Hemoglobinopathies (HbP’s = abnormal hemoglobines and thalassemias) are the most common autosomal recessive monogenic disease in mankind. The “World Health Organization” has established that 5% of the world population is a carrier of HbP.
Carriers of the most common HbP’s (HbS, HbE, HbC, HbD, β- and α-thalassemia) are highly frequent especially in Mediterranean, African and Asiatic populations. This is as a consequence of a selection mechanism which protects HbP carriers from the severe consequences of malaria tropica infection. The price for this genetic advantage is the risk that parents who are both carriers run of having progeny severely affected with one of the major HbP forms (Thalassemia major and sickle cell disease).
Couples at risk have 25% chance of a severe HbP in their progeny. Thus 350,000 affected children are born worldwide each year.
HbS, HbC, HbE and HbD are frequent in the Dutch population of recent foreign origin as well as in the population of other Northern European countries with an elevated foreign population. All these mutants are β-globin defects and are recessively inherited (Thus no severe symptoms in the carriers). Conversely, children of parents who are both carriers may be homozygous or double heterozygous for combinations such as HbS/S, S/D, S/E, S/β-thal, HbE/β-thal and be affected shortly after birth by a very severe pathology.
β- and α-thalassemia are also frequent in the immigrant populations of Northern European countries. Also these disease are mostly recessively inherited. The pathology in patients with β-thal major (β-thal/β-thal, HbS/β-thal, HbE/β-thal, etc..) manifests at about 6 months of age and is usually very severe. The α-thalassemias present as severe forms during prenatal life (Hb Bart’s hydrops foetalis) only if the expression of the 4 available α-genes is totally absent. The postnatal pathology of α-thalassemia is mild with 1 or 2 and intermediate with 3 affected genes (HbH disease).
HbP’s are not frequent in Northern European, this is because malaria tropica has never played a significant role in the selection of the genetic background in these populations. However, 10 to 15% of the actual Dutch population is of recent foreign origin (similar to other industrialized countries of Northern Europe) and many HbP carriers are present in areas where, until recently, these traits were not frequent at all. Moreover, 40 to 60% of the population in the large Dutch cities below the age of 18 is of recent immigrant origin and make up 20% of the newborns each year. This means that undoubtedly a number of HbP carriers and perhaps couples at risk are present in each multi-ethnic GP practice, and that in case of a persisting mild microcytic hypochromic anemia not responding to iron therapy the GP should consider the reality of HbP carriers.
“1 in 15” or epidemiology in the multiethnic GP practice
- You may assume that that in your practice only 1 of 1300 patients of Northern European origin will be a carrier of HbP.
- You may expect that about 1 in 50 patients with more remote foreign ancestors will be a carrier of HbP, mostly α-thalassemia (α-thal), but β-thal en HbE are also present. Be alert for persisting microcytic hypochromic parameters with or without anemia.
- You may certainly expect that 1 of 15 patients of recent foreign origin (Mediterranean, Turkey, Morocco, Africa, Middle and Far East, Surinam, Caribbean etc.) will be HbP carrier (α-thal, β-thal, HbS, HbC, HbE, HbD or others). The chance of having couples at risk, especially if the partners are endogamous or consanguineous, is high. At each and every conception these couples have 25% chance of having a severely affected child. These couples have the right to get information and prevention.
- You may expect that 1 of 30 of your patients of Chinese/East Asiatic origin will be carrier of α or β-thalassemia. The chance of couples at risk is for endogamous partners as high as in the countries of origin. Partners who are both carriers of β-thalassemia have 25% chance to have a child affected by β-thalassemia major. Partners who are both carriers of a°-thalassemia have 25% chance of a foetus affected by Hb Bart’s hydrops foetalis. Partners who are carriers of α°- and α+-thalassemia may have either a 25% or 50% risk for HbH-disease in their progeny.
Every HbP carrier in your practice has the right to receive information and carrier diagnostics. Couples at risk have (moral and legal) rights to be informed about their risk and about prevention. For every HbP carrier of reproductive age partner diagnostics is recommended.
