35 Inherited Bone Marrow Failure Syndromes
- Inherited BMF syndromes: pancytopenia ± dysplasia & extraskeletal features
- Fanconi anemia (FA): most common; ↑ MDS/AML risk ~1% yearly
- TBDs: telomere biology disorders w/ triad—pancytopenia, dysplasia, hepatic/pulmonary disease
- GATA2 deficiency: → MDS/AML (high risk), immune defects, disseminated MAC
- Dx: telomere length, DEB/MMC breakage, genetic sequencing
- HSCT only curative; timing critical before progression
35.1 Fanconi Anemia
Definition & epidemiology - Autosomal recessive DNA repair defect; hypersensitive to crosslinking agents - Incidence ~1:130,000; ~70% of inherited BMF - Pathognomonic DEB/MMC test: ↑ chromosomal breakage - ~15% lack classic symptoms at dx
Clinical features - Short stature, skeletal/thumb anomalies, microcephaly, hypogonadism - Renal/cardiac anomalies; café-au-lait spots, hyperpigmentation - Progressive pancytopenia ± dysplasia (median age ~6 y) - 90% risk MDS/AML; median onset ~15 y (wide range)
Pathophysiology & genetics - 22 complementation groups (FANCA, FANCG, FANCC = 95% cases) - Somatic mutations in germline cells; FANCG reversions protective in some - Defective interstrand crosslink repair → genomic instability - RUNX1 mutations: ↑ AML risk - Somatic abnormalities (trisomy 7, monosomy 7): predict advanced disease
Diagnosis - DEB/MMC breakage test: ↑ breakage pathognomonic - Telomere length testing (some FA: short telomeres) - Genetic sequencing confirmation - BM exam: assess dysplasia, AML
Treatment - Androgens (danazol) may ↑ counts; bridge to HSCT - HSCT definitive cure; HLA-matched sibling excellent; unrelated donor ~75-80% - HSCT before advanced disease (MDS cytogenetics, severe dysplasia) - Surveillance: annual BM, malignancy screening (skin, GYN) - Avoid DEB-damaging agents (mitomycin, cisplatin)
Clinical Pearls - DEB test essential; negative doesn’t exclude FA (somatic reversion) - Monitor secondary MDS cytogenetics (trisomy 7, monosomy 7) → prompt HSCT - Solid tumor risk ~40% lifetime (skin, GYN, head/neck)
35.2 Telomere Biology Disorders
Definition & epidemiology - Shortened telomeres & impaired telomerase function - DKC1 (X-linked), TERT, TERC (AD/AR) most common - Median dx age ~15 y; variable penetrance & severity w/in families - ~60% POT1 mutation carriers develop classical features
Classical triad 1. Pancytopenia ± dysplasia, hypocellular BM 2. Hepatic cirrhosis, pulmonary fibrosis (often overlooked initially) 3. Dyskeratosis congenita (DC): oral leukoplakia, skin pigmentation, nail dystrophy
Pathophysiology - Defective telomerase complex (TERT, TERC, TINF2, RTEL1, PARN) - ↓ telomerase activity → HSC replicative senescence - Compensatory hematopoiesis ↑ telomere shortening - HSC exhaustion → MDS/AML (~10% lifetime risk) - Pulmonary fibrosis & cirrhosis: tissue-specific stem cell failure
Diagnosis - Telomere length (flow-FISH): very short for age (diagnostic) - DKC1: classic male-limited w/ skin pigmentation, oral leukoplakia - TERT, TERC, TINF2: adults, subtle phenotype - Genetic sequencing: identify adult-onset disease - Monoclonal T-cell expansion common (not diagnostic)
Treatment - Androgens may ↑ counts; limited efficacy - HSCT: outcomes better than FA; conditional regimens preferred - Avoid high-dose HSCT (↑ pulmonary/hepatic toxicity) - HSCT early (before BM failure deepens) - Screen malignancies (~40% lifetime); monitor pulmonary fibrosis - G-CSF cautiously (may ↑ telomere erosion)
