ml. Stool examination revealed occult blood. His condition improved, along with his anemia and craving for ice, when he was given iron therapy (6 mg/kg) for three months. The polyp was surgically removed.

Mathew and Gowri (2005) reported a spontaneous triplet pregnancy in a 26-year old Omani lady with SCD/beta-thalassemia. She had four similarly affected siblings and was married to a normal, unrelated man. Her previous pregnancy was complicated by vaso-occlusive crisis and post partum hemorrhage, but resulted in a healthy boy. During this pregnancy, a prophylactic cervical cerclage was inserted at 15 weeks and she was put on Penicillin V and folic acid supplements. Serial ultrasound scans showed viable and growing three fetuses. She was admitted several times for top up and exchange transfusions, and at 26 weeks, she received two doses of dexamethasone injections to promote fetal lung maturity (in case of preterm delivery). Although an elective Cesarean section was planned at 32-34 weeks, it was performed at 30 weeks, after removal of the cerclage, as she presented with labor pain. Three babies (two girls and a boy) with good apgar scores were born with birth weights of 1.4, 1.3, and 1.27 kg, respectively. The mother received two units of blood (600 mls loss) and anti-D (300 microgram) as she was Rh negative but without antibodies, and she was then discharged after six days. The babies were kept for 35 days as they all had RDS and metabolic acidosis and were ventilated for 15 hours. Upon follow up after six weeks, the mother was well and was started on contraception, and at three months, the babies were healthy and thriving, with no evidence of retinopathy of prematurity.

Palestine

Fathalla (1986) reported a comorbidity case of sickle-thalassemia with the hand-foot syndrome in a 12-year-old Palestinian boy. The patient, previously diagnosed with sickle-thalassemia at the age of 3 years, was admitted because of severe pain in both hands for two days after an exposure to cold weather. Clinical investigations showed typical features of chronic hemolytic anemia, the spleen enlarged to about 4 cm below the left costal margin and the liver about 3 cm below the right margin. The patient's upper extremities were normal except for diffuse swollen small joints of both hands with shiny warm skin. Radiographic examinations of both hands revealed wide medullary cavities and thinning of the cortex of the metacarpal bones with diffuse soft tissue swelling. Fathalla (1986) noted that this case seemed to be an unusual presentation of hand-foot syndrome, since to his knowledge a similar case has not been reported in the literature with the onset of symptoms after exposure to cold weather. [Fathalla M. Unusual age of presentation of hand-foot syndrome. Emirates Med J. 1986; 4:143-45.]

Ged et al. (2004) described a Palestinian Muslim family with congenital erythropoietic protoporphyria (CEP). The parents were non consanguineous, but originated from the same village. Two male and two female sibs showed the symptoms of the disease during infancy. The affected sibs were homozygous for a new mutation in the UROS gene (substitution of serine by praline at position 47, S47P). The mother and one of her sons were heterozygous carriers, and another son was healthy non carrier. The mother was also heterozygous for the SCT. Surprising findings were observed in a sister who had a moderate uroporphyrinuria, and presented the mutation (S47P) at the homozygous state with profound deficiency of UROS activity. Ged et al. (2004) proposed that she was protected from the accumulation of porphyrins which might be attributed to the non-hyperactive porphyrin biosynthesis. However, her hemoglobin electrophoresis was normal which ruled out the hypothesis that certain hematological disorders could limit porphyrin synthesis.

Qatar

Bakioglu et al. (1985) studied five patients with a mild form of SCD, of which two were siblings from Qatar. The proband in this Qatari family had a diagnostic hemolytic crisis at the age of 3-years, followed by several other crises that decreased with age. At the time of examination, he was a college student, occasionally experiencing respiratory and urinary tract infections. His 10-year old sister had mild splenomegaly and occasional respiratory tract infections, without experiencing any crisis, and was erroneously thought to be an HbS heterozygote, up until the time of molecular analysis. Both parents were found to be heterozygotes, while the patients were homozygous for the beta S mutation. Both patients had modest anemia, without significant microcytosis, and were found to have normal alpha globin genes. The siblings also showed high HbF levels. Haplotype analysis revealed the presence of one chromosome with haplotype 19, and the other with haplotype 31. Two identical haplotype 19 had previously been found to be associated with a severe form of the disease. However, this was the first report of haplotype 31 in patients with sickle cell. Bakioglu et al. (1985) suggested that this haplotype could lead to a milder form of the disease, characterized by an increased production of gamma chains.

Fawzi et al. (2003) undertook a hospital-based study, in which they studied 1,702 Qatari nationals (905 females and 797 males) referred for investigation on suspicion of a hemoglobinopathy. Of these, 17% showed a normal electrophoresis pattern, while in another 9%, the pattern was considered inconclusive, either due to the presence of iron deficiency anemia or due to a recent blood transfusion. HbS occurred in 15% of the patients, whereas SCT and SCD was detected in 7% and 4%, respectively. In addition, 2% and 3% of the patients were seen to have HbS/beta-thalassemia and HbS/alpha-thalassemia, respectively. Fawzi et al. (2003) found sickle cell hemoglobin to be the most common hemoglobinopathy among the referred Qatari patients, constituting 90% of all structural hemoglobinopathies detected in this group.

Saudi Arabia

Wood et al. (1980) studied fetal hemoglobin (HbF) synthesis in 22 SCD cases from Saudi Arabia and compared with an equal number of cases of African origin. Among the Saudi Arabs gamma chain synthesis ranged from 4.0% to 19.9% of the total non-alpha chain synthesis (mean 8.1%) while the corresponding range for the Negro cases was < 0.3% to 4.6% (mean 1.7%). In both groups the peripheral blood HbF level was on average 3-4 times higher than the proportion synthesized, indicating that the selective survival of HbF containing cells (F cells) was an important factor in determining the final H F levels. Wood et al. (1980) realized that a high proportion of the cases in both groups were carriers of alpha thalassemia in addition to SCD, but did not observe any effect of alpha thalassemia on HbF production.

Kulozik et al. (1986) found that the sickle gene in Saudi Arabia and on the west and east coasts of India exists in a haplotype not found in Africa. They concluded that the data are most consistent with an independent Asian origin of the sickle cell mutation. The distribution of the Asian beta-S-haplotype corresponded to the reported geographic distribution of a mild clinical phenotype of homozygous SS disease. SCD patients from the eastern province of Saudi Arabia have high circulating levels of fetal hemoglobin, 17% HbF on the average, and, as a consequence, have a mild form of the disease.

Miller et al. (1987) found a single-base cytosine-to-thymidine substitution at the 158 bp 5-prime to the cap (preinitiation) site of the G-gamma-globin gene of the high-hemoglobin-F chromosome. The substitution was present in nearly 100% of SCD patients or trait carriers and in 22% of normal Saudis. Homozygosity for this mutation had no demonstrable effect on HbF production in the normal Saudi population.

Abbag (1997) analyzed febrile illnesses from data of 269 admissions for 94 young SCD patients (66 boys and 28 girls) in the Southwest region of Saudi Arabia. Of 207 admissions due to SCD crisis, 54% had associated fever, of which, 71% were associated with fever without obvious infection. The infections found in patients with temperature over 38.5 degrees C, were upper respiratory tract infection (19%), pneumonia (10%), septicemia (6%), osteomyelitis (5%), urinary tract infection (4%), gastroenteritis (3%), malaria, septic arthritis, and cervical lymphadenopathy (one patient each). SCD patients are particularly susceptible to Streptococcus pneumonia, Hemophilus influenza, Salmonella species, and other Gram negative bacteria. However, the study of Abbag (1997) identified only one patient with a serious infection of Streptococcus pneumonia, pointing to the rarity of this infection in SCD patients in Southwest Saudi Arabia. Half of the cases of septicemia and probably three of the five cases of osteomyelitis were due to Salmonella typhi infection, suggesting a possible choice of antibiotics to effectively combat febrile infections in SCD patients. [Abbag FI. Fever in young patients with sickle cell disease in Southwest region of Saudi Arabia. Emirates Med J. 1997; 15(1):13-5.]

As part of the hemoglobinopathies' neonatal screening program in Qatif and Al Hasa, Nasserullah et al. (1998) carried out a molecular study to estimate the frequency of SCD in a total of 12,220 infants, including 11,313 (92.6%) Saudis. The study group included 4,744 males (4,410 Saudi and 334 non-Saudi) and 4,722 females (4,378 Saudi and 344 non-Saudi); and 1,370 males (1,254 Saudi and 116 non-Saudi) and 1,279 females (1,172 Saudi and 107 non-Saudi), in Al Hasa and Qatif, respectively. This target population included all babies born in Qatif Central hospital, Qatif, and King Fahad Hospital, Al Hasa, from December 1992 to December 1993. In addition, babies delivered at home in the Qatif and Al Hasa areas, and coming to primary health care centers for vaccination, were also included. The diagnosis of SCD was based on cellulose acetate electrophoresis and confirmed by agar gel electrophoresis. The common phenotypes detected in these infants included AF, AF Bartâs, SFA, SFA Bartâs, FS and FS Bartâs. Hemoglobin variants occurred in 47 samples (0.4%); without further characterization. Homozygous SCD occurred in 2% and 1% of Saudi infants, and 0.45% and zero in non-Saudi infants, in Qatif and Al Hasa, respectively. The frequencies of sickle cell gene were found to be 0.1545% and 0.1109% in Saudi newborns, and 0.0357 and 0.0095 in non-Saudi infants, in Qatif and Al Hasa, respectively. The incidence of SCT in Saudi neonates was found to be very high, 28% and 20% in Qatif and Al Hasa, respectively. Based on these findings, Nasserullah et al. (1998) concluded that the Saudi populations in Qatif and Al Hasa are at risk for SCD.

Zaki and Al Husain (1999) described a boy with the karyotype [46, XY, del(3) (q21q25.3)], suggestive for the presence of the deletion syndrome, and heterozygosity for the sickle cell gene. The parents were first cousins with normal karyotypes. [Zaki OK, Al Husain MA. Interstitial deletion of the long arm of chromosome 3. Emirates Med J. 1999; 17(3):159-61.]

