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Hereditary Red Blood Cell Disorders in Middle Eastern Patients

      Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.

      Abbreviations:

      G6PD (glucose-6-phosphate dehydrogenase), NADPH (nicotinamide adenine dinucleotide phosphate), RBC (red blood cell)
      A 68-year-old man from Saudi Arabia traveled to a large American medical center for a total knee arthroplasty. Preoperative evaluation revealed mild microcytosis. Extensive evaluation for an occult bleeding source (including several endoscopic procedures) was unrevealing. Eventually, hemoglobin electrophoresis was performed, and the patient was found to have ×-thalassemia trait.
      The orthopedic procedure was uncomplicated, but during convalescence the patient developed a urinary tract infection related to bladder catheterization. Trimethoprim-sulfamethoxazole and phenazopyridine were administered. This was followed by hemoglobinuria and mild icterus. He recalled a similar episode when he was treated for malaria during military service 40 years earlier. Hemolysis due to glucose-6-phosphate dehydrogenase (G6PD) deficiency was suspected, and further exposure to oxidative drugs was avoided. A subsequent assay confirmed G6PD deficiency. He was advised to avoid taking oxidative drugs such as sulfonamides and to avoid ingestion of fava beans. The patient returned home.
      Red blood cell (RBC) abnormalities are extremely common in human populations. More than 700 abnormal hemoglobins have been described,
      • Huisman THJ
      • Carver MFH
      • Efremov GD
      hundreds of different genetic mutations causing thalassemia have been identified,
      The thalassemia repository (9th ed; part II).
      and more than 200 million people worldwide have an RBC enzyme abnormality.
      • Beutler E
      Glucose-6-phosphate dehydrogenase deficiency.
      • Arya R
      • Layton DM
      • Bellingham AJ
      Hereditary red cell enzymopathies.
      Truly, we are “surrounded by a vast sea of erythropathology.”
      • Keitt AS
      Diagnostic strategy in a suspected red cell enzymopathy.
      Human erythrocyte abnormalities have a broad spectrum of importance, from mutations that are lethal in utero or in childhood to incidental, inconsequential mutations detected either serendipitously or as part of large screening programs. Approximately 4.5% of all humans have a hemoglobin abnormality or thalassemia mutation. These genetic lesions are a major cause of morbidity and mortality around the world.
      • Angastiniotis M
      • Modell B
      • Englezos P
      • Boulyjenkov V
      Prevention and control of haemoglobinopathies.
      In this article, we review some of the most common RBC disorders seen in persons from the Middle East. This review does not include an exhaustive list of hemoglobin variants in Middle Eastern populations, since many of these variants have been found in only a single family or individual or have no clinical consequence. Instead, we focus on the most common and most important conditions, those most likely to be seen by Western clinicians. Much of the discussion also applies to patients living in the West who are of Middle Eastern descent.

      WHEN TO SUSPECT AN RBC ABNORMALITY

      The illustrative example at the beginning of this article points to the potential hazard of failing to recognize an RBC disorder in patients from regions of the world with a high prevalence of these mutations, such as the Middle East. Some hemoglobin and enzyme abnormalities are much more common in particular ethnic groups. Preventive health organizations recognize these epidemiological patterns and have adopted recommendations about which groups of adults should be screened for hemoglobinopathies and thalassemias.
      • US Office of Disease Prevention and Health Promotion
      • Office of Public Health and Science
      • US Department of Health and Human Services
      • Canadian Task Force on the Periodic Health Examination
      The periodic health examination.
      • Goldbloom RB
      Screening for hemoglobinopathies in Canada.
      • American College of Obstetricians and Gynecologists
      • Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists
      ACOG technical bulletin: hemoglobinopathies in pregnancy: No. 220—February 1996 (replaces No. 185, October 1993).
      • US Preventive Services Task Force
      • American Academy of Family Physicians
      • Commission of Public Health and Scientific Affairs
      The systematic screening of young adults before they attempt conception and the availability of genetic counseling have markedly reduced the incidence of homozygous thalassemia in some areas of the world such as Cyprus, Turkey, Greece, and Italy.
      • Angastiniotis M
      • Modell B
      • Englezos P
      • Boulyjenkov V
      Prevention and control of haemoglobinopathies.
      • Cao A
      Results of programmes for antenatal detection of thalassemia in reducing the incidence of the disorder.
      Patients from the Middle East frequently seek medical care in North America and Western Europe. Some medical centers in the West care for thousands of patients from this region each year (unpublished data, 1993–1998 Mayo Clinic, obtained January 2000). Occasionally, during the evaluation of a Middle Eastern patient for another medical condition, microcytosis, anemia, or another anomaly is discovered that raises the possibility of an RBC disorder (Table 1). Unexplained anemia or polycythemia, microcytosis or macrocytosis (especially macrocytosis due to reticulocytosis), or biochemical evidence of hemolysis (elevated levels of indirect bilirubin, lactate dehydrogenase, aspartate aminotransferase, etc) can all be clues to the presence of abnormal erythrocytes. Unexplained growth retardation, splenomegaly or hyposplenism, paradoxical results on assays for glycosylated hemoglobin,
      • Schnedl WJ
      • Trinker M
      • Lipp RW
      HbA1c determination in patients with hemoglobinopathies [letter].
      hematuria, isosthenuria, and evidence of recurrent vaso-occlusive episodes (bone or abdominal pain, priapism, digital infarction, etc) are all nonspecific signs and symptoms that may suggest a hemoglobinopathy in the appropriate clinical setting. A hemolytic episode after starting a drug known to precipitate hemolysis in G6PD-deficient patients should raise strong suspicion of this enzyme deficiency.
      Table 1Clinical and Laboratory Findings That May Raise Concern About the Presence of a Red Blood Cell Disorder
      • Anemia of any degree
      • Polycythemia
      • Microcytosis (with or without anemia), especially with normal iron studies and red blood cell distribution width
      • Macrocytosis (especially due to reticulocytosis)
      • Target cells or basophilic stippling
      • Evidence of hemolysis, especially during an infection or after administration of an oxidative drug
        • Elevated lactate dehydrogenase
        • Elevated indirect (unconjugated) bilirubin
        • Elevated aspartate aminotransferase
        • Decreased haptoglobin
        • Hemoglobinuria or hemosiderinuria
        • Bilirubin cholelithiasis
      • Hematuria or isosthenuria
      • Splenomegaly and/or hyposplenism (including indirect evidence such as Howell-Jolly inclusions on a peripheral blood smear)
      • Paradoxical or implausible glycosylated hemoglobin measurements
      • Growth retardation
      • Unexplained vaso-occlusive episodes
        • Bone pain or avascular necrosis of bone
        • Colicky abdominal pain
        • Priapism
        • Retinal infarction and vitreous hemorrhage
        • Digital ischemia and dactylitis (sometimes mistaken for arthritis)
      Although the more severe RBC disorders are often diagnosed in the patients’ native countries, patients with milder RBC variants may arrive in the West without foreknowledge of the diagnosis. Medical care in many areas of the Middle East is excellent, but mild anemia is extremely common as a result of the high prevalence of iron deficiency. Therefore, mild anemia or microcytosis may not engender a high level of concern.

