Clinical case

• A pregnant woman heterozygous for Hb S

• Her partner is tested for an haemoglobinopathy • Absence of HbA

• HbS 60%

• HbF 38%

• HbA2 2%

• Questions

Couple Hb AS and HbSS with Hb F 38% and no clinical symptoms since birth. What to do next?

1. You test the sample with another technique of separation of the haemoglobin fractions

2. You call the gynaecologist to know the ethnic origin of the partner

3. You look at other biological results, in particular the complete blood count

4. You don’t know what to do in such situation

Couple Hb AS and HbSS with Hb F 38% and no clinical symptoms since birth. Couple at risk of having a child with a severe sickle cell syndrome?

1. No, HbSHPFH and HbSdelta-beta°-thalassaemia are clinically harmless

2. It is mandatory to make the differential diagnosis between HbSHPFH and HbSdelta-beta°-thalassaemia

3. I don’t know

4. I don’t know and will send the couple to a geneticist

Switch HbF HbA

4

Mutations involved

5

BUT genuine HPFH should be defined as non-gene deletion related: no association with a reduced expression of the β-globin gene Example: Xmn-I polymorphism with enhancement of HbF expression only during erythropoietic stress (increase therapeutic effect of hydoxyurea)

Heterocellular distribution of Hb F: non gene-deletion of HPFH

Human Molecular Genetics, 2009, Vol. 18, Review Issue 2 R217

Guidelines: Eur J Hum Genet. 2015; 23(4): 560.

• Hb F >5%, are associated with • δb or γδb-thalassaemia

heterozygotes (along with normal or low Hb A2 levels and reduced RBC indices)

• or hereditary persistence of fetal haemoglobin (HPFH).

« deletional HPFH »

• Most often • HPFH-2 and 1

• Pancellular distribution of F cells

• Hb F > 30-35%

• Haemoglobin level around the lower reference value

• MCV (> 18 y.o.) 75 ± 6 fl (F cells are larger than non F cells)

• Hb A2 normal or low

• No clinical sign (sickle cell disease or beta-thalassaemia)

Offer prenatal diagnosis Eur J Hum Genet. 2015; 23(4): 560.

Take home message

• HbF < 5% = most often not clinically relevant

• Harmless HPFH conditions • Beneficial effect in the presence of sickle cell disease (and thalassemia major)

• Doubt? • (Genetic counselling) Molecular analysis in a specialized laboratory

Clinical case

• A pregnant woman heterozygous for Hb S

• Her partner is tested for an haemoglobinopathy • Absence of HbA

• HbS 60%

• HbF 38%

• HbA2 2%

• Questions

Couple Hb AS and HbSS with Hb F 38%. What to do next?

1. You test the sample with another technique of separation of the haemoglobin fractions

2. You call the gynaecologist to know the ethnic origin of the partner

3. You look at other biological results and seek clinical data

4. You don’t know what to do in such situation

Couple Hb AS and HbSS with Hb F 38% since birth. What to do next?

1. You test the sample with another technique of separation of the haemoglobin fractions

2. You call the gynaecologist to know the ethnic origin of the partner

3. You look at other biological results and seek clinical data

4. You don’t know what to do in such situation

Couple HbAS and HbSS with HbF 38% and no clinical symptoms since birth?

1. It is certainly a hereditary persistence of foetal haemoglobin

2. It is certainly a delta-beta° thalassaemia

3. Molecular genetic analysis will give the diagnosis

4. You ask the advice of an expert in the field

Couple HbAS and HbSS with HbF 38% and no clinical symptoms since birth?

1. It is certainly a hereditary persistence of foetal haemoglobin

2. It is certainly a delta-beta° thalassaemia

3. Molecular genetic analysis will give the diagnosis

4. You ask the advice of an expert in the field

Couple Hb AS and HbSS with Hb F 38% and no clinical symptoms since birth. Couple at risk of having a child with a severe sickle cell syndrome?

1. No, HbSHPFH and HbSdelta-beta°-thalassaemia are clinically harmless

2. It is mandatory to make the differential diagnosis between HbSHPFH and HbSdelta-beta°-thalassaemia

3. I don’t know

4. I don’t know and will send the couple to a geneticist

Couple Hb AS and HbSS with Hb F 38% and no clinical symptoms since birth. Couple at risk of having a child with a severe sickle cell syndrome?

1. No, HbSHPFH and HbSdelta-beta°-thalassaemia are clinically harmless

2. It is mandatory to make the differential diagnosis between HbSHPFH and HbSdelta-beta°-thalassaemia

3. I don’t know

4. I don’t know and will send the couple to a geneticist