Clinical Pearls - Telomere length essential for dx (distinguish MDS, aplastic anemia) - Occult cirrhosis & pulmonary fibrosis common; baseline imaging + lung function - MDS/AML risk lower than FA but substantial; annual BM surveillance
35.3 GATA2 Deficiency
Definition & epidemiology - Monoallelic GATA2 mutations → autosomal dominant (variable penetrance) - Variable presentation: immunodeficiency, BMF, neoplasia, disseminated MAC - Age of dx varies (childhood to adulthood)
Clinical features - Pancytopenia ± dysplasia, monosomy 7 (common cytogenetic finding) - Disseminated Mycobacterium avium complex (MAC) - Immune defects: ↓ B cells, ↓ NK cells, ↑ HPV/EBV cancers - MDS/AML evolution: 40-70% lifetime risk - Warts, viral infections
Pathophysiology - Transcription factor deficiency → hematopoietic & immune dysregulation - Monosomy 7: somatic loss of normal GATA2 allele - Clonal evolution → MDS/AML - MAC predisposition: aberrant macrophage differentiation
Diagnosis - BM: pancytopenia w/ dysplasia, monosomy 7 - GATA2 genetic testing (sequencing) - Recurrent infections, especially MAC - Flow cytometry: ↓ B cells, ↓ NK cells
Treatment - HSCT early (before MDS/AML progression) - Prophylaxis: MAC (azithromycin), PCP, CMV - Monitor for viral malignancies (HPV, EBV) - Aggressive treatment of infections
Clinical Pearls - Monosomy 7 + immune defects → suspect GATA2 - MAC screening essential; MAC infection may be first presentation - Early HSCT before disease progression improves outcomes
35.4 SAMD9/SAMD9L Deficiency
Definition & clinical features - Intrauterine growth restriction, adrenal hypoplasia, enteropathy - Progressive cytopenias w/ MDS/AML evolution - Gain-of-function mutations (SAMD9 upd7q somatic reversions in BM) - ~200 reported cases; germline mutations on genetic testing
Pathophysiology - Gain-of-function: ↑ innate immune activation - MDS evolution in subset - Somatic SAMD9L mutations: may reverse cellular toxicity in HSCs - Cellular selection favors mutant clones
Diagnosis - Monosomy 7 from somatic SAMD9/L mutations (cultured fibroblasts, BM) - Genetic sequencing: germline mutations - UPD7q: genetic rescue observed in some
Treatment - Surveillance: infections, malignancy screening - HSCT if MDS progresses - Monitor somatic reversion events in BM (may ↑ hematopoiesis) - Supportive care early
35.5 Diamond-Blackfan Anemia
Definition & clinical features - Hereditary hypoproliferative anemia; ~50% dx by age 2 y - Pure RBC aplasia (normal WBC/platelets—vs. FA) - Macrocytic anemia; ↑ HbF - Short stature, skeletal/cardiac anomalies (20-50%) - Thumb/radius anomalies, cardiac defects, cleft palate
Pathophysiology & genetics - Ribosomal protein mutations (RPS19, RPL5, RPL35a, RPS26, RPL11, RPS24; >40% cases) - GATA1, TP53 (gain-of-function), ADAT2 also causative - Defective ribosome biogenesis → ↓ erythroid progenitor proliferation - Somatic mutations w/ selective advantage (e.g., PIGA hemizygous loss for X-linked reversion)
Diagnosis - ↑ HbF; pure RBC aplasia w/ normal WBC/platelets - NO chromosomal breakage (DBA ≠ DEB hypersensitivity) - Genetic sequencing: ribosomal protein mutations - ↑ RBC adenosine deaminase (RDA) diagnostic
Treatment - Steroids (prednisone, dexamethasone) first-line; ~75% respond - Chronic RBC transfusions for failures (↑ iron overload risk) - HSCT curative for subset; variable outcomes - Malignancy risk: ~3-4% lifetime solid tumors, AML - Monitor: SDS-like syndrome, cardiac defects
Clinical Pearls - RDA level diagnostic; normal chromosomal fragility (vs. FA) - Somatic reversions (PIGA loss) may appear; monitor clonal expansion - Steroid response variable; ~75% initial response, many develop dependence