      SPECIAL CONCERNS WITH RESPECT TO MIDDLE EASTERN POPULATIONS

      In common parlance, the term Middle East is sometimes used nonspecifically. The Encyclopaedia Britannica states, “The term Middle East has come to be applied to the lands around the southern and eastern shores of the Mediterranean Sea, extending from Morocco to the Arabian Peninsula and Iran and sometimes beyond.” The Britannica definition is similar to that of the US State Department designation, “Middle East and North African Region,” which includes Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, United Arab Emirates, and Yemen. With the addition of Cyprus, Turkey, and Sudan, the State Department definition is the one used in this article (Figure 1).
      Figure thumbnail gr1
      Figure 1The Middle East, as defined in this article.
      The region has traditionally been divided into a western zone (the Maghrib, which encompasses North Africa west of Egypt) and an eastern zone (the Mashriq, extending from Egypt to Iran). The World Health Organization's Eastern Mediterannean Region includes most of the states in the Mashriq and some in the Maghrib. Table 2 shows some data on the prevalence of hemoglobinopathies in the Eastern Mediterannean Region. The World Health Organization estimates that approximately 5% of the population in the Eastern Mediterannean Region have a hemoglobin disorder.
      • Angastiniotis M
      • Modell B
      Global epidemiology of hemoglobin disorders.
      There is extensive local variation within the region, however.
      Table 2Percentage of the Population in the World Health Organization Eastern Mediterranean Region With an Abnormal Hemoglobin
      These figures include thalassemias and hemoglobinopathies but not enzymopathies (such as G6PD deficiency, which affects tens of millions of people) or membrane disorders. Numbers rounded to the nearest whole percent. Data derived from Angastiniotis and Modell.16
      Proportion of populationCountry
      >10%Cyprus (17%), Bahrain (13%)
      6%-10%Saudi Arabia, Morocco, Sudan, Iraq, Oman, Qatar, Syria, Yemen
      4%-6%Tunisia, United Arab Emirates, Pakistan, Libya, Iran, Kuwait, Lebanon
      <4%Jordan, Afghanistan, Egypt, Ethiopia
      * These figures include thalassemias and hemoglobinopathies but not enzymopathies (such as G6PD deficiency, which affects tens of millions of people) or membrane disorders. Numbers rounded to the nearest whole percent. Data derived from Angastiniotis and Modell.
      • Angastiniotis M
      • Modell B
      Global epidemiology of hemoglobin disorders.
      Certain regional cultural and geographic considerations markedly affect the prevalence and natural history of RBC disorders.
      • Kamel K
      Hemoglobin variants in the Middle East.
      Consanguinity is common in some regions of the Middle East. Depending on the area studied, between 20% and 70% of Middle Eastern families are consanguineous.
      • Hoodfar E
      • Teebi AS
      Genetic referrals of Middle Eastern origin in a Western city: inbreeding and disease profile.
      The practice is ancient and serves to keep property within families. In addition, populations around oases are often small and isolated, and this may favor consanguinity. First-cousin marriages are traditional.
      • el-Hazmi MA
      • al-Swailem AR
      • Warsy AS
      • al-Swailem AM
      • Sulaimani R
      • al-Meshari AA
      Consanguinity among the Saudi Arabian population.
      Consanguinity increases the frequency of homozygosity for autosomal recessive conditions
      • Hoodfar E
      • Teebi AS
      Genetic referrals of Middle Eastern origin in a Western city: inbreeding and disease profile.
      and is thought to be responsible for some of the morbidity from severe ×-thalassemia.
      • Basson PM
      Genetic disease and culture patterns in Lebanon.
      The climate in the Middle East can be extreme. The daily high temperature in certain areas of the Arabian Peninsula can reach 54×C (130×F) for extended periods. In some areas, no rain at all may fall between April and October. The mean daily high temperature in Kuwait can reach 47.8×C during the summer months.
      • Ibrahim AS
      Relationship between meteorological changes and occurrence of painful sickle cell crises in Kuwait.
      Kuwait.
      Such conditions favor dehydration, which increases the likelihood of sickling crises in patients with sickle cell anemia. There is a relationship between the frequency of sickle cell crises in Kuwait and meteorological conditions.
      • Ibrahim AS
      Relationship between meteorological changes and occurrence of painful sickle cell crises in Kuwait.
      Infections that are rare in the West are common in certain areas of the Middle East. Malaria, schistosomiasis, and Old World hookworm parasites contribute to anemia and may obscure the presence of hemoglobin disorders. Thalassemias, sickle hemoglobin, and G6PD deficiency are protective against falciparum malaria, and the geographic distribution of these conditions parallels the distribution of Plasmodium falciparum.
      • Ruwende C
      • Hill A
      Glucose-6-phosphate dehydrogenase deficiency and malaria.
      • Bienzle U
      • Ayeni O
      • Lucas AO
      • Luzzatto L
      Glucose-6-phosphate dehydrogenase and malaria: greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant.
      • Tse WT
      • Lux SE
      Red blood cell membrane disorders.
      • el-Hazmi MA
      Haemoglobinopathies, thalassaemias and enzymopathies in Saudi Arabia: the present status.
      • Roth Jr, EF
      • Raventos-Suarez C
      • Rinaldi A
      • Nagel RL
      Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum.
      Iron deficiency is widespread and may complicate the hematologic picture by affecting hemoglobin electrophoresis results and RBC indices.
      The ethnic makeup of some Middle Eastern nations is complex.
      • Kamel K
      Hemoglobin variants in the Middle East.
      The population of some of the oil-producing Gulf states now comprises more immigrant workers than native Arabs. In the United Arab Emirates, for example, only 20% of the 1.8 million residents are citizens of the Emirates; the rest of the population consists of Arabs from other countries, Filipinos, Pakistanis, and Indians.
      Although this might lead to a more diverse set of erythrocyte genes locally, the more wealthy native populations of such nations are most likely to seek medical care in the West.

      G6PD AND RBC ENZYMOPATHIES

      The story of RBC enzyme abnormalities worldwide is overwhelmingly the story of G6PD deficiency. This is especially true in the Middle East. Pyruvate kinase deficiency, the most common enzyme-related cause of hereditary nonspherocytic anemia, appears to be quite rare in the Middle East.
      • Beutler E
      • Gelbart T
      Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population.
      • Karadsheh NS
      Pyruvate kinase (PK) deficiency in Jordan.
      Although many other human erythrocyte enzyme disorders exist, all are much less common than G6PD deficiency, and some are found in only a single patient or family.
      • Prchal JT
      • Gregg XT
      Red cell enzymopathies.
      • el-Hazmi MA
      • Al-Swailem AR
      • Al-Faleh FZ
      • Warsy AS
      Frequency of glucose-6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population.
      Unlike most RBC enzymes, G6PD is X linked. In fact, studies of G6PD established the fact of X chromosome mosaicism in women.
      • Beutler E
      The genetics of glucose-6-phosphate dehydrogenase deficiency.
      • Beutler E
      • Yeh M
      • Fairbanks VF
      The normal human female as a mosaic of X-chromosome activity: studies using the gene for G-6-PD-deficiency as a marker.
      Males are most likely to be affected by G6PD deficiency, but chance inactivation of the normal X chromosome has led to equally severe G6PD deficiency in females.
      • Kaplan M
      • Beutler E
      • Vreman HJ
      • et al.
      Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes.
      An important “housekeeping” enzyme, G6PD helps protect RBCs from oxidative stress. It performs this function by catalyzing the initial step in a series of critical oxidation-reduction reactions: the conversion of oxidized nicotinamide adenine dinucleotide phosphate (NADP+) to its reduced form, NADPH. NADPH maintains glutathione in a reduced state, which in turn keeps sulfhydryl groups on hemoglobin and other proteins in a reduced state by preventing the formation of disulfide bonds. This housekeeping function is critically important to prevent hemoglobin precipitation and hemolysis. Hemoglobin precipitated in this way may form a Heinz body, an erythrocyte inclusion that is detected by staining with crystal violet.
      Worldwide, G6PD deficiency affects hundreds of millions of people.
      • Beutler E
      Glucose-6-phosphate dehydrogenase deficiency.
      • Beutler E
      G6PD: population genetics and clinical manifestations.
      Some areas in the Middle East have an extremely high prevalence of G6PD deficiency. The prevalence is 62% among male Kurdish Jews,
      • Szeinberg A
      Investigation of genetic polymorphic traits in Jews: a contribution to the study of population genetics.
      24% among male Bahrainis,
      • Angastiniotis M
      • Modell B
      • Englezos P
      • Boulyjenkov V
      Prevention and control of haemoglobinopathies.
      13% among male Saudis,
      • Gelpi AP
      Glucose-6-phosphate dehydrogenase deficiency in Saudi Arabia: a survey.
      and 7% to 10% among male Cypriots.
      • Angastiniotis M
      • Modell B
      • Englezos P
      • Boulyjenkov V
      Prevention and control of haemoglobinopathies.
      More than 300 different variants of the enzyme have been discovered. Many of these variants have no hematological consequences.
      • Beutler E
      • Vulliamy T
      • Luzzatto L
      Hematologically important mutations: glucose-6-phosphate dehydrogenase.
      Commonly, however, intermittent episodes of hemolytic anemia with or without chronic hemolysis may be associated with G6PD deficiency. Hemolytic crises may be precipitated by oxidative drugs or by infections such as hepatitis and pneumonitis.
      • Mengel CE
      • Metz E
      • Yancey WS
      Anemia during acute infections: role of glucose-6-phosphate dehydrogenase deficiency in Negroes.
      • Beutler E
      G6PD deficiency.
      Some have hypothesized that the release of oxidative enzymes by neutrophils during acute infections may contribute to hemolysis, but this remains speculative.
      • Beutler E
      G6PD deficiency.
      In susceptible persons, particularly in the Middle East, the ingestion of fava beans (especially fresh spring beans
      • Sartori E
      On the pathogenesis of favism.
      ) is also associated with severe hemolysis and prostration that has been fatal in up to 10% of cases.
      • Jandl JH
      Heinz body hemolytic anemias.
      Although much concern has focused on drug-induced hemolysis in G6PD-deficient patients, infections are probably the most common precipitant of hemolysis.
      • Burka ER
      • Weaver III, Z
      • Marks PA
      Clinical spectrum of hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency.
      Many misleading case reports have been published in which an infected G6PD-deficient patient developed hemolysis after receiving a drug, and the drug was blamed.
      • Beutler E
      Glucose-6-phosphate dehydrogenase deficiency.
      Although the list of drugs and chemicals alleged to precipitate hemolysis in G6PD-deficient patients is long, relatively few of these agents are both still marketed and definitely associated with hemolytic crises (Table 3). Other drugs are clearly safe to give to G6PD-deficient patients, such as aspirin and acetaminophen in standard doses. Some drugs that cause hemolysis in experimental assays are probably safe in the clinical setting, such as trimethoprim-sulfamethoxazole.
      • Markowitz N
      • Saravolatz LD
      Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient population.
      The small subset of drugs linked to clinically important hemolysis in G6PD-deficient patients should be used with caution in patients who come from ethnic groups with a high prevalence of this condition, unless the enzyme disorder has been ruled out.
      Table 3A Select List of Currently Available Drugs and Chemicals to Avoid in Patients Who May Have G6PD Deficiency
      • Methylene blue
        • Prchal JT
        • Gregg XT
        Red cell enzymopathies.
      • Naphthalene (eg, in mothballs)
        • Todisco V
        • Lamour J
        • Finberg L
        Hemolysis from exposure to naphthalene mothballs [letter].
      • Nitrofurantoin (Macrodantin, Macrobid)
        • Gilbert DN
        • Moellering Jr, RC
        • Sande MA
      • Phenazopyridine (Pyridium)
        • Tishler M
        • Abramov A
        Phenazopyridine-induced hemolytic anemia in a patient with G6PD deficiency [letter].
      • Primaquine
        • Beutler E
        The hemolytic effect of primaquine and related compounds: a review.
      • Sulfonamides and sulfones (eg, sulfamethoxazole, dapsone),
        • Gilbert DN
        • Moellering Jr, RC
        • Sande MA
        but see also Markowitz & Saravolatz
        • Markowitz N
        • Saravolatz LD
        Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient population.
      • Toluidine blue and trinitrotoluene (TNT)
      A G6PD missense genetic mutation that leads to the “Mediterranean variant” of G6PD deficiency is very common throughout the Middle East and the Mediterranean basin.
      • Beutler E
      G6PD: population genetics and clinical manifestations.
      The half-life of the Mediterranean variant enzyme in RBCs is very short (several hours) in comparison with several other common G6PD variants (eg, the A–type that is associated with hemolysis in sub-Saharan Africa has a half-life of 13 days) and normal G6PD (a half-life of 60 days).
      • Jandl JH
      Heinz body hemolytic anemias.
      • Piomelli S
      • Corash LM
      • Davenport DD
      • Miraglia J
      • Amorosi EL
      In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency.
      Since enucleated RBCs cannot synthesize new G6PD, all except the very youngest RBCs of affected Middle Eastern patients are severely deficient in G6PD and therefore vulnerable to oxidative destruction.
      The diagnosis is easily made by assay of conversion of NADP+ to NADPH, but false negatives may be seen in some groups (eg, African Americans, who commonly have the A– enzyme) during the weeks following an acute hemolytic episode. This phenomenon occurs because the senescent RBCs most deficient in G6PD are also those most likely to be destroyed by an oxidative stress, leaving a select population of younger RBCs with anomalously high G6PD levels. If hemolysis due to G6PD deficiency is suspected in an African American, it is best to wait several weeks before pursuing laboratory testing. However, this does not normally apply to Middle Eastern patients, who have the much more severe Mediterranean variant of G6PD deficiency. Supportive care during hemolytic crises (including the transfusion of healthy G6PD-containing erythrocytes if necessary) and avoidance of fava beans and other oxidative stresses are appropriate management strategies for G6PD-deficient patients.