Carriers of β- and α-thalassemia and HbE present with microcytic hypochromic parameters with moderate or slight anemia. Carriers of HbS, C and D usually have normal or border-line blood indices, usually without anemia. Family history or ethnical origin are in these cases the only indications for carrier analysis.
Prevention through information and carrier diagnostics in the GP practice
Basic carrier diagnostics is offered in the GP practice in a stepwise manner. Firstly is to one of the two partners, preferably the female. If the result is negative, no risk for HbP major is present and the partner will not be examined (unless hematological complains are present). If the result is positive, the partner will be examined. If the partner is not a carrier the couple is not at risk. If the partner is a carrier, the couple is potentially at risk and referral to a genetic center is highly recommended (Click here for a prevention scheme).
Answers to few practical questions
How can the GP recognize possible HbP carriers?
The indications may vary from clear and persisting microcytic blood parameters with or without anemia, to slight abnormal indices, family history or ethnical background.
A microcytic hypochromic anemia, with normal ferritin or persisting after iron therapy, especially in a foreign patient is a clear indication for thalassemia, HbE and HbS associated with α-thalassemia (1/3 of the HbS cases). Immigrant patients with sub- or normal parameters and a positive family history may be carriers of plain HbS, C or D.
How to give information?
Reassurance and a clear explanation about the meaning and the consequences of being a HbP carrier should be given (Click here for information leaflets). The patient should not leave with an anxious feeling. It should be made very clear to the patient that a carrier will never develop the illness. That carriers should have their partner checked in order to be able to predict and eventually prevent severe risk in their progeny, should also be made very clear.
How to take care of the symptoms of the carriers?
HbP carriers may suffer of a moderate anemia, which may eventually be aggravated by iron or folic acid deficiency. The ferritin and folic acid level should be measured and if too low, supplemented. Iron should only be given in case of depletion and not repeatedly without monitoring.
How to assess the carrier state for the most common HbP’s?
Send a blood sample to the lab for HbP analysis. The lab will perform a Hb-electrophoresis or Hb-chromatography (HPLC) with estimation of the HbA2 and HbF fractions. By this analysis the normal (HbA, HbA2 en HbF) and most common abnormal Hb fractions (HbS, C, E, D, ea.) are analyzed.
How to interpret the results?
- An abnormal Hb fraction on electrophoresis or of HPLC on position S is usually confirmed by a sickle test. The HbS fraction in the presence of 60% HbA (in a non-transfused patient !) indicate a patient carrier of the HbS mutant (heterozygous HbA/S).
- An abnormal Hb band on electrophoresis or HPLC on position S and a positive sickle test without HbA indicate a patient with sickle cell disease (homozygous HbS/S, of HbS/β-thalassemia).
- Abnormal bands on positions C, D, E or other positions, either in combination with HbA or S should be examined in a specialized laboratory.
- An HbA2 percentage between 3.5 and 8 % will indicate an heterozygous β-thalassemia (the HbA2 value is not significant in babies and some types of β-thalassemia present with normal HbA2 values of 2.5-3.5%).
- An HbA2 percentage < 2.5% without iron deficiency may indicate a mild α-thalassemia (analyses for α-thalassemia should be done in a specialized laboratory).
- HbF percentages higher than 1% are abnormal after two years of age. β-thalassemia heterozygotes may have a delayed switch and an elevated HbF. β-thalassemia homozygous babies, healthy at birth, present with absence of HbA and virtually only HbF.
After providing information and carrier analysis, the preventive task of the GP is completed.
What to do with partners at risk?
Partners at risk should be referred to clinical genetic centers and specialized laboratories.
The lab will determine the risk of the progeny based on the characterization of the defects.
The geneticist will inform the couple about the risk and the prevention possibilities and will advise family analysis.
If prevention via prenatal diagnosis is requested:
- A chorion villi sample can be collected at 11 weeks pregnancy.
- Molecular analysis of fetal DNA will reveal the genotype of the foetus an the presence or absence of the defect combinations responsible for a severe HbP.