Banjar (2002) reported a two and a half year old male suffering from a comorbid occurrence of cystic fibrosis (CF) and SCD in Saudi Arabia. The subject was born to first cousin parents by Cesarean section, he had an uncle and an aunt with SCD disease, one niece passed away at the age of 2 years due to CF, and another niece was diagnosed with CF and SCD disease at the age of 6 months. Banjar (2002) proposed increasing awareness for the existence of the combination of CF/SCD disease. [Banjar H. Simultaneous occurrence of cystic fibrosis and sickle cell disease in one patient: is it a rare phenomenon? A letter to the editor. Kuwait Med J. 2002, 34(2):159-60.]

Sudan

Omer et al. (1972) studied the incidence of abnormal hemoglobin among five indigenous [Nubians (Northern Sudan), Kalakla (Central), Dinka (Southern), Ingassena (South Eastern), and Beja (Eastern)] and two immigrant groups [Nigerians (Western bank of the Blue Nile) and Tchiendians (Central Sudan)] in Sudan. Blood samples were collected from about 100 unrelated males of each tribe, except for Tchiendians in which the collected samples were only 54 samples. The highest SCT incidence was found in the immigrant tribes, the Nigerians (27%) and Tchiendians (20%). Igassena tribe showed no evidence of abnormal hemoglobin and that tribe was thought to be a pure line of the original population of Sudan. Similarly, Beja tribe had no abnormal hemoglobin which could be referred to its close community. The incidence of abnormal hemoglobin in Dinka was about 8% which was higher than the previously reported studies. Different results in Dinka were attributed to the test method variations. Kalakla displayed zero percent of abnormal hemoglobin, however, it is considered to be of mixed origin.

Prehu et al. (2002) described a heterozygous hemoglobin variant that combined the change of HbO-Arab and Hb Hamilton on the same beta-globin allele. The other allele carried the HbS mutation. The patient was a child of Chad-Sudanese descent, suffering from SCD. Compared to the classic description of the HbS/HbO-Arab association, the additional Hb Hamilton mutation did not seem to modify the clinical presentation.

United Arab Emirates

Kamel (1984) described biochemical features of 11 Arab SCD patients (7 males and 4 females; mean age 13 years) diagnosed over a 4-year period in Abu Dhabi. All patients were found to have homozygous SCD, while the parents had SCT. In three of these patients, the hemoglobin level was stable at below 8 g/dl, and in another two, it often went below this level. Four other patients had hemoglobin level above 11 g/dl without transfusion and two patients had anemia of moderate severity (9.5-14 G/dl). Two patients required transfusions at least once a year. Mean HbF in these 11 patients was 11.9% and showed no correlation with the clinical characteristics of the patients. [Kamel K. Sickle cell hemoglobin: origin and clinical manifestations in Arabs and relation to fetal hemoglobin levels. Qatar Med J. 1984; 5(1):23-6.]

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of SCD in the United Arab Emirates to be 1.9%.

Awaad and Bayoumi (1993) studied the severity of SCD in adult Bedouins in Al-Ain Hospital. The parameters used to gauge severity of SCD included frequency of admissions crisis, blood transfusion requirements, and complications. The analyzed group included homozygous SCD and SCD/beta-thalassemia patients. Homozygous SCD patients showed normal MCV, MCH and HbA2 levels, while the SCD/beta-thalassemia patients had low MCV, MCH and high HbA2. HbF levels were elevated in all patients and that did not seem to relate to the clinical severity of the disease. There was no noticeable difference in the severity of the disease between homozygous SCD and SCD/beta-thalassemia, which ranged from mild to moderate. [Awaad MO, Bayoumi R. Sickle cell disease in adult Bedouins of Al-Ain district, United Arab Emirates. Emirates Med J. 1993; 11:21-24.]

In a study on the hemoglobinopathies in the United Arab Emirates, Baysal (2001) examined the HbS gene in UAE nationals with SCD. The Saudi Arabian/Indian haplotype was the most prevalent in the population (68%) followed by the Bantu haplotype (8%), signifying the presence of an African influence.

Miller et al. (2003) carried out a cross-sectional community clinic-based capillary blood survey to produce a hematological profile of preschool national children of the United Arab Emirates. The sample included 1-5-year-old Emirati children attending a Primary Health Care Center in Al-Ain from April to October 2000. Those children with capillary hemoglobin (Hb) and mean corpuscular volume (MCV) values below predetermined cutoffs were offered venous blood hematological workup. A random sample of children with values above those cutoffs was also offered the same workup. In total, 496 children were surveyed. The mean Hb and adjusted MCV rose with increasing age but were not significantly different by gender. Two hundred and sixty-two children with Hb or MCV below the cutoffs and 50 children above the cutoffs were venous blood tested. The estimated abnormalities for this population of children were as follows: anemia 36%; iron deficiency anemia 10%; G6PD deficiency 9%; SCT 5%; and beta thalassemia 9%.

[See also: Palestine > Fathalla, 1986; Oman > Baysal, 2001].

Yemen

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of SCD in Yemen to be 0.95%.

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