      THE THALASSEMIAS

      The thalassemias are a diverse group of disorders that result from any of the numerous genetic mutations associated with decreased synthesis of 1 or more globin chains. The name thalassemia reflects a former belief that the disorder affected only the people of the Mediterranean Sea region: the term is derived from the Greek words ?α?αssα (“thalassa”: sea, referring to the Mediterranean) and α?µα (“[h]aima”: blood). However, thalassemia has a worldwide equatorial distribution. The first description of severe thalassemia as a unique disorder discernible from the other anemias of childhood was by Thomas Cooley, a pediatrician in Detroit, Mich and a colleague, Pearl Lee.
      • Cooley TB
      • Lee P
      Series of cases of splenomegaly in children with anemia and peculiar bone change.
      The term Cooley anemia is still commonly used to describe homozygous ×-thalassemia.
      Humans have 4 α globin genes on chromosome 16 and 2 × globin genes on chromosome 11, so symptomatic α-thalassemia is rarer than ×-thalassemia. This is particularly true in the Middle East, where symptomatic α-thalassemia is encountered only sporadically, but ×-thalassemia is widespread. Homozygous ×-thalassemia and the severe forms of α-thalassemia are usually diagnosed at birth or in early childhood. However, the milder forms of α-thalassemia and some heterozygous ×-thalassemia mutations may escape detection until adulthood. The clinical and laboratory findings classically associated with the various thalassemias are detailed in Table 4, Table 5.
      Table 4Typical Clinical and Laboratory Manifestations of α-Thalassemia
      State (No. of deleted genes)Effective genotype
      The α symbol represents the presence of a functional globin gene, while the minus sign (−) symbolizes a dysfunctional gene. The absence of a functional globin gene may be due to simple deletion or to the Saudi polyadenylation mutation described in the text.
      Clinical manifestationsErythrocyte findingsElectrophoretic findings
      Hemoglobin A2 molecule contains 2 α globin chains and 2 δ chains and normally represents 2.0% to 3.3% of the total hemoglobin. Hemoglobin H consists of 4 β globin chains and is unstable and inefficient at carrying oxygen to tissues. Hemoglobin Bart's represents 4 γ chains and is almost completely ineffective at delivering oxygen.
      α-Thalassemia-2 trait (silent carrier state) (1)αα/α–None; detectable only by genetic analysisNone or mild microcytosisUsually normal; hemoglobin A2 may be low
      α-Thalassemia-1 trait (2)α–/α– or αα/−−Usually noneMild microcytosis, with or without mild anemiaMay be normal or hemoglobin A2 may be low
      Hemoglobin H disease (3)α–/––Moderate hemolytic anemiaMarkedly microcytic anemia with many target cellsHemoglobin H
      Hemoglobin Bart's and hydrops fetalis (4)– –/– –Catastrophic; death in utero or early infancySevere anemia, abundant nucleated red cellsHemoglobin Bart's
      * The α symbol represents the presence of a functional globin gene, while the minus sign (−) symbolizes a dysfunctional gene. The absence of a functional globin gene may be due to simple deletion or to the Saudi polyadenylation mutation described in the text.
      Hemoglobin A2 molecule contains 2 α globin chains and 2 δ chains and normally represents 2.0% to 3.3% of the total hemoglobin. Hemoglobin H consists of 4 β globin chains and is unstable and inefficient at carrying oxygen to tissues. Hemoglobin Bart's represents 4 γ chains and is almost completely ineffective at delivering oxygen.
      Table 5Typical Clinical and Laboratory Manifestations of β-Thalassemia Phenotypes
      The β-thalassemias represent a spectrum of disease, and strict classification into one syndrome or another is sometimes not possible.
      • Asymptomatic states (usually result from a single heterozygous β globin mutation)
        • Silent carrier state
          • Not anemic, but may have mild microcytosis and occasional target cells
          • Increased levels of hemoglobin A2 are seen on electrophoresis (usually >4%)
        • β-Thalassemia trait
          • Anemia is mild or absent, but hypochromia and microcytosis are present
          • Target cells and basophilic stippling are seen on peripheral blood smear
          • Increased levels of hemoglobin A are seen on electrophoresis (usually >4%)
      • Symptomatic states (usually result from compound heterozygosity or homozygosity)
        • β-Thalassemia intermedia
          • Come to attention later in childhood than those with β-thalassemia major; growth may be normal or mildly retarded
          • Moderate hypochromic microcytic anemia, splenomegaly
          • Prominent target cells on blood smears
          • Skeletal changes from marrow space expansion may be seen but are mild
          • May be transfused but not transfusion dependent
        • β-Thalassemia major (Cooley anemia)
          • Patients come to medical attention very early in life; can be catastrophic
          • Severe growth retardation and prominent skeletal changes including facial malformation
          • Severe hypochromic microcytic anemia with jaundice and splenomegaly
          • Ubiquitous target cells, basophilic stippling, and nucleated red cells
          • Transfusion dependent
      * The β-thalassemias represent a spectrum of disease, and strict classification into one syndrome or another is sometimes not possible.
      The α-thalassemias are most often the result of simple deletions of α globin genes. There may be deletion of 1 or 2 α globin genes on a single allele of chromosome 16. Deletion of 3 or 4 of the α globin genes is quite uncommon in Middle Eastern populations. This is because individuals in this region commonly have the “α–” gene haplotype (ie, 1 α gene deletion on 1 allele of chromosome 16) and only rarely carry the “– –” gene haplotype (2 α gene deletions on the same allele of chromosome 16). Inheritance of the latter is usually necessary to develop the 2 most serious forms of α-thalassemia.
      • Whitelaw E
      • Pagnier J
      • Verdier G
      • Henni T
      • Godet J
      • Williamson R
      Mapping the alpha-globin genes in an Algerian HbH patient and his family.
      However, hemoglobin H disease due to dysfunctional α globin genes occurs with some frequency in eastern Saudi Arabia. This is because of a polyadenylation signal mutation found in the region that renders 1 copy of the α globin gene nonfunctional; the other allele on the same chromosome may be deleted.
      • Pressley L
      • Higgs DR
      • Clegg JB
      • Perrine RP
      • Pembrey ME
      • Weatherall DJ
      A new genetic basis for hemoglobin-H disease.
      When these 2 mutations are coinherited with 1 of the more common “α–” alleles, hemoglobin H disease results, usually manifest as a chronic, microcytic hemolytic anemia.
      The ×-thalassemias are a heterogeneous group of disorders both clinically and genetically, making a simple classification difficult.
      • Olivieri NF
      The -thalassemias [published correction appears in N Engl J Med. 1999;341:1407].
      Individuals inherit 1 × globin gene from each parent, so only 4 general genetic patterns are possible: 2 normal genes; 1 normal gene and 1 abnormal gene (simple heterozygous state); 2 different abnormal genes (compound heterozygous state); or 2 copies of the same abnormal gene (homozygous state). However, at the genetic level, there are many different × globin mutations leading to thalassemia. In contrast to α-thalassemia, simple deletions are rare in ×-thalassemia; instead, messenger RNA splicing errors, promoter lesions, and nonsense mutations leading to premature chain termination are frequent.
      • Weatherall DJ
      The thalassemias.
      This genotypic heterogeneity leads to a very diverse set of phenotypes, compounded by the coinheritance of other genes affecting globin synthesis or its consequences. Because of this, the clinical manifestations seen in patients who have identical × globin gene mutations (eg, siblings) may be quite different.
      The majority of Middle Eastern patients with ×-thalassemia detected incidentally on medical visits to the West are simple heterozygotes, ie, they have ×-thalassemia trait. More severe thalassemia is inevitably detected early in life.
      The major danger of an undetected minor thalassemia mutation is that it may be mistaken for iron deficiency. Numerous cases have been reported of patients who were prescribed long-term iron supplementation for presumed iron deficiency who instead had thalassemia; a few of these patients have developed complications of iron overload, including liver failure and diabetes.
      • Van der Weyden MB
      • Fong H
      • Hallam LJ
      • Harrison C
      Red cell ferritin and iron overload in heterozygous beta-thalassemia.
      Patients with thalassemia trait have also been subject to unnecessary endoscopic evaluations in search of a gastrointestinal bleeding source. The use of various “discriminant functions” based on RBC indices may help exclude iron deficiency,
      • Eldibany MM
      • Totonchi KF
      • Joseph NJ
      • Rhone D
      Usefulness of certain red blood cell indices in diagnosing and differentiating thalassemia trait from iron-deficiency anemia [published correction appears in Am J Clin Pathol. 1999;112:428].
      but specificity and sensitivity are low. In addition, iron deficiency and thalassemia mutations often coexist, compounding the difficulty. Careful analysis of iron studies (especially measurement of the serum ferritin concentration), RBC indices, and hemoglobin electrophoresis results is critical. A low serum ferritin concentration is diagnostic of iron deficiency but does not rule out concomitant thalassemia. A brief trial of iron therapy followed by retesting or direct genetic analysis of globin genes may be required for definitive diagnosis.
      No treatment is usually required for the milder thalassemias. The more severe forms often require aggressive management with RBC transfusions, chelation of excess iron, other supportive care, and occasionally bone marrow transplantation.
      • Olivieri NF
      The -thalassemias [published correction appears in N Engl J Med. 1999;341:1407].
      Such care may be best coordinated within the context of a long-term relationship with a physician who has expertise in treating severe hemoglobinopathies. Lack of access to a safe blood supply and modern medical care is associated with severe morbidity among thalassemia patients in some parts of the world.
      • Mohamed N
      • Jackson N
      Severe thalassaemia intermedia: clinical problems in the absence of hypertransfusion.

      SICKLE CELL SYNDROMES

      The sickle cell syndromes are most common in patients of Central and West African descent. However, 2 other areas of the world have a high prevalence of the sickle mutation (hemoglobin S): the Arabian Peninsula and the Indian subcontinent. The mutation also occurs throughout the Mediterranean littoral. Haplotype analysis has shown that the mutation found commonly in Saudi Arabia arose separately from the African mutations.
      • Kulozik AE
      • Wainscoat JS
      • Serjeant GR
      • et al.
      Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation.
      The mutations in Africa and Arabia were probably selected for the same reason: hemoglobin S–containing erythrocytes are relatively resistant to P falciparum.
      • el-Hazmi MA
      Haemoglobinopathies, thalassaemias and enzymopathies in Saudi Arabia: the present status.
      In certain Middle Eastern populations, such as Arabs living within the state of Israel,
      • Eliakim R
      • Rachmilewitz EA
      Hemoglobinopathies in Israel.
      Saudi Arabian oasis dwellers,
      • Perrine RP
      • John P
      • Pembrey M
      • Perrine S
      Sickle cell disease in Saudi Arabs in early childhood.
      and Eti-Turks (an Arabic-speaking group in southern Turkey),
      • Aluoch JR
      • Kilinc Y
      • Aksoy M
      • et al.
      Sickle cell anaemia among Eti-Turks: haematological, clinical and genetic observations.
      hemoglobin S may be found in as much as 25% of the population. Hemoglobin S can be found in more than 30% of inhabitants of certain villages in Greece and Cyprus.
      • Campbell JJ
      • Oski FA
      Sickle cell anemia in an American white boy of Greek ancestry.
      • Deliyannis GA
      • Tavlarakis N
      Compatibility of sickling with malaria.
      Rare cases of homozygous sickle cell disease seen in English and North American “white” populations may reflect gene drift from Middle Eastern and African populations.
      • Campbell JJ
      • Oski FA
      Sickle cell anemia in an American white boy of Greek ancestry.
      • Noronha PA
      • Honig GR
      Sickle cell anemia in two White American children: essential laboratory criteria for diagnosis.
      • Boussiou M
      • Loukopoulos D
      • Christakis J
      • Fessas P
      The origin of the sickle mutation in Greece: evidence from beta S globin gene cluster polymorphisms.
      The clinical manifestations of Arabic patients with homozygous hemoglobin S are usually milder than those in patients with African hemoglobin S mutations, but cases with severe manifestations do exist.
      • el Mouzan MI
      • al Awamy BH
      • al Torki MT
      Clinical features of sickle cell disease in eastern Saudi Arab children.
      • Al-Awamy B
      • Wilson WA
      • Pearson HA
      Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia.
      • Wood WG
      • Pembrey ME
      • Serjeant GR
      • Perrine RP
      • Weatherall DJ
      Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin.
      • Kamel K
      Heterogeneity of sickle cell anaemia in Arabs: review of cases with various amounts of fetal haemoglobin.
      The milder manifestations in Arabic patients are in part due to the frequent coinheritance of elevated levels of hemoglobin F, which inhibits the polymerization of hemoglobin S.
      • el Mouzan MI
      • al Awamy BH
      • al Torki MT
      Clinical features of sickle cell disease in eastern Saudi Arab children.
      • Wood WG
      • Pembrey ME
      • Serjeant GR
      • Perrine RP
      • Weatherall DJ
      Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin.
      • Kulozik AE
      • Thein SL
      • Kar BC
      • Wainscoat JS
      • Serjeant GR
      • Weatherall DJ
      Raised Hb F levels in sickle cell disease are caused by a determinant linked to the beta globin gene cluster.
      Some Arabic patients with homozygous hemoglobin S may even have preserved splenic function,
      • Al-Awamy B
      • Wilson WA
      • Pearson HA
      Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia.
      especially those who coinherit a variant of α-thalassemia.
      • Perrine RP
      • John P
      • Pembrey M
      • Perrine S
      Sickle cell disease in Saudi Arabs in early childhood.
      Nonetheless, sickle cell anemia causes much morbidity in affected Arabic patients.
      There are several compound heterozygous conditions in which hemoglobin S is coinherited with another abnormal hemoglobin gene. Hemoglobin S C disease, for instance, is seen particularly in North Africa and results from inheritance of hemoglobin C from one parent and hemoglobin S from the other.
      • Chami B
      • Blouquit Y
      • Bardakdjian-Michau J
      • et al.
      Hemoglobin variants in North Africa.
      The clinical effects of this combination are similar to homozygous hemoglobin S disease but are usually somewhat less severe, and loss of splenic function occurs later and is more variable.
      • Sills RH
      • Oski FA
      RBC surface pits in the sickle hemoglobinopathies.
      Splenomegaly is common during early decades of life. Proliferative retinopathy is more common and more severe in this group,
      • Goldberg MF
      Natural history of untreated proliferative sickle retinopathy.
      and aseptic necrosis of the hip is also common but occurs later in life.
      • Milner PF
      • Kraus AP
      • Sebes JI
      • et al.
      Sickle cell disease as a cause of osteonecrosis of the femoral head.
      Hemoglobin S ×-thalassemia has a wide variety of clinical presentations, depending on the level of synthesis of the thalassemic × globin chain. The severity ranges from moderate to severe. Hemoglobin S O Arab disease, despite its name, is rarely found in Middle Eastern patients.
      • Kamel K
      Hemoglobin variants in the Middle East.
      In the United States it occurs principally in African Americans. It is clinically indistinguishable from homozygous hemoglobin S disease, as hemoglobin O Arab copolymerizes with hemoglobin S.
      • Zimmerman SA
      • O'Branski EE
      • Rosse WF
      • Ware RE
      Hemoglobin S/OArab: thirteen new cases and review of the literature.
      Other less common heterozygous conditions also exist.
      The management of the sickling syndromes is in evolution and must be individualized.
      • Steinberg MH
      Management of sickle cell disease.
      Even heterozygotes should avoid the most strenuous physical conditioning regimens, such as military boot camp, which may be life-threatening.
      • Kark JA
      • Posey DM
      • Schumacher HR
      • Ruehle CJ
      Sickle-cell trait as a risk factor for sudden death in physical training.
      Some homozygous patients such as those with a very high level of fetal hemoglobin may need little more than long-term folate supplementation, but others may have a catastrophic course and require aggressive supportive care, frequent hospitalizations, generous use of narcotics for pain relief, and transfusions. Pulmonary symptoms in particular must be addressed urgently and aggressively, as the acute chest syndrome remains a major cause of death in this group.
      • Vichinsky EP
      • Styles LA
      • Colangelo LH
      • Wright EC
      • Castro O
      • Nickerson B
      • Cooperative Study of Sickle Cell Disease
      Acute chest syndrome in sickle cell disease: clinical presentation and course.
      Hydroxyurea can be used to raise the level of fetal hemoglobin and decrease the number of painful sickle crises by approximately 50%.
      • Charache S
      • Terrin ML
      • Moore RD
      • Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
      • et al.
      Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
      As with the severe thalassemia syndromes, the care of these patients may best be coordinated within the context of a long-term relationship with a physician who has expertise in treating severe hemoglobinopathies.

      RBC MEMBRANE DISORDERS

      The RBC membrane disorders are uncommon in the Middle East. The major inherited RBC membrane abnormalities worldwide are hereditary spherocytosis and hereditary elliptocytosis. Quite rare are hereditary pyropoikilocytosis (which is biochemically related to hereditary elliptocytosis and is sometimes seen in the same families) and hereditary stomatocytosis.
      • Tse WT
      • Lux SE
      Red blood cell membrane disorders.
      These conditions may be associated with chronic hemolytic anemia of varying severity, depending on the specific genetic mutation.
      Hereditary spherocytosis is most common in Northern Europeans, but it also occurs in North Africa.
      • Zerhouni F
      • Guetarni D
      • Henni T
      • Colonna P
      Occurrence and characteristics of hereditary spherocytosis in Algeria.
      Hereditary elliptocytosis is found at a low level in all ethnic groups. Hereditary pyropoikilocytosis is most common in persons of sub-Saharan African descent and is rare in other ethnic groups. Occasional cases have been seen in the Middle East.
      • Mallouh A
      • Sa'di AR
      • Ahmad MS
      • Salamah M
      Hereditary pyropoikilocytosis: report of two cases from Saudi Arabia.
      Hereditary stomatocytosis and hereditary xerocytosis are quite rare and have been seen in individuals in many different populations.

      OTHER HEMOGLOBIN DISORDERS

      Although many other hemoglobin disorders have been reported in patients from the Middle East, most are found in very small groups of patients or single families and are likely to be of no consequence for primary care physicians. One possible exception is hemoglobin C, which is seen occasionally throughout the Mediterranean littoral. The heterozygous state for hemoglobin C is clinically silent (unless it is coinherited with hemoglobin S), and the homozygous state typically causes a mild chronic hemolytic anemia. The name of 1 abnormal hemoglobin, hemoglobin O Arab, suggests a Middle Eastern predominance, but this is misleading. Although it was first identified in an Egyptian and in a Palestinian, hemoglobin O Arab has been seen with frequency only in Eastern Europe. Its highest prevalence is among Bulgarians, and it is actually uncommon in Arab individuals.
      • Kamel K
      Hemoglobin variants in the Middle East.

      CONCLUSION

      It is important for Western clinicians to be aware of RBC disorders in Middle Eastern patients. G6PD deficiency and the thalassemias (especially heterozygous ×-thalassemia) are quite common in this group and must always be considered. Sickle cell disease is not limited to Central and West African populations but also occurs in the Arabian Peninsula. Erythrocyte membrane disorders, in contrast, are not a major concern in the Middle East.
      If a hemoglobinopathy or thalassemia is suspected, hemoglobin electrophoresis or chromatography is the test of choice. Known oxidative drugs should be avoided unless G6PD deficiency has been ruled out. By keeping these principles in mind, unnecessary complications and unfruitful diagnostic evaluations may be avoided.

      REFERENCES

        • Huisman THJ
        • Carver MFH
        • Efremov GD
        A Syllabus of Human Hemoglobin Variants. Sickle Cell Anemia Foundation, Augusta, Ga1996
      1. The thalassemia repository (9th ed; part II).
        Hemoglobin. 1998; 22: 287-310
        • Beutler E
        Glucose-6-phosphate dehydrogenase deficiency.
        N Engl J Med. 1991; 324: 169-174
        • Arya R
        • Layton DM
        • Bellingham AJ
        Hereditary red cell enzymopathies.
        Blood Rev. 1995; 9: 165-175
        • Keitt AS
        Diagnostic strategy in a suspected red cell enzymopathy.
        Clin Haematol. 1981; 10: 3-30
        • Angastiniotis M
        • Modell B
        • Englezos P
        • Boulyjenkov V
        Prevention and control of haemoglobinopathies.
        Bull World Health Organ. 1995; 73: 375-386
        • US Office of Disease Prevention and Health Promotion
        • Office of Public Health and Science
        • US Department of Health and Human Services
        Clinician's Handbook of Preventive Services: Put Prevention Into Practice. 2nd ed. International Medical Publishing, Inc, McLean, Va1998: 183-186
        • Canadian Task Force on the Periodic Health Examination
        The periodic health examination.
        Can Med Assoc J. 1979; 121: 1193-1254
        • Goldbloom RB
        Screening for hemoglobinopathies in Canada.
        in: Canadian Task Force on the Periodic Health Examination The Canadian Guide to Clinical Preventive Health Care. Minister of Supply and Services, Ottawa, Ontario1994: 205-218
        • American College of Obstetricians and Gynecologists
        Guidelines for Women's Health Care. American College of Obstetricians and Gynecologists, Washington, DC1996
        • Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists
        ACOG technical bulletin: hemoglobinopathies in pregnancy: No. 220—February 1996 (replaces No. 185, October 1993).
        Int J Gynaecol Obstet. 1996; 53: 184-194
        • US Preventive Services Task Force
        Guide to Clinical Preventive Services. 2nd ed. Williams & Wilkins, Baltimore, Md1996: 231-246
        • American Academy of Family Physicians
        • Commission of Public Health and Scientific Affairs
        Age Charts for Periodic Health Examination. American Academy of Family Physicians, Kansas City, Mo1994
        • Cao A
        Results of programmes for antenatal detection of thalassemia in reducing the incidence of the disorder.
        Blood Rev. 1987; 1: 169-176
        • Schnedl WJ
        • Trinker M
        • Lipp RW
        HbA1c determination in patients with hemoglobinopathies [letter].
        Diabetes Care. 1999; 22: 368-369
        • Angastiniotis M
        • Modell B
        Global epidemiology of hemoglobin disorders.
        Ann N Y Acad Sci. 1998; 850: 251-269
        • Kamel K
        Hemoglobin variants in the Middle East.
        in: Winter WP Hemoglobin Variants in Human Populations. Vol 2. CRC Press, Boca Raton, Fla1987: 45-64
        • Hoodfar E
        • Teebi AS
        Genetic referrals of Middle Eastern origin in a Western city: inbreeding and disease profile.
        J Med Genet. 1996; 33: 212-215
        • el-Hazmi MA
        • al-Swailem AR
        • Warsy AS
        • al-Swailem AM
        • Sulaimani R
        • al-Meshari AA
        Consanguinity among the Saudi Arabian population.
        J Med Genet. 1995; 32: 623-626
        • Basson PM
        Genetic disease and culture patterns in Lebanon.
        J Biosoc Sci. 1979; 11: 201-207
        • Ibrahim AS
        Relationship between meteorological changes and occurrence of painful sickle cell crises in Kuwait.
        Trans R Soc Trop Med Hyg. 1980; 74: 159-161
      2. Kuwait.
        in: 15th ed. Encyclopaedia Britannica. Vol 7. Encyclopaedia Britannica, Chicago, Ill1974: 50-51
        • Ruwende C
        • Hill A
        Glucose-6-phosphate dehydrogenase deficiency and malaria.
        J Mol Med. 1998; 76: 581-588
        • Bienzle U
        • Ayeni O
        • Lucas AO
        • Luzzatto L
        Glucose-6-phosphate dehydrogenase and malaria: greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant.
        Lancet. 1972; 1: 107-110
        • Tse WT
        • Lux SE
        Red blood cell membrane disorders.
        Br J Haematol. 1999; 104: 2-13
        • el-Hazmi MA
        Haemoglobinopathies, thalassaemias and enzymopathies in Saudi Arabia: the present status.
        Acta Haematol. 1987; 78: 130-134
        • Roth Jr, EF
        • Raventos-Suarez C
        • Rinaldi A
        • Nagel RL
        Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum.
        Proc Natl Acad Sci U S A. 1983; 80: 298-299
      3. Background Notes: United Arab Emirates. US Dept of State, Washington, DC1991
        • Beutler E
        • Gelbart T
        Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population.
        Blood. 2000; 95: 3585-3588
        • Karadsheh NS
        Pyruvate kinase (PK) deficiency in Jordan.
        Haematologica. 1993; 78: 80-83
        • Prchal JT
        • Gregg XT
        Red cell enzymopathies.
        in: Hoffman R Benz Jr, EJ Shattil SJ Hematology: Basic Principles and Practice. 3rd ed. Churchill Livingstone, New York, NY2000: 561-576
        • el-Hazmi MA
        • Al-Swailem AR
        • Al-Faleh FZ
        • Warsy AS
        Frequency of glucose-6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population.
        Hum Hered. 1986; 36: 45-49
        • Beutler E
        The genetics of glucose-6-phosphate dehydrogenase deficiency.
        Semin Hematol. 1990; 27: 137-164
        • Beutler E
        • Yeh M
        • Fairbanks VF
        The normal human female as a mosaic of X-chromosome activity: studies using the gene for G-6-PD-deficiency as a marker.
        Proc Natl Acad Sci U S A. 1962; 48: 9-16
        • Kaplan M
        • Beutler E
        • Vreman HJ
        • et al.
        Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes.
        Pediatrics. 1999; 104: 68-74
        • Beutler E
        G6PD: population genetics and clinical manifestations.
        Blood Rev. 1996; 10: 45-52
        • Szeinberg A
        Investigation of genetic polymorphic traits in Jews: a contribution to the study of population genetics.
        Isr J Med Sci. 1973; 9: 1171-1180
        • Gelpi AP
        Glucose-6-phosphate dehydrogenase deficiency in Saudi Arabia: a survey.
        Blood. 1965; 25: 486-493
        • Beutler E
        • Vulliamy T
        • Luzzatto L
        Hematologically important mutations: glucose-6-phosphate dehydrogenase.
        Blood Cells Mol Dis. 1996; 22: 49-56
        • Mengel CE
        • Metz E
        • Yancey WS
        Anemia during acute infections: role of glucose-6-phosphate dehydrogenase deficiency in Negroes.
        Arch Intern Med. 1967; 119: 287-290
        • Beutler E
        G6PD deficiency.
        Blood. 1994; 84: 3613-3636
        • Sartori E
        On the pathogenesis of favism.
        J Med Genet. 1971; 8: 462-467
        • Jandl JH
        Heinz body hemolytic anemias.
        in: Jandl JH Blood: Textbook of Hematology. 2nd ed. Little, Brown and Co, Boston, Mass1996: 503-518
        • Burka ER
        • Weaver III, Z
        • Marks PA
        Clinical spectrum of hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency.
