Fanconi Anemia Genetics Quiz

Inherited Bone Marrow Failure Syndromes

• Inherited Bone Marrow Failure Syndromes (IBMFSs) are a group of rare monogenic disorders.
• Characterized by blood cytopenia and non-hematologic effects.
• 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), and thrombocytopenia-absent radii (TAR).
• Two recently described conditions are GATA2 deficiency and SAMD9/9L mutations, potentially more common.

Introduction

• IBMFSs comprise a group of rare monogenic disorders characterized by blood cytopenias and non-hematological effects.
• Examples of included syndromes: 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).
• Other rare entities exist.
• GATA2 deficiency and SAMD9/9L mutations are two recently described syndromes.

The Inherited BMF Syndromes

• Pancytopenia (usually with a global hematopoietic defect): Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Reticular dysgenesis, Pearson syndrome, Familial aplastic anemia.
• Single cytopenia: Includes anemia such as Diamond-Blackfan anemia, Congenital dyserythropoietic anemia.
• Neutropenia: Severe congenital neutropenia, including Kostmann syndrome.
• Thrombocytopenia: Congenital amegakaryocytic thrombocytopenia, Amegakaryocytic thrombocytopenia with absent radii.
• Non-hematological syndromes: Down syndrome, Dubowitz syndrome (and other related syndromes).

Manifestations

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

Genetic Diagnoses

• Advances in genetic diagnostics have identified germline mutations in DNA repair, telomere maintenance, and ribosome biogenesis.
• These functions are critical for the self-renewal of hematopoietic stem cells (HSCs) and the production of mature blood cells.
• Aplastic anemia and IBMFSs share similar biological features (decreased hematopoietic stem cells, progenitor, or precursor cells), but IBMFS is due to an intrinsic defect in HSCs while aplastic anemia has an exogenous attack on HSCs.

The Role of Inflammatory Cytokines

• Significant heterogeneity exists in the development and phenotypes of IBMFSs, even among patients sharing the same gene mutation.
• Cytokine dysregulation in the hematopoietic and stromal cells may contribute to hematologic and non-hematologic manifestations.
• Inflammatory cytokines, like IL-6 and IL-8, and anti-inflammatory cytokines, like TGF-β, have shown elevated levels in particular IBMFS types (e.g., FA, SDS).
• Oxidative stress and reactive oxygen species (ROS) are also commonly observed in the disease models of IBMFS. Mitochondrial dysfunction may further exacerbate ROS.
• These combined responses trigger stress responses like TP53/p21 axis, p16, and p38 MAPK/NF-κB axis.
• Exogenous stimuli can increase inflammatory cytokines, promoting cell cycle arrest and apoptosis.

Fanconi Anemia (FA)

• Perhaps the most frequent form of IBMFS, often characterized by pancytopenia or myeloid neoplasia (MDS/AML) between 5 and 15 years of age.
• Systemic traits include "Fanconi" facies with microphthalmia, radial deformities, and genitourinary defects.
• High risk of MDS/AML during adolescence and adulthood. Wider range of solid tumors, particularly esophageal/pharyngeal carcinomas, and genitourinary malignancies.
• Characterized by high frequency of spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents like diepoxybutane (DEB) and mitomycin C (MMC).

Dyskeratosis Congenita (DC)

• Classic DC involves the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia.
• Bone marrow failure (BMF) is a significant cause of early mortality in DC, along with predispositions for hematological and non-hematological malignancies and pulmonary complications.
• X-linked recessive, autosomal dominant (AD), and autosomal recessive (AR) forms have been recognized.
• Clinical presentation is highly variable, but pigmenting, and nail changes typically appear first during childhood, usually around the age of 10.
• Telomere shortening plays a significant role in the pathogenesis. Defectiveness in telomere preservation leads to chromosomal instability and progressive shortening of telomeres, ultimately causing cell death or senescence.

Shwachman-Diamond Syndrome (SDS)

• Second most prevalent cause of exocrine pancreatic insufficiency after cystic fibrosis.
• Characterized by a triad of exocrine pancreatic dysfunction, skeletal abnormalities, and bone marrow dysfunction.
• Also associated with cardiac abnormalities, immune dysfunction, and hematologic disorders.
• Mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, 7q11.22 are found in 90% of cases.

Diamond-Blackfan Anemia (DBA)

• Congenital type of anemia with pure red cell aplasia and sometimes featuring congenital bone abnormalities.
• Usually, a chronic macrocytic-normocytic anemia.
• Presents in 40-45% of cases as an autosomal dominant inheritance and in 55-60% of cases sporadically.
• Mutations in the ribosomal genes are common causes.
• Defective ribosomal protein biosynthesis initiates apoptosis of erythroid progenitor cells.
• Loss of function of ribosomal protein genes leads to ribosomal stress and subsequent erythroid failure.

Congenital Dyserythropoietic Anemia (CDA)

• Belong to a wide group of conditions characterized by impaired erythropoiesis, causing monolinear cytopenia.
• Diagnostic Features include bone marrow abnormalities like erythroid hyperplasia with binuclearity or multinuclearity of late erