Congenital anemia Notes

NOTES NOTES CONGENITAL ANEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inherited macrocytic-normochromic anemias ▫ Diamond–Blackfan anemia ▫ Fanconi anemia COMPLICATIONS ▪ Congenital anomalies, ↑ blood malignancy risk, solid tumor cancers SIGNS & SYMPTOMS ▪ See individual disorders DIAGNOSIS ▪ See individual disorders TREATMENT ▪ See individual disorders 368 OSMOSIS.ORG

Chapter 44 Congenital Anemia DIAMOND–BLACKFAN ANEMIA (DBA) osms.it/diamond-blackfan-anemia PATHOLOGY & CAUSES ▪ Autosomal dominant ribosomopathy resulting in inherited bone-marrow failure syndrome, macrocytic-normochromic anemia, associated congenital anomalies ▪ Genetic mutation → ribosomopathy → impaired hematopoiesis → red blood cell aplasia → macrocytic-normochromic anemia ▫ No other significant cytopathies evident ▫ Sporadic, unpredictable penetrance → high degree of genotypic heterogeneity → variety of possible congenital anomalies OSMOSIS.ORG 369

COMPLICATIONS ▪ Genetic predisposition to malignancies like myelogenous leukemia, myelodysplastic syndrome, solid tumors ▪ Congenital anomalies increase complication risk SIGNS & SYMPTOMS ▪ Anemia often present at birth → signs and symptoms of impaired oxygen-carrying capacity (e.g. pallor, tachycardia, apnea, lethargy) ▪ Low birth weight, evidence of growth restriction usually present Congenital anomalies ▫ Craniofacial: low-set ears, micrognathia, high-arched/cleft palate, broad nasal bridge ▫ Neck: short, may be webbed ▫ Ophthalmological: congenital glaucoma, cataracts, strabismus ▫ Thumbs: duplex/bifid; flat thenar eminence ▫ Urogenital: absent/horseshoe kidney ▫ Cardiac: ventricular/atrial septal defect, coarctation of the aorta DIAGNOSIS ▪ DBA usually diagnosed within first month of life DIAGNOSTIC IMAGING Renal imaging/echocardiography ▪ Find internal congenital anomalies LAB RESULTS ▪ Complete blood cell count (CBC) with red blood cell indices ▫ ↓ red blood cell count, hemoglobin, hematocrit ▫ Reticulocytopenia ▫ ↑ mean corpuscular volume (MCV) ▫ Normal mean corpuscular hemoglobin (MCH), white blood cell, platelet counts ▪ Bone marrow aspirate normal, except few/ 370 OSMOSIS.ORG no erythroid precursors ▪ Serum erythropoietin, fetal hemoglobin (HbF) increased secondary to stress hematopoiesis ▪ Elevated erythrocyte adenosine deaminase (eADA) OTHER DIAGNOSTICS ▪ Classical physical congenital anomalies associated with DBA ▪ Genetic testing, family history TREATMENT ▪ 25% chance of spontaneous remission MEDICATIONS Corticosteroids ▪ Hemoglobin ↑ observed after steroid therapy initiation ▪ Weigh dose, duration of steroid treatment against adverse effects (e.g. growth disturbances, adrenal suppression, immunosuppression, pathological fractures) SURGERY Curative ▪ Allogeneic hematopoietic stem cell transplant OTHER INTERVENTIONS ▪ Monitor for development of malignancies ▪ Specialist care (e.g. cardiology, nephrology, urology) ▪ Family support, genetic counseling Transfusions ▪ Packed red blood cells ▫ Maintain Hgb ≥ 8g/dL ▫ Must be leukocyte poor to decrease transmission of cytomegalovirus ▫ Monitor for iron overload, hemosiderosis

Chapter 44 Congenital Anemia FANCONI ANEMIA (FA) osms.it/fanconi-anemia PATHOLOGY & CAUSES ▪ Autosomal recessive/X-linked disorder of chromosome fragility causing inherited bone marrow failure syndrome, macrocyticnormochromic anemia, pancytopenia Physical abnormalities ▪ Short stature, malformations associated with the VACTERL-H (vertebral, anal, cardiac, tracheoesophageal, renal, limb and hydrocephalus) association ▫ Microcephaly, congenital heart disease, imperforate anus, conductive deafness, hypogenitalia, cafe-au-lait spots CAUSES ▪ Mutation of several genes responsible for DNA repair ▫ Impaired cellular repair of DNA crosslinks → impaired regulation of cell cycle, genomic instability → hematopoietic stem cell loss → macrocyticnormochromic anemia → bone marrow aplasia → pancytopenia ▫ Predisposition for development of blood/ solid tumor malignancies ▪ Bone marrow biopsy usually normocellular at birth ▪ Macrocytic-normochromic anemia and other cytopenias develop gradually → usually diagnosed within first eight years of life COMPLICATIONS ▪ Neutropenia: life-threatening infections ▪ Thrombocytopenia: bleeding tendencies ▪ Malignancies: e.g. myelogenous leukemia, myelodysplastic syndrome, solid tumors ▪ Endocrine derangements: hypothalamicpituitary axis disruption during fetal development ▪ Congenital anomalies SIGNS & SYMPTOMS ▪ Cytopenias develop → clinical manifestations → increased bruising/ bleeding, frequent infections ▪ Symptomatic anemia related to impaired oxygen-carrying capacity develops late in disease DIAGNOSIS ▪ History, physical examination LAB RESULTS ▪ CBC assessment, bone marrow examination FA testing indicators ▪ Evidence of single-/multilineage cytopenias with no other identified cause ▫ ↓ absolute neutrophil count, platelet count, absolute reticulocyte count, hemoglobin ▪ Hypocellular bone marrow (without evidence of malignancy/other known cause) ▪ Congenital anomalies ▪ Family history: people of Ashkenazi Jewish descent have ↑ carrier frequency FA-specific testing ▪ Chromosome DEB assay ▫ Laboratory test for chromosomal breakage performed on leukocytes (indicates chromosome instability syndrome; not FA-specific) ▪ Cytometric flow analysis ▫ Examines cellular growth, division; cytometry following DNA crosslinking shows cells unable to repair DNA damage, cellular arrest in cell cycle G2 phase ▪ Chromosomal breakage test positive → FA gene sequencing recommended OSMOSIS.ORG 371

TREATMENT MEDICATIONS Growth factors ▪ Granulocyte colony-stimulating factor (GCSF) ▪ Granulocyte-macrophage-stimulating factor (GM-CSF) ▪ Thrombopoietin mimetics (e.g. romiplostim) Androgen therapy ▪ (e.g. oxymetholone) sometimes ↑ blood cell count SURGERY Bone marrow failure ▪ Allogeneic hematopoietic stem cell transplant 372 OSMOSIS.ORG OTHER INTERVENTIONS ▪ Screen, monitor for malignancies ▪ Specialist care (e.g. cardiology, nephrology, endocrinology) ▪ Family support, genetic counselling Transfusions ▪ Leukoreduced, irradiated packed red blood cells ▫ Symptomatic anemia ▫ Hemodynamic instability ▪ Platelet transfusions ▫ Platelet count < 10,000/microL ▫ Evidence of severe bruising, bleeding