79 Bone Marrow Failure Syndormes
79.1 Introduction
Bone marrow failure syndromes (BMFS) refer to a heterogeneous group of disorders in which the bone marrow is unable to produce an adequate number of one or more blood cell lines. These disorders may affect red blood cells, white blood cells, and/or platelets, leading respectively to anemia, leukopenia, and thrombocytopenia. Clinically, they present with fatigue, recurrent infections, mucosal bleeding, and growth impairment in children.
BMFS may be congenital (inherited) or acquired, and early recognition is essential for timely management. In sub-Saharan Africa, including Ghana, diagnosis is often delayed due to limited access to specialized laboratory investigations such as bone marrow cytogenetics, flow cytometry, telomere length testing, and genetic sequencing. As a result, these disorders may be misdiagnosed as nutritional anemia, malaria, leukemia, or sepsis.
This chapter provides a comprehensive review of both congenital and acquired bone marrow failure syndromes in children, with a focus on clinical features, diagnostic challenges, and management approaches applicable within Ghana and similar resource-limited settings.
79.2 Normal Structure and Physiology of Bone Marrow
Bone marrow is responsible for hematopoiesis — the production of red cells, white cells, and platelets. Key components include:
- Hematopoietic stem cells (HSCs): pluripotent cells capable of self-renewal and differentiation.
- Stromal cells: including fibroblasts, adipocytes, endothelial cells, and macrophages that support HSC survival.
- Growth factors and cytokines: such as erythropoietin, G-CSF, and thrombopoietin.
Any insult to stem cells, stromal support, or regulatory cytokines can lead to bone marrow failure.
79.3 Classification of Bone Marrow Failure Syndromes
BMFS can be broadly categorized as:
79.3.1 Congenital (Inherited) Bone Marrow Failure Syndromes (IBMFS)
These include: - Fanconi anaemia
- Diamond–Blackfan anaemia
- Shwachman–Diamond syndrome
- Dyskeratosis congenita (telomeropathies)
- Congenital amegakaryocytic thrombocytopenia
- Thrombocytopenia with absent radius (TAR) syndrome
- Congenital neutropenias (e.g., Kostmann syndrome)
79.3.2 Acquired Bone Marrow Failure Syndromes
Including: - Aplastic anaemia
- Transient erythroblastopenia of childhood (TEC)
- Drug-induced bone marrow suppression
- Viral-associated marrow suppression (e.g., Parvovirus B19, HIV)
- Nutritional (e.g., severe malnutrition with marrow hypoplasia)
- Immune-mediated marrow aplasia
79.4 Congenital Bone Marrow Failure Syndromes
79.4.1 Fanconi Anaemia (FA)
79.4.1.1 Overview and Pathophysiology
Fanconi anaemia is the most common inherited cause of aplastic anemia in children. It is an autosomal recessive disorder characterized by impaired DNA repair, leading to chromosomal instability and progressive marrow failure.
79.4.1.2 Clinical Features
FA presents with a wide spectrum of abnormalities: - Hematologic: pancytopenia, usually presenting between ages 5–10 years. - Physical anomalies: - Short stature
- Absent or hypoplastic thumbs
- Radial ray defects
- Skin hyperpigmentation or café-au-lait spots
- Renal anomalies
- Microcephaly - Endocrine features: hypothyroidism, glucose intolerance, delayed puberty. - Malignancy risks: - Acute myeloid leukemia
- Squamous cell carcinoma of head/neck and genital tract
79.4.1.3 Diagnosis
- CBC: pancytopenia
- Bone marrow: hypocellular
- Chromosomal breakage test using diepoxybutane (DEB) or mitomycin C is diagnostic
- Genetic testing (if available)
- Screening for associated anomalies (renal ultrasound, endocrine evaluation)
79.4.1.4 Management
- Supportive care: transfusions, infection control
- Androgens (e.g., oxymetholone) may improve counts temporarily
- Hematopoietic stem cell transplantation (HSCT) is curative
- Cancer surveillance
- Genetic counselling for families
79.4.1.5 Ghana Context
FA is likely underdiagnosed. Limited access to DEB testing hampers confirmation, often leading to misclassification as idiopathic aplastic anemia.
