Thanks to everyone who has taken part in this week’s case. It focused on childhood anaemia and it’s investigations. See a link to our Storify of this week’s case https://storify.com/TeamHaem/case-63-a-pale-child
There are a number of causes of anaemia in children:
- Iron deficiency (bleeding, inadequate intake, malabsorption)
- B12 or folate deficiency
- Bone marrow infiltration (acute leukamia or other solid organ tumour)
- Inherited bone marrow failure sydrome (e.g. Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan Anaemia, sideroblastic anaemia etc.)
- Haemoglobinopathy (sickle cell anaemia, thalassaemia, other variant haemoglobin etc.)
- Inherited red cell membrane disorder (hereditary spherocytosis, elliptocytosis etc.)
- Inherited red cell enzymopathy (e.g. PK deficiency, G6PD deficiency)
- Congenital dyserythropoietic anaemia
- Transient erythroblastopenia of childhood (a rare disorder due to viral infection which may last for months)
- Other haemolytic anaemia e.g. autoimmune or paroxysmal cold haemoglobinuria
Making the diagnosis
A systematic approach is required in order to solve the problem. This was an acute history of suddenly becoming pale indicating an acute problem or an acute on chronic problem. History and examination are important. Has the child previously been well, is there a family history. Are there any features of marrow infiltration (limp, bony pains, lymphadenopathy, hepatosplenomegaly etc.). The MCV and other features in the full blood count are key here to ruling out certain disorders. It would be unusual to have a global inherited bone marrow failure syndrome without deficiencies in other cell lines (neutropenia/thrombocytopenia). In addition these syndromes are frequently associated with other features such as bony abnormalities or dysmorphia. Iron deficiency and thalassaemia would cause the MCV to be low and B12/folate deficiency would usually cause macrocytosis and other symptoms at this level of anaemia (but would still check levels). The blood film is also key in looking for potentially life-threatening causes of anaemia such as acute leukaemia. The reticulocyte count would usually be elevated in haemolytic processes.
In this case the MCV was normal; as were B12/folate/ferritin. There were no abnormalities in the rest of the blood count and there were no extra-haematological features. Diamond Blackfan anaemia is usually diagnosed in the neonatal period less than six months. There was mild splenomegaly on examination. The blood film showed spherocytosis but surprisingly there was no polychromasia which indicates lack of red cell production. Spherocytosis is seen in various haemolytic anaemias including hereditary spherocytosis, autoimmune haemolytic anaemia and congenital dyserythropoietic anaemias. In keeping with lack of polychromasia the reticulocyte count was very low.
The family history and ethnic origin may point towards a particular problem. What are the FBC and film of the parents? Is there a history of splenectomy in the family? Any problems with neonatal jaundice or blood transfusions as a child? In our case there had been some neonatal jaundice and the father later admitted to having a splenectomy as a child.
Potential investigations in a child with anaemia (tailor to history/examination and initial FBC parameters)
- FBC including reticulocyte count
- Blood film
- Haemoglobinopathy screen
- DAT +/- group and antibody screen
- Basic biochemistry – U&E, LFT, bone profile, LDH
- Haematinics – ferritin, B12, folate
- Coeliac screen
- Urine haemosiderin
This is usually an autosomal dominant disorder (less commonly recessive) with a prevalence of 200-300/million population in Europe. There is a defect in the ankyrin-spectrin complex, band 3 or pallidin componments of the red cell membrane resulting in reduced red cell survival and increased destruction. Red cells are destroyed in the spleen resulting in splenomegaly. The disorder presents usually with haemolytic anaemia or neonatal jaundice. If the phenotype is mild it may go unnoticed until there is a complication. The phenotype tends to run in families (if parent mildly affected the child is usually mildly affected).
Diagnosis of hereditary spherocytosis
Start with a basic haemolysis screen:
- FBC, reticulocyte count, blood film
- LFTs (direct/indirect bilirubin)
Red cell morphology in neonatal films can be difficult and if uncertain then repeat film should be performed in a few week’s time. Mushroom cells may be seen in a band 3 disorder. The MCHC is characteristically raised and this points towards HS. Some guidelines suggest typical morphological appearances along with a negative DAT and positive family history require no further investigation. Some clinicians may wish to confirm the findings with further testing. The EMA (eosin-5’malmalide) binding test is the most commonly performed test. EMA binds to red cell membrane band 3 proteins which are reduced in HS due to instability in the lipid bilayer. Analysis by flow cytometry measures the flourescent intensity of labelled intact red cells. This will be reduced in HS compared to normal controls. EMA binding can also be reduced in HbSS, CDA type II, SE Asian ovalocytosis, hereditary pyropoikilocytosis, renal failure. The osmotic fragility test is less commonly performed as it is less specific. Protein electrophoresis and DNA can also be used in difficult cases. A bone marrow biopsy is not needed.
Complications of HS
- Hydrops if severe
- Aplastic crisis (especially parvovirus but other viruses can cause this) – this happens as patients rely on increased red cell production in the marrow and if this is halted, even for a short time, it is enough to render the patient anaemic. Parvovirus causes reticulocytopenia in most patients but does not cause anaemia unless there is increased red cell destruction.
- Iron overload (rare unless heterozygous/homozygous for haemochomotosis gene)
- Folate deficiency
- Anaemia during pregnancy
- Splenic sequestration (very rare)
Management of HS
- Folic acid – only need if moderate-severe
- Monitor ferritin
- Education re aplastic crisis
- Antenatal counselling
- Splenectomy if:
- Recurrent severe anaemia
- Requiring regular transfusion
- leg ulcers
- Anaemia causing stunted growth
- Symptomatic gallstones (usually remove gallbladder at same time)
He was transfused red cells and monitored closely. We thought about doing a bone marrow but decided to monitor with a plan for a marrow if he didn’t recover as expected. After two weeks his reticulocytes returned and required no further transfusion. His baseline haemoglobin was 95-105g/L. Serology showed development of immunity to parvovirus. IvIg can be used in parvovirus-induced aplastic crisis but it was not necessary in this case.
- BCSH (archived) guidelines: Guidelines for the Diagnosis and Management of Hereditary Spherocytosis (Paula H.B. Bolton-Maggs , Jacob C. Langer , Achille Iolascon , Paul Tittensor , May-Jean King) http://www.bcshguidelines.com/documents/HS_BCSH_Sept_2011_final.pdf
- ICSH Laboratory diagnosis of non-immune hereditary red cell membrane disorders (King MJ, Garçon L, Hoyer JD, Iolascon A, Picard V, Stewart G, Bianchi P, Lee SH, Zanella A) http://onlinelibrary.wiley.com/doi/10.1111/ijlh.12335/epdf Int J Lab Hematol. 2015 Jun;37(3):304-25. doi: 10.1111/ijlh.12335