Paediatrics: Aplastic anaemia

Aplastic anaemia

Due to severe bone marrow suppression of RBC, WBC and platelet pre-cursors (pancytopaenia). Rare. May be acquired or congenital.

Acquired aplastic anaemia

Causes Idiopathic is most common. Rarely, s to radiotherapy, chemotherapy, idiosyncratic reaction to drugs or chemicals (chloramphenicol, carbamazepine, phenytoin, NSAIDs, mesalazine, several solvents), viral (hepatitis A, B, C; CMV; EBV; parvovirus—more common in adults). Note: Bone marrow invasion, e.g. malignant cells, osteopetrosis, displaces normal marrow; causes pancytopenia, not aplastic anaemia.

Presentation

Features of pancytopenia

·  Anaemia: due to dd RBC production.

·  Infection: particularly bacterial and fungal. Due to WCC dd, particularly if neutrophils <0.5 × 10⁹/L (severe aplastic anaemia, SAA), <0.2 × 10⁹/L (very severe aplastic anaemia, VSAA).

·  Mucosal bleeding, purpura, and bruising. Due to platelet count dd.

Investigations

·  FBC: WBCd, platelets < 20 × 10⁹/L, reticulocytes < 20 × 10⁹/L.

·  Bone marrow aspirate and trephine: aplasia (marrow cellularity <25%).

·  CD55/CD59 immunophenotyping to exclude PNH (see Paroxysmal nocturnal haemoglobinuria (PNH)).

·  Cytogenetics and chromosomal breakage studies to detect myelo-dysplastic syndrome (MDS), Fanconi’s anaemia or dyskeratosis congenita.

Treatment

·  Remove or treat underlying cause, e.g. drugs.

·  Depending on severity: RBC +/– platelet transfusion.

·  Bone marrow transplant (BMT) may be curative.

·  Immunosuppression, e.g. rabbit anti-thymocyte globulin followed by ciclosporin is best second line therapy for those with no BMT donor.

Prognosis 

Depends on underlying cause. Some patients recover sponta-neously. Most will progress to more severe disease, PNH or leukaemia. Long-term survival is unlikely in severe disease without good response to immunosuppressive therapy or BMT.

Paroxysmal nocturnal haemoglobinuria (PNH)

·  Rare, acquired clonal disorder of marrow cells deficient in glycosylphosphatidylinositol (GPI) anchors that protect against complement lysis.

·  Usually associated with background aplasia, allowing PNH clone a positive selective advantage.

·  Complement lysis leads to chronic haemolytic anaemia, with intermittent haemoglobinuria but persistent haemosidinuria. Urine is Hb +ve.

·  High risk of recurrent and fatal venous thrombosis e.g. Budd Chiari, venous thrombosis, cerebral sagittal sinus.

·  FBC: ‘rise’reticulocytes, ‘fall’ WBC, and ‘fall’ platelets

·  Bone marrow is hypoplastic with erythropoietic islands.

Flow cytometry detects CD55 and CD59 deficient cells

Treatment 

Blood transfusion, iron replacement (rarely) or iron chelation, warfarin (anticoagulant therapy), immunosuppression (e.g. with steroids). Ecluzimab (anti-complement antibody) may reduce severity. BMT can be curative of both PNH and aplasia. Otherwise, median survival is 8–10yrs. Death is due to thrombosis or complications of pancytopenia.

Inherited and congenital bone marrow failure syndromes

Fanconi’s anaemia (FA) 

This rare, autosomal recessive condition leads to progressive bone marrow failure affecting all three haemopoietic cell pre-cursors. Associated with chromosomal fragility and defective DNA repair.

Presentation

·May present at any age, but typically at 4–10yrs.

·Usually presents with bruising and purpura or insidious onset anaemia.

·Associations: short stature (80%); skin hyperpigmentation (café au lait spots, 75%); skeletal abnormalities, particularly upper limb and thumb (66%); renal malformations (30%); microcephaly (40%); cryptorchism

(20%); mental retardation (17%); deafness (7%); abnormal facies.

Investigations

·FBC: pancytopenia, or just thrombocytopenia initially.

·Bone marrow: hypoplastic, dyserythropoietic, or megaloblastic changes.

·Chemically-induced cell culture lymphocyte chromosomal breakages.

·Investigate to detect renal abnormalities or hearing loss.

·Most of the 12 FA genes have been cloned and can be screened for in families where the mutation is known. Diagnosis is essential as standard BMT conditioning is fatal and appropriate modifications are essential.

Treatment

·Supportive, e.g. RBC transfusion, hearing aids, orthopaedic.

·Immunosuppression with corticosteroids and androgens (oxymetholone).

·Successful BMT curative for haematological defects but problems post BMT as FA is a constitutional and multi-organ disorder.

Prognosis 

Most respond to steroids/androgens but treatment is long term. Patients not responding to immunosuppression usually die within a few years due to complications of pancytopenia or acute leukaemia.

Shwachman–Diamond syndrome

A rare autosomal recessive disorder. Most patients have mutations in the SBDS gene on 7q11. The condition typically affects bone marrow, pancreas and skeleton. Neutropenia occurs more than thrombocytopenia and anae-mia, leading to infections due to immunocompromise. Exocrine pancreat-ic enzyme insufficiency causes diarrhea and FTT. Skeletal effects include metaphyseal dysostosis and dental problems. Bone marrow examination is diagnostic +/– pancreatic function testing. SBDS genotyping can be helpful. Treatment is supportive, e.g. pancreatic enzyme supplements. BMT is an option but survival is relatively poor (i.e. order of 50%).

Dyskeratosis congenita 

This is a very rare condition with dystrophic nails, skin pigmentation, and mucous membrane (oral) leucoplakia. Bone mar-row shows hypo/aplastic changes. Treatment is BMT.