Both Parents Are Microcytic, One With a Normal HbA2

The wife has a β-thalassaemia trait picture:

• Microcytosis (MCV 60 fL) and hypochromia with a raised HbA2 of 5.9% and a mildly raised HbF - the classic triad, with iron deficiency excluded by a ferritin of 52 µg/L.
• The differential of a raised HbA2 includes HbE (which co-elutes with HbA2 on HPLC and can be separated by capillary electrophoresis or sequencing), megaloblastic change, hyperthyroidism and some unstable haemoglobins; none is suggested by this film and history.
• A mild anaemia with a low MCH and normal ferritin in a woman with a family history and consanguinity is typical of β-trait.

Confirmatory work

• HBB sequencing (or targeted mutation panel) to identify the exact β-globin variant. This matters practically: prenatal diagnosis by CVS requires knowing the parental mutations so that the laboratory can design the assay, and some variants are β⁺ (milder) versus β⁰.
• Family studies (parents, siblings) and partner testing are part of the workup, and results should be documented in a genetic report, not just a haematology comment.
• Full blood count and ferritin on any existing children, and a haemoglobinopathy screen on stored antenatal samples.

The wife's result alone establishes her as a carrier; the question of an affected child depends entirely on the husband's status.

A normal HbA2 does not exclude β-thalassaemia trait when iron deficiency coexists. Iron deficiency suppresses HbA2 (δ-chain synthesis is iron-dependent), so a carrier can fall from, say, 5.0% to 3.2–3.4%. His ferritin of 9 µg/L with a CRP of 4 mg/L makes iron deficiency almost certain and makes the HbA2 uninterpretable.

Plan

1. Treat the iron deficiency with oral iron (with attention to the usual antenatal context and his own symptoms) for 8–12 weeks and confirm a marrow response (rise in Hb, MCV, reticulocytes) and a ferritin above about 30 µg/L.
2. Repeat HbA2 and full blood count once iron-replete. If HbA2 rises to ≥3.5%, he is a β-trait carrier. If HbA2 stays normal and microcytosis persists, consider α-thalassaemia trait (MCV 64 with normal HbA2 in a non-iron-deficient state) - gap-PCR for the common deletions (−α³·⁷, −α⁴·², −−MED, −−SEA, −−FIL) with reflex testing for non-deletional α variants if negative.
3. Do not wait indefinitely before doing the molecular test. Because α- and β-globin genotyping can be run in parallel, send HBB sequencing and α-gap-PCR now rather than after the iron trial; the iron repletion then serves as the phenotypic confirmation. This is essential given the four-week turnaround and a 10-week gestation - the CVS window (11–14 weeks) will pass if testing is deferred by 3 months.
4. Document the reasoning in the laboratory report so the 'he just has iron deficiency' interpretation is not repeated, and inform the couple that the earlier reassurance was incomplete rather than wrong.

If he is confirmed as a β-carrier, both parents carry a β variant and prenatal diagnosis is indicated; if he carries only an α deletion, the offspring cannot have β-thalassaemia major.

Risk figures

Two β-trait carriers have a 25% risk of an affected child (β-thalassaemia major or intermedia, depending on the variants), 50% carriers, 25% unaffected. The consanguinity does not change this arithmetic but does raise the background risk of other recessive conditions, which should be addressed separately by genetic counselling.

Options

• Prenatal diagnosis: chorionic villus sampling at 11–14 weeks (result usually within 1–2 weeks with a targeted assay) or amniocentesis from 15 weeks. The laboratory needs both parental mutations documented beforehand; testing for the couple's specific variants is more reliable than generic sequencing.
• Preimplantation genetic testing for monogenic disease, with IVF, if the couple prefers to avoid termination.
• Accepting the risk with postnatal diagnosis and early transfusion/haematology follow-up - a legitimate choice that must be presented neutrally.
• Cascade testing of siblings on both sides.

Laboratory limitations to state explicitly

• Capillary electrophoresis/HPLC is a screening phenotype, not a genotype; rare variants can migrate atypically and HbE can be misread as a raised HbA2.
• Gap-PCR detects only the targeted deletions; negative α testing does not exclude rare or point-mutation α-thalassaemia.
• Sanger sequencing will miss large deletions in HBB; MLPA or deletion/duplication analysis is needed if sequencing is uninformative in an obvious carrier.
• CVS carries a procedure-related miscarriage risk of roughly 1 in 200–500 and, rarely, confined placental mosaicism; a normal result reduces but does not eliminate all risk.
• Turnaround time is a clinical variable: a four-week in-house turnaround is incompatible with a 13-week CVS, so send the samples to a reference laboratory or prioritise them.

The couple should leave with a written summary of risks, options and the laboratory's test limitations, and be offered a follow-up genetic counselling appointment after the genotype results are available.