A 3-year-old with sickle cell anaemia and a second pregnancy
A couple from a village near Bathinda bring their 3-year-old son to a district hospital. Over two years he has had three episodes of severe bone and abdominal pain, one needing admission for five days. His haemoglobin is 7.2 g/dL, MCV 78 fL, reticulocytes 12%, and the peripheral smear shows sickle-shaped red cells. Haemoglobin electrophoresis at alkaline pH shows the boy has a single band in the HbS position, with 18% HbF; both parents show two bands, HbA and HbS, in roughly equal amounts, and both have haemoglobin values of 13-14 g/dL. The parents are first cousins. The mother is 10 weeks pregnant and asks whether 'this baby will be all right'. Their 5-year-old daughter's electrophoresis shows only an HbA band. The father has read that people with sickle cell trait 'have a mild form of the disease' and wants to know what treatment he needs.
1. Assign genotypes to the boy, both parents and the daughter, and explain what each electrophoresis pattern shows. Which single result in this family would you interpret most cautiously, and why?
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HbS comes from a single base change in codon 6 of the beta-globin gene (glutamate to valine), which removes negative charge; at alkaline pH the protein therefore migrates more slowly than HbA and separates into a distinct band.
The boy shows only an HbS band (HbF persists at a variable level in sickle cell disease and modifies severity) so both his beta-globin genes carry HbS: genotype SS, sickle cell anaemia, which fits the Hb 7.2 g/dL, reticulocytosis and pain crises.
The parents each show HbA and HbS in roughly equal amounts: both are AS heterozygotes. They are healthy because about 55-60% of their haemoglobin is normal HbA, which is enough for oxygen transport; the trait is not a mild disease.
The daughter shows only HbA, so she is AA, the expected outcome for one quarter of the children of two carriers. This is the result I would treat most cautiously: electrophoresis cannot exclude a carrier state if the child was recently transfused, and a coinherited beta-thalassaemia allele or alpha-thalassaemia can distort band proportions. HPLC with quantitation, plus a check of transfusion history, is more reliable than a single band pattern.
2. State the probability that the fetus has sickle cell disease and justify it. What prenatal testing can be offered at this stage of pregnancy, and what information must accompany the offer?
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Each pregnancy from two AS parents is an independent event with a 1 in 4 chance of SS, 2 in 4 of AS and 1 in 4 of AA. The earlier affected child does not change this: the previous outcomes have no memory, so the recurrence risk is still 25% for disease and 50% for carrier state. The couple should hear the positive framing too - a 75% chance the baby is not affected.
At 10 weeks the timely option is chorionic villus sampling at 11-13 weeks, because DNA from villi can be tested by PCR for the codon 6 mutation; amniocentesis at 15-18 weeks is the later alternative. Both carry a procedure-related miscarriage risk of roughly 1 in 100 to 1 in 200, which must be quoted, along with the small chance of an inconclusive result needing a repeat sample. Ultrasound cannot diagnose the genotype.
If the fetus is SS, the couple need counselling on what that means in practice - early penicillin prophylaxis, pneumococcal vaccination, folate, hydration and prompt treatment of fever - not only the option to continue or not. The carrier result also matters, because an AS child will need partner screening as an adult.
3. The father believes his carrier status is 'a mild form of the disease' and asks for treatment. Explain the carrier state to him and identify what action is actually useful in this family.
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The father has one normal beta-globin gene and one HbS gene. His red cells contain mostly HbA, and sickling needs deoxygenation and dehydration that his cells do not reach under ordinary conditions. So he has no anaemia, no pain crises, no shortened life expectancy and needs no medicine, no hydroxyurea and no folate. Calling it 'mild disease' invites unnecessary treatment and unnecessary fear; it is a carrier state.
What he should know is that the trait offers some protection against severe falciparum malaria, that extreme dehydration, prolonged hypoxia at high altitude or severe infection are the rare situations where caution is sensible, and that the only important consequence is the risk passed to children.
The useful action is therefore screening of partners in the extended family, which consanguinity makes urgent. The wife's sisters and the husband's brothers should be tested before marriage or conception, and the daughter's AA status should be documented so she is not retested needlessly but her future partner is screened. Testing the boy's siblings by electrophoresis at 6-12 months of age is standard in affected families.