Inherited bone marrow failure syndromes (IBMFS)
Introduction and Definition
- Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by the decreased bone marrow production of one or more major hematopoietic lineages.
- These disorders can manifest initially as a single cytopenia (e.g., isolated neutropenia, anemia, or thrombocytopenia) or as global pancytopenia with a hypoplastic or aplastic bone marrow.
- IBMFS share three key clinical hallmarks:
- bone marrow failure,
- congenital physical anomalies, and
- a marked predisposition to cancer, particularly myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and various solid tumors.
Pathophysiology
- The central pathophysiologic mechanism across most IBMFS is a low apoptotic threshold of mutant hematopoietic stem cells (HSCs), leading to accelerated apoptosis, premature senescence, and progressive depletion of bone marrow progenitors.
- These disorders are typically monogenic and arise from defects in critical, fundamental cellular pathways.
- Fanconi anemia is primarily driven by defects in DNA repair and homologous recombination, specifically involving the DNA interstrand cross-linking repair pathways.
- Dyskeratosis congenita is a telomeropathy resulting from pathogenic variants in genes encoding the telomerase complex and telomere-shelterin complex, leading to impaired telomere maintenance and extremely short telomeres.
- Diamond-Blackfan anemia and Shwachman-Diamond syndrome are classified as ribosomopathies, caused by defects in ribosome biosynthesis and ribosome assembly, respectively.
Major Syndromes and Clinical Features
| Condition | Physical Findings | Hematologic Abnormalities | Associated Malignancies | Genetic Basis | Laboratory/Diagnostic Tests |
|---|---|---|---|---|---|
| Fanconi anemia | Short stature, low birth weight, microcephaly, microphthalmia, hearing loss, triangular face, micrognathia, high broad forehead, bulbous nose, low set ears, hypertelorism, cardiac anomalies, tracheoesophageal fistula, esophageal atresia, kidney/renal anomalies, radial ray defects (hypoplastic thumb/radius), hypoplastic thenar eminence, clinodactyly, café-au-lait spots, hyperpigmentation. | Progressive pancytopenia, macrocytosis (increased MCV), elevated HbF, acellular or hypocellular bone marrow; may present initially with isolated thrombocytopenia. | Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), squamous cell carcinomas (SCC) of head/neck, esophagus, vulva, anus, cervix, liver tumors (hepatocellular carcinoma), Wilms tumor. | AR, XLR, or AD; Pathogenic variants in 22 FANC genes (notably FANCA, FANCC, FANCG, FANCB, BRCA2/FANCD1, RB1). | Increased chromosomal breakage/fragility in clastogenic assay (diepoxybutane/DEB or mitomycin C/MMC), G2/M cell cycle arrest by flow cytometry, NGS (WES/WGS). |
| Diamond Blackfan anemia | Short stature, craniofacial anomalies (depressed nasal bridge, high-arched palate, cleft lip/palate, microcephaly), skeletal/upper limb anomalies (triphalangeal thumb, flat thenar eminence), absent radial pulse, cardiac, and genitourinary (absent/horseshoe kidney) abnormalities. | Pure red cell aplasia/failure, macrocytic anemia, reticulocytopenia, paucity of bone marrow erythroid precursors; occasionally neutropenia, thrombocytosis, or thrombocytopenia. | Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), colon/colorectal carcinoma, osteogenic sarcoma, female genital (breast) cancers. | AD (mostly) or XLR (GATA1, TSR2); Mutations in ribosomal protein genes (RPS19, RPL5, RPL11, RPS10, RPS24, RPS26). | Increased erythrocyte adenosine deaminase (eADA) activity, macrocytosis, elevated HbF, bone marrow aspirate showing paucity of erythroid precursors, normal chromosome breakage test. |
| Shwachman Diamond syndrome | Exocrine pancreatic insufficiency (fat malabsorption, steatorrhea, diarrhea), failure to thrive, short stature, skeletal abnormalities (metaphyseal dysostosis, rib cage abnormalities), neurodevelopmental delay. | Neutropenia (chronic or intermittent), anemia, thrombocytopenia, progression to pancytopenia and bone marrow failure; hypocellular bone marrow. | Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) (8.1% incidence at 10 years; up to 30% risk). | AR (SBDS, DNAJC21, EFL1) or AD (SRP54); also associated with abnormalities of chromosome 7. | Low serum isoamylase, low serum trypsinogen, fecal elastase reduction, pancreatic ultrasound (lipomatosis), low B cells, abnormal T-cell proliferation, genetic analysis. |