        Ann Intern Med. 1966; 64: 817-825
        • Todisco V
        • Lamour J
        • Finberg L
        Hemolysis from exposure to naphthalene mothballs [letter].
        N Engl J Med. 1991; 325: 1660
        • Gilbert DN
        • Moellering Jr, RC
        • Sande MA
        The Sanford Guide to Antimicrobial Therapy, 1998. 28th ed. Antimicrobial Therapy, Inc, Vienna, Va1998
        • Tishler M
        • Abramov A
        Phenazopyridine-induced hemolytic anemia in a patient with G6PD deficiency [letter].
        Acta Hematol. 1983; 70: 208-209
        • Beutler E
        The hemolytic effect of primaquine and related compounds: a review.
        Blood. 1959; 14: 103-139
        • Markowitz N
        • Saravolatz LD
        Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient population.
        Rev Infect Dis. 1987; 9: S218-S229
        • Piomelli S
        • Corash LM
        • Davenport DD
        • Miraglia J
        • Amorosi EL
        In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency.
        J Clin Invest. 1968; 47: 940-948
        • Cooley TB
        • Lee P
        Series of cases of splenomegaly in children with anemia and peculiar bone change.
        Trans Am Pediatr Soc. 1925; 37: 29-30
        • Whitelaw E
        • Pagnier J
        • Verdier G
        • Henni T
        • Godet J
        • Williamson R
        Mapping the alpha-globin genes in an Algerian HbH patient and his family.
        Blood. 1980; 55: 511-516
        • Pressley L
        • Higgs DR
        • Clegg JB
        • Perrine RP
        • Pembrey ME
        • Weatherall DJ
        A new genetic basis for hemoglobin-H disease.
        N Engl J Med. 1980; 303: 1383-1388
        • Olivieri NF
        The -thalassemias [published correction appears in N Engl J Med. 1999;341:1407].
        N Engl J Med. 1999; 341: 99-109
        • Weatherall DJ
        The thalassemias.
        in: Stamatoyannopoulos G Nienhuis AW Majerus PW Varmus H The Molecular Basis of Blood Diseases. 2nd ed. WB Saunders Co, Philadelphia, Pa1994: 157-205
        • Van der Weyden MB
        • Fong H
        • Hallam LJ
        • Harrison C
        Red cell ferritin and iron overload in heterozygous beta-thalassemia.
        Am J Hematol. 1989; 30: 201-205
        • Eldibany MM
        • Totonchi KF
        • Joseph NJ
        • Rhone D
        Usefulness of certain red blood cell indices in diagnosing and differentiating thalassemia trait from iron-deficiency anemia [published correction appears in Am J Clin Pathol. 1999;112:428].
        Am J Clin Pathol. 1999; 111: 676-682
        • Mohamed N
        • Jackson N
        Severe thalassaemia intermedia: clinical problems in the absence of hypertransfusion.
        Blood Rev. 1998; 12: 163-170
        • Kulozik AE
        • Wainscoat JS
        • Serjeant GR
        • et al.
        Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation.
        Am J Hum Genet. 1986; 39: 239-244
        • Eliakim R
        • Rachmilewitz EA
        Hemoglobinopathies in Israel.
        Hemoglobin. 1983; 7: 479-485
        • Perrine RP
        • John P
        • Pembrey M
        • Perrine S
        Sickle cell disease in Saudi Arabs in early childhood.
        Arch Dis Child. 1981; 56: 187-192
        • Aluoch JR
        • Kilinc Y
        • Aksoy M
        • et al.
        Sickle cell anaemia among Eti-Turks: haematological, clinical and genetic observations.
        Br J Haematol. 1986; 64: 45-55
        • Campbell JJ
        • Oski FA
        Sickle cell anemia in an American white boy of Greek ancestry.
        Am J Dis Child. 1977; 131: 186-188
        • Deliyannis GA
        • Tavlarakis N
        Compatibility of sickling with malaria.
        BMJ. 1955; 2: 301-302
        • Noronha PA
        • Honig GR
        Sickle cell anemia in two White American children: essential laboratory criteria for diagnosis.
        Pediatrics. 1979; 63: 242-246
        • Boussiou M
        • Loukopoulos D
        • Christakis J
        • Fessas P
        The origin of the sickle mutation in Greece: evidence from beta S globin gene cluster polymorphisms.
        Hemoglobin. 1991; 15: 459-467
        • el Mouzan MI
        • al Awamy BH
        • al Torki MT
        Clinical features of sickle cell disease in eastern Saudi Arab children.
        Am J Pediatr Hematol Oncol. 1990; 12: 51-55
        • Al-Awamy B
        • Wilson WA
        • Pearson HA
        Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia.
        J Pediatr. 1984; 104: 714-717
        • Wood WG
        • Pembrey ME
        • Serjeant GR
        • Perrine RP
        • Weatherall DJ
        Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin.
        Br J Haematol. 1980; 45: 431-445
        • Kamel K
        Heterogeneity of sickle cell anaemia in Arabs: review of cases with various amounts of fetal haemoglobin.
        J Med Genet. 1979; 16: 428-430
        • Kulozik AE
        • Thein SL
        • Kar BC
        • Wainscoat JS
        • Serjeant GR
        • Weatherall DJ
        Raised Hb F levels in sickle cell disease are caused by a determinant linked to the beta globin gene cluster.
        Prog Clin Biol Res. 1987; 251: 427-439
        • Chami B
        • Blouquit Y
        • Bardakdjian-Michau J
        • et al.
        Hemoglobin variants in North Africa.
        Hemoglobin. 1994; 18: 39-51
        • Sills RH
        • Oski FA
        RBC surface pits in the sickle hemoglobinopathies.
        Am J Dis Child. 1979; 133: 526-527
        • Goldberg MF
        Natural history of untreated proliferative sickle retinopathy.
        Arch Ophthalmol. 1971; 85: 428-437
        • Milner PF
        • Kraus AP
        • Sebes JI
        • et al.
        Sickle cell disease as a cause of osteonecrosis of the femoral head.
        N Engl J Med. 1991; 325: 1476-1481
        • Zimmerman SA
        • O'Branski EE
        • Rosse WF
        • Ware RE
        Hemoglobin S/OArab: thirteen new cases and review of the literature.
        Am J Hematol. 1999; 60: 279-284
        • Steinberg MH
        Management of sickle cell disease.
        N Engl J Med. 1999; 340: 1021-1030
        • Kark JA
        • Posey DM
        • Schumacher HR
        • Ruehle CJ
        Sickle-cell trait as a risk factor for sudden death in physical training.
        N Engl J Med. 1987; 317: 781-787
        • Vichinsky EP
        • Styles LA
        • Colangelo LH
        • Wright EC
        • Castro O
        • Nickerson B
        • Cooperative Study of Sickle Cell Disease
        Acute chest syndrome in sickle cell disease: clinical presentation and course.
        Blood. 1997; 89: 1787-1792
        • Charache S
        • Terrin ML
        • Moore RD
        • Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
        • et al.
        Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
        N Engl J Med. 1995; 332: 1317-1322
        • Zerhouni F
        • Guetarni D
        • Henni T
        • Colonna P
        Occurrence and characteristics of hereditary spherocytosis in Algeria.
        Eur J Haematol. 1991; 47: 42-47
        • Mallouh A
        • Sa'di AR
        • Ahmad MS
        • Salamah M
        Hereditary pyropoikilocytosis: report of two cases from Saudi Arabia.
        Am J Med Genet. 1984; 18: 413-417