35.6 Congenital Dyserythropoietic Anemias
Definition, features & pathophysiology - Congenital dyserythropoiesis w/ ineffective erythropoiesis despite ↑ EPO - CDA I (majority): rare skeletal defects, chromatin bridging; CDIN1 mutations - CDA II: SEC23B mutations; HEMPAS antigen; dyserythropoiesis on smear - CDA III: KIF23, transcription factors (GATA1); multinucleate erythroblasts - Hemolysis, splenomegaly, iron overload common - Gallstones, cardiac dysfunction, rarely AML
Diagnosis - BM: dysplastic erythroblasts (multinucleated, abnormal nuclear membranes) - Flow cytometry: HEMPAS antigen (CDA II only) - Genetic sequencing: CDIN1 (type I), SEC23B (type II) - NGS: increasingly identifies causative mutations
Treatment - RBC transfusions, iron chelation - Folic acid, EPO if responsive - HSCT for severe cases (variable outcomes) - Splenectomy if hypersplenism
35.7 Shwachman-Diamond Syndrome
Definition & clinical features - Autosomal recessive: exocrine pancreatic insufficiency (>90%) & BM dysfunction - Metaphyseal chondrodysplasia, short stature, pancreatic atrophy - Pancytopenia w/ MDS/AML propensity (~30% lifetime risk) - Failure to thrive, diarrhea, malabsorption; arthritis, lipodystrophy in some
Pathophysiology & genetics - SBDS gene (>90% cases); DNAJC21, EFL1 also causative - Defective ribosome assembly → ↓ protein synthesis - Somatic TP53, DNAJC21, EFL1 mutations drive MDS/AML - Clonal hematopoiesis common precursor to leukemia
Diagnosis - BM: hypocellularity, dysplasia - SBDS genetic testing (most reliable); biallelic mutations diagnostic - ↑ Fecal fat, ↓ lipase, exocrine insufficiency - High-risk cytogenetics (monosomy 7, complex karyotype) → prompt HSCT
Treatment & prognosis - Pancreatic enzyme replacement; G-CSF for severe neutropenia - Allogeneic HSCT: only curative (poor outcomes in SDS-related MDS/AML) - Cytoreductive chemotherapy (low-dose) if HSCT deferred - TP53 mutations: worse prognosis, poor cytotoxic response - Disease progression common; median HSCT age older than FA
Clinical Pearls - SBDS mutations most frequent; somatic events (TP53) predict AML - Difference from FA: exocrine pancreatic disease, normal DEB, ↓ chromosome fragility - SDS-related MDS/AML: poor prognosis; early HSCT crucial
35.8 Congenital Amegakaryocytic Thrombocytopenia
Definition & clinical features - CAMT: autosomal recessive; thrombocytopenia at birth (often <10k) - Absent radii & other THPO signaling abnormalities (variable) - Additional blood cell cytopenias; mild-moderate anemia common - Progressive pancytopenia; median HSCT age ~1 y
Pathophysiology & genetics - THPO, MPL mutations (germline); THPO deficiency or MPL receptor impairment - Absent/severely ↓ megakaryocytes on BM - Additional somatic mutations (e.g., SETBP1) → MDS evolution - ~13% CAMT: marked cytogenetic abnormalities
Diagnosis - ↓/absent megakaryocytes on BM - THPO, MPL genetic testing - Platelet counts typically <30k; bleeding risk
Treatment - Early HSCT: only curative (higher failure risk vs. FA due to early stem cell exhaustion) - Corticosteroid trials; limited efficacy - Splenectomy if post-HSCT relapse - Untransplanted: poor outcomes due to bleeding
35.9 Inherited Thrombocytopenias
35.9.1 Thrombocytopenia-Absent Radius Syndrome
Definition & clinical features - TAR: autosomal recessive; leukocytic thrombocytopenia, bilateral radial aplasia - Thumbs normal; radii absent (key distinction) - Radioulnar synostosis, micromelia in some - Bleeding tendency; platelets often <10k; ↑ risk in childhood - Immune-mediated component → IVIG responsive in subset
Pathophysiology & genetics - RBMSA gene mutations; protein important for RNA metabolism - Mechanism unclear; normal TPO → problem in megakaryopoiesis - Autosomal recessive; variable penetrance
Diagnosis - Bilateral radial aplasia on X-ray; thumbs normal (vs. FA) - BM: normal or ↑ megakaryocytes - Platelets <50 × 10^9/L typical
Treatment - Supportive care, transfusions PRN - IVIG, corticosteroids for immune component - HSCT rarely needed - Prognosis favorable; most improve spontaneously by late childhood
35.9.2 Familial Platelet Disorder w/ Associated Myeloid Malignancy
Definition & clinical features - RUNX1 germline mutations → autosomal dominant - Mild thrombocytopenia, platelet dysfunction - ≥95% lifelong risk: thrombocytopenia, clonal hematopoiesis, AML
Pathophysiology & genetics - Transcription factor RUNX1: critical for hematopoietic development - Somatic RUNX1 mutations + additional hits → AML/MDS - Immune abnormalities (psoriasis, RA) in some
Diagnosis - Mild bleeding, mild thrombocytopenia - Family history AML/MDS - RUNX1 genetic testing
Treatment - Surveillance for myeloid malignancy - HSCT potential MRD screening - Germline mutation screening in families
35.10 Comparison Table
| Syndrome | Age | Cytopenias | Extraskeletal Features | MDS/AML | Diagnosis |
|---|---|---|---|---|---|
| Fanconi anemia | ~6 y | Pancytopenia, dysplasia | Short stature, thumb, kidney, ↑ cancers | 90% | DEB/MMC breakage |
| TBDs | ~15 y | Pancytopenia, dysplasia | DC skin, oral leukoplakia, pulmonary fibrosis, cirrhosis | 10–15% | ↓ telomere length, genetic testing |
| GATA2 | ~20 y | Pancytopenia ± dysplasia | MAC, immune deficit (↓B/NK), HPV/EBV cancers | 40–70% | Monosomy 7, GATA2 mutation |
| SAMD9/SAMD9L | Childhood | Mild-moderate cytopenias | Adrenal hypoplasia, enteropathy, infection | Moderate | UPD7q, germline mutation |
| DBA | <2 y | Pure RBC aplasia | Short stature, skeletal defects, cardiac | 3–5% | ↑ RDA, genetic testing |
| SDS | Infancy | Pancytopenia | Exocrine pancreatic failure, fatty infiltration | ~30% | SBDS mutation, ↑ fecal fat |
| Congenital dyserythropoiesis | Variable | RBC, dysplasia | Hemolysis, splenomegaly, iron overload, rare AML | Low | BM morphology, CDIN1/SEC23B |
| TAR | Infancy | Mild thrombocytopenia | Bilateral absent radii (thumbs normal), normal megakaryocytes | None | Radiology, normal DEB |
35.11 General Management Principles
Diagnosis - BM exam w/ cytogenetics & morphology essential - Genetic testing increasingly available; multiplex panels recommended - Telomere length testing for suspected TBDs - DEB/MMC cytogenetic testing for suspected FA
Surveillance - Annual BM: assess dysplasia, new cytogenetic abnormalities - Malignancy screening (skin, GYN, solid tumors): age-dependent protocols - Monitor progression signals (↑ blasts, monosomy 7, complex karyotype) → prompt HSCT
HSCT considerations - Only curative therapy; timing critical before advanced disease - FA: HLA-identical sibling ~90% success; unrelated donor ~75-80% - TBDs: ~60-75%; avoid high-dose (↑ toxicity) - GATA2: early HSCT before MDS/AML - SDS: poor MDS/AML prognosis; defer until advanced in many
Antimyeloid strategies - Somatic TP53, DNAJC21, EFL1, additional mutations: poor outcome predictors - Allogeneic HSCT, MRD-directed approaches emerging - Hypomethylating agents (azacitidine) active in some; limited IBMF evidence
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