| Dyskeratosis congenita | Mucocutaneous triad (lacy reticular skin pigmentation, nail dysplasia/dystrophy, oral leukoplakia), pulmonary fibrosis, esophageal stenosis/webs, liver fibrosis, short stature, epiphora, early graying, lymphedema, ectodermal dysplasia. | Progressive bone marrow failure (pancytopenia), macrocytosis (high MCV), elevated HbF, acellular or hypocellular bone marrow; cytopenias may present at later ages. | Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), solid tumors (SCC of head and neck, skin, GI tract, anorectal adenocarcinoma). | XLR (DKC1), AD (TINF2, TERC, TERT, RTEL1, ACD), or AR (NHP2, NOP10); mutations in telomere maintenance genes. | Very short telomeres measured by flow-FISH (diagnostic hallmark), genetic sequencing (NGS/WES). |
| Congenital amegakaryocytic thrombocytopenia (CAMT) | Petechial rash, bruising, bleeding, intracranial hemorrhage; occasionally neurologic (cerebral/cerebellar atrophy), cardiac, orthopedic, renal anomalies, or microcephaly; often no physical anomalies at birth. | Severe isolated neonatal thrombocytopenia, absent or greatly reduced megakaryocytes in bone marrow; progression to pancytopenia/severe aplastic anemia by childhood. | Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML). | AR (MPL, THPO) or AD (HOXA11, MECOM); pathogenic variants in MPL (TPO receptor gene). | Bone marrow aspirate/biopsy showing absence of megakaryocytes, elevated plasma thrombopoietin (TPO) levels, MPL gene sequencing. |
Other Notable Syndromes
- Thrombocytopenia-Absent Radius (TAR) Syndrome: Characterized by bilateral absent radii but with present thumbs, alongside severe thrombocytopenia that often improves after the first year of life.
- Severe Congenital Neutropenia (SCN): Includes disorders like Kostmann syndrome (HAX1 mutation) and ELANE mutations, presenting with severe bacterial infections and a maturation arrest of myelopoiesis at the promyelocyte stage.
- GATA2-Related Disorders: Autosomal dominant mutations causing immunodeficiency (MonoMAC syndrome), lymphedema (Emberger syndrome), and a high predisposition to primary MDS and AML.
Diagnostic Approach
- A detailed family history, history of medication or toxin exposure, and a thorough physical examination looking for specific congenital anomalies must be performed for any child presenting with cytopenias.
- Initial laboratory evaluation should include a complete blood count with reticulocyte count, peripheral blood smear, mean corpuscular volume (MCV), and fetal hemoglobin (HbF) levels.
- Bone marrow aspiration and trephine biopsy are essential to assess overall cellularity, evaluate for multilineage dysplasia, and perform cytogenetic studies to rule out MDS or leukemia.
- Specific screening tests include the chromosomal breakage assay (using clastogens like diepoxybutane or mitomycin C) for Fanconi anemia.
- Telomere length measurement via flow-FISH is utilized to diagnose dyskeratosis congenita.
- Erythrocyte adenosine deaminase (eADA) activity is typically elevated in Diamond-Blackfan anemia.
- Comprehensive genetic testing, including next-generation sequencing (NGS) panels for known IBMFS genes or whole-exome sequencing, is increasingly the standard of care to establish a definitive molecular diagnosis.
Management
- Supportive care is a mainstay of treatment, utilizing judicious, leukocyte-depleted, irradiated red blood cell and platelet transfusions only when clinically indicated to prevent severe alloimmunization and iron overload.
- Corticosteroids (e.g., prednisone) are the primary medical therapy for Diamond-Blackfan anemia, inducing a reticulocyte response in approximately 80% of patients.
- Androgen therapy (e.g., oxymetholone or danazol) can stimulate hematopoiesis and is effective in improving blood counts in about 50% of patients with Fanconi anemia and Dyskeratosis congenita.
- Cytokine therapy with Granulocyte Colony-Stimulating Factor (G-CSF) is utilized to manage severe neutropenia in SCN, SDS, and occasionally FA, though it must be monitored closely due to the risk of promoting leukemic transformation.
- Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the bone marrow failure, MDS, and leukemia associated with IBMFS.
- Preparative regimens for HSCT must frequently employ reduced-intensity conditioning (avoiding radiation and high-dose alkylating agents) due to the exquisite sensitivity of patients (especially those with FA and DC) to DNA-damaging therapies.
- Rigorous, lifelong cancer surveillance is mandatory, including regular bone marrow evaluations for clonal evolution, screening for head/neck and gynecologic squamous cell carcinomas, and monitoring of liver and endocrine function.