Fanconi Anemia Quiz

Inherited Bone Marrow Failure Syndromes

• Inherited bone marrow failure syndromes (IBMFSs) are rare monogenic disorders.
• They are characterized by blood cytopenia and non-hematological effects.
• Examples of IBMFSs include Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), severe congenital neutropenia (SCN), congenital dyserythropoietic anemia (CDA), congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia-absent radii (TAR), and other rare entities.
• Two conditions, GATA2 deficiency and SAMD9/9L mutations, have recently been identified as more common.

Introduction

• IBMFSs comprise a group of rare monogenic disorders characterized by blood cytopenia(s) and non-hematological effects.
• Examples include Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), severe congenital neutropenia (SCN), congenital dyserythropoietic anemia (CDA).
• Congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia-absent radii (TAR), and other rare entities.

Inherited BMF Syndromes

• Pancytopenia, often with a global hematopoietic defect
• Fanconi anemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• Reticular dysgenesis
• Pearson syndrome
• Familial aplastic anemia (autosomal and X-linked forms)
• Myelodysplasia
• Non-hematological syndromes (e.g., Down, Dubowitz syndromes)
• Single cytopenia (usually anemia)
• Diamond-Blackfan anemia
• Congenital dyserythropoietic anemia
• Neutropenia
• Severe congenital neutropenia (including Kostmann syndrome)
• Thrombocytopenia
• Congenital amegakaryocytic thrombocytopenia
• Amegakaryocytic thrombocytopenia with absent radii

Manifestations

• Some syndromes manifest during the neonatal period (e.g., DBA, SCN)
• Others develop in childhood (e.g., FA, DC)
• Others may present at any time in life (e.g., DC or SDS).
• IBMFSs do not respond to immunosuppressive therapy.
• IBMFSs are associated with a high risk of developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and, in some cases, solid tumors.

Recent Advances in Genetic Diagnosis

• Recent advances in the genetic diagnoses of IBMFSs have identified germline mutations affecting DNA repair, telomere maintenance, and ribosome biogenesis.
• These functions are necessary for hematopoietic stem cell/progenitor cell (HSC/HSPC) self-renewal and the generation of mature blood cells.
• Aplastic anemia and IBMFS share similar biological features of decreased HSCs, progenitors, or precursors, but IBMFS is caused by an intrinsic defect in HSC/HSPC, while aplastic anemia has an exogenous attack against HSC/HSPC.

The Role of Inflammatory Cytokines

• There is heterogeneity in IBMFS development and phenotypes, even with the same gene mutation.
• Inflammatory cytokines produced by and acting on hematopoietic and stromal cells control hematopoiesis.
• Dysregulation between lymphocyte and cytokine activities has been reported in aplastic anemia and hypoplastic MDS, though understudied in IBMFS.
• Most IBMFSs are associated with an increased risk of myeloid or solid malignancies where aberrant cytokine profiles may play a role.
• Pro-inflammatory cytokines (IL-6 and IL-8) and an anti-inflammatory cytokine (TGF-β) are elevated in certain IBMFSs.
• Oxidative stress and reactive oxygen species (ROS) are common in IBMFS models.
• Mitochondrial dysfunction may exacerbate ROS.

Summary of Inflammatory Profiles

• Data are shown from multiple studies regarding inflammatory profiles in IBMFS subtypes (FA, DC, DBA, SDS).
• Increased or decreased levels of various cytokines are seen depending on the subtype.

Inherited Marrow Failure Syndromes with Predominantly Pancytopenia

• Fanconi anemia (FA) is the most frequent IBMFS.
• Often characterized by pancytopenia or myeloid neoplasia (MDS/AML).
• Typically occurs between 5 and 15 years of age, often with systemic traits like "Fanconi facies" present.
• Increased risk of MDS/AML in adolescence/young adulthood, and later solid tumors, particularly esophageal/pharyngeal and genitourinary malignancies.
• Physical anomalies can also be present

Dyskeratosis Congenita (DC)

• Classical DC involves an abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia triad.
• Bone marrow failure (BMF) is a major cause of early mortality in DC.
• Higher risk of hematological and non-hematological malignancies, and fatal pulmonary complications are present.
• X-linked recessive, autosomal dominant, and autosomal recessive are forms of the illness; DC is heterogeneous clinically and genetically.
• Clinical manifestations usually start in childhood, beginning with pigmentation and nail changes by 10 years old.
• Frequent causes of death include BMF/immunodeficiency, pulmonary complications, and malignancy.

Shwachman-Diamond Syndrome (SDS)

• Autosomal recessive disorder.

• Second most common cause of exocrine pancreatic insufficiency after cystic fibrosis.

• Presents with a common triad of exocrine pancreatic dysfunction, skeletal abnormalities, and bone marrow dysfunction.

• Some cases also include immune or hematological disorders.

• A mutation in the SBDS gene on chromosome 7 is found in 90% of cases.

• The SBDS protein is widely expressed throughout the body in various organ systems.

• Spectrum of hematological abnormalities includes neutropenia (60%) or another cytopenia (20%) and pancytopenia (25%).

• Common age range for the development of leukemia is from 1–43.

• Unexplained predominance for leukaemia among males.

Diagnosis of Marrow Failure

• The chromosomal breakage/stress cytogenetics test is a diagnostic test for patients with severe pancytopenia.
• Patients with abnormal chromosome breakage or hypersensitivity to certain DNA cross-linking agents will be screened for potential marrow failure syndromes.

Additional Lab Evaluations and Diagnosis

• Evaluate patients with pancytopenia, characteristic malformations, and family history of bone marrow failure.
• A complete blood count should be completed along with an evaluation of red blood cells, white blood cells, and platelets. Serum erythropoietin levels should be increased due to the low numbers of blood cells.
• A bone marrow aspiration and biopsy may be done for an in-depth view of the marrow, presenting with hypocellularity, aplasia with fatty marrow, presence or absence of myeloid, erythroid, and megakaryocyte stem cell lines.
• Additionally, karyotyping and cytogenetics testing may be used to screen for chromosomal abnormalities.

Congenital Dyserythropoietic Anemias (CDAs)

• CDAs include a group of conditions characterized by ineffective erythropoiesis resulting in monolinear cytopenia.
• For a long time, the bone marrow's morphological abnormalities (e.g., erythroid hyperplasia or multinuclearity) have been used for CDA diagnoses.
• Unfortunately, these features are seen in other stress-inducing conditions (e.g., iron deficiency, in premature birth).
• Working classification includes 3 types based on morphological abnormalities of erythroblasts in the bone marrow.
  • Type I is characterized by abnormal chromosomes and mild-moderate anemia.
  • Type II presents with variable anemia and an increased degree of jaundice.
  • Type III is a rare subtype with an increased prevalence of lymphoproliferative disorders.

Congenital and Cyclical Neutropenias

• Congenital neutropenia is a heterogeneous disorder.
• The neutropenia is often recognized at birth. Neutrophil counts are typically below 0.2 x 10⁹/L.
• Peripheral blood counts and bone marrow analysis may be used to help find a cause.

Thrombocytopenia with Absent Radii (TAR)

• TAR is an autosomal recessive disorder characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia.
• Typically characterized by a low platelet count and abnormalities at birth.
• Additional skeletal abnormalities may be present.

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

• Usually characterized by isolated thrombocytopenia and deficient megakaryocytes in the bone marrow.
• Frequently appears in infancy with no other somatic abnormalities.
• Genetic subtypes include autosomal recessive and X-linked.
• Approximately 50% of cases will develop aplastic anemia (AA) by the age of 5.
• Treatment options include hematopoietic stem cell transplantation (HSCT).

Diamond-Blackfan Anemia (DBA)

• Congenital anemia characterized by pure red cell aplasia.

• Associated with congenital bone abnormalities and is a heterogeneous genetic disease.

• Autosomal dominant inheritance in 40-45% of cases, with sporadic presentation in the remaining 55-60%.

• In some cases, autosomal recessive inheritance with less frequency has been noted.

• Ribosomal gene mutations are common in DBA.

• The mutation of a transcription factor GATA1 has also been noted in some studies.

• Chromosomal abnormalities have been identified.

Other Inherited Bone Marrow Failure Syndromes and Information

• Other syndromes and important details regarding specific disorders (e.g., autosomal recessive or X-linked inheritance, additional features, diagnosis) is also available from the study notes.

Test your knowledge on Fanconi Anemia (FA) and its associated cytokines, genetic factors, and clinical manifestations. This quiz covers key aspects of FA pathology, including cytokine levels, genetic inheritance, and diagnostic criteria. Challenge yourself and deepen your understanding of this rare genetic disorder.