79.4.2 Diamond–Blackfan Anaemia (DBA)
79.4.2.1 Overview
DBA is a congenital pure red cell aplasia presenting in infancy due to mutations affecting ribosomal protein synthesis.
79.4.2.2 Clinical Features
- Onset before 1 year of age
- Severe macrocytic anemia
- Reticulocytopenia
- Physical anomalies in 30–50%:
- Craniofacial abnormalities
- Thumb anomalies
- Short stature
- Cardiac defects
- Craniofacial abnormalities
79.4.2.3 Diagnosis
- CBC: macrocytic anemia with low reticulocytes
- Bone marrow: absent or decreased erythroid precursors
- Elevated erythropoietin levels
- Genetic testing (RPS19 mutations common)
79.4.2.4 Management
- Prednisolone (first-line therapy)
- Chronic transfusion therapy for steroid-resistant patients
- Iron chelation if transfusion-dependent
- HSCT is curative
- Nutritional and endocrine monitoring
79.4.3 Shwachman–Diamond Syndrome (SDS)
79.4.3.1 Overview
Autosomal recessive disorder characterized by: - Bone marrow failure (neutropenia common)
- Exocrine pancreatic insufficiency
- Skeletal abnormalities
79.4.3.2 Clinical Features
- Failure to thrive
- Recurrent infections
- Steatorrhea due to pancreatic insufficiency
- Variable cytopenias
79.4.3.3 Diagnosis
- CBC showing neutropenia
- Low fecal elastase (pancreatic insufficiency)
- Bone marrow with hypocellularity
- Genetic testing (SBDS mutations)
79.4.3.4 Management
- Pancreatic enzyme replacement therapy
- G-CSF for severe neutropenia
- HSCT for marrow failure
- Monitor for malignant transformation (risk of AML)
79.4.4 Dyskeratosis Congenita (DC)
79.4.4.1 Overview
A telomere biology disorder with triad: - Reticular skin pigmentation
- Nail dystrophy
- Oral leukoplakia
79.4.4.2 Clinical Features
- Progressive marrow failure
- Pulmonary fibrosis
- Liver disease
- Increased cancer risk
79.4.4.3 Diagnosis
- Telomere length assays
- Bone marrow: hypocellularity
- Genetic testing (TERT, TERC genes)
79.4.4.4 Management
- Supportive care
- HSCT for marrow failure
- Monitoring for liver and lung complications
79.4.5 Congenital Amegakaryocytic Thrombocytopenia (CAMT)
79.4.5.1 Features
- Severe thrombocytopenia early in infancy
- Absent megakaryocytes in marrow
- Mutations in thrombopoietin receptor (c-MPL gene)
- Progresses to pancytopenia
79.4.5.2 Management
- Platelet transfusions
- HSCT is curative
79.4.6 TAR Syndrome (Thrombocytopenia with Absent Radius)
79.4.6.1 Features
- Normal thumbs (unlike FA)
- Severe thrombocytopenia in infancy
- Cow’s milk intolerance
79.4.6.2 Management
- Supportive care
- Platelet transfusions
- Nutritional management
- Usually improves with age
79.4.7 Congenital Neutropenias (including Kostmann syndrome)
79.4.7.1 Features
- Severe neutropenia < 500/µL
- Recurrent bacterial infections
- Bone marrow with maturation arrest of granulocytes
79.4.7.2 Management
- G-CSF is highly effective
- HSCT if refractory or transformation to MDS/AML occurs
79.5 Acquired Bone Marrow Failure Syndromes
79.5.1 Aplastic Anaemia
79.5.1.1 Overview
Aplastic anaemia is characterized by peripheral pancytopenia and hypocellular bone marrow due to immune-mediated destruction of stem cells.
79.5.1.2 Causes
- Idiopathic (most common)
- Drugs: chloramphenicol, anticonvulsants, NSAIDs
- Viruses: hepatitis, EBV, HIV
- Toxins: benzene
- Autoimmune disorders
79.5.1.3 Clinical Features
- Fatigue (anemia)
- Infections (neutropenia)
- Bleeding/bruising (thrombocytopenia)
- No physical anomalies (helps distinguish from congenital causes)
79.5.1.4 Diagnosis
- Pancytopenia
- Bone marrow biopsy: hypocellularity without fibrosis or malignancy
79.5.1.5 Management
- Supportive care
- Immunosuppressive therapy (ATG + cyclosporine)
- HSCT (curative)
79.5.1.6 Ghana Context
Availability of ATG and cyclosporine may be limited; supportive care and referral are essential.
79.5.2 Transient Erythroblastopenia of Childhood (TEC)
79.5.2.1 Overview
Acquired, temporary suppression of erythropoiesis, often post-viral.
79.5.2.2 Features
- Occurs in children 6 months–6 years
- Normocytic anemia
- Reticulocytopenia
- Well child apart from pallor
79.5.2.3 Management
- Observation
- Transfusion rarely needed
- Recovery in 1–2 months
79.5.3 Parvovirus B19–Associated Aplastic Crisis
Especially severe in children with chronic hemolytic anaemias (e.g., HbC, thalassemia, sickle cell).
79.5.3.1 Features
- Sudden drop in Hb
- Reticulocytopenia
- Fever
79.5.3.2 Management
- Transfusion support
- Treat underlying infection
- Immunoglobulin therapy in immunodeficiency
79.5.4 Drug-Induced Bone Marrow Suppression
Common culprits: - Sulphonamides
- Chloramphenicol
- Anticonvulsants
- Cytotoxic chemotherapy
79.5.4.1 Management
- Stop offending drug
- Supportive care
- G-CSF or EPO in selected cases
79.5.5 Nutritional Marrow Failure
Severe malnutrition can lead to hypoplastic marrow with cytopenias.
Management focuses on nutritional rehabilitation.
79.6 Diagnosis of Bone Marrow Failure Syndromes
Key investigations include: - CBC with differential
- Reticulocyte count
- Bone marrow aspiration and biopsy (cellularity, morphology)
- Cytogenetics
- Genetic testing (if available)
- Telomere length testing
- Screening for infections (HIV, hepatitis, parvovirus B19)
Where such investigations are unavailable, careful clinical evaluation and referral are essential.
79.7 Management Principles
- Identify and treat reversible causes
- Provide supportive care
- Transfusions
- Infection prophylaxis
- Growth and endocrine monitoring
- Transfusions
- Consider HSCT early in congenital syndromes
- Provide family counselling
- Monitor for long-term complications (e.g., AML, MDS)
- Vaccination and infection prevention strategies
79.8 Local Context: Ghana and Sub-Saharan Africa
- Diagnostic gaps are significant; few centres perform bone marrow biopsies routinely.
- Congenital syndromes may be under-recognised and misdiagnosed as aplastic anaemia or malnutrition.
- HSCT is not widely available; most children rely on supportive care.
- Parvovirus B19–induced crises are common due to high background prevalence.
- Drug-induced marrow failure is an important consideration due to widespread use of chloramphenicol and sulphonamides in some settings.
79.9 Key Points for Clinical Practice
- Always distinguish congenital from acquired causes through careful history and examination.
- Congenital anomalies (thumb abnormalities, skin changes) are important diagnostic clues.
- HSCT is the only curative option for many congenital syndromes.
- Avoid unnecessary transfusions unless clinically indicated.
- Maintain high suspicion for viral causes in acute marrow suppression.
79.10 Further Reading
- Alter BP. Inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program.
- Young NS. Aplastic anemia. N Engl J Med.
- Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders.
- Hoffbrand AV, Higgs DR. Postgraduate Haematology.
- Ghana Health Service. Guidelines for Paediatric Haematology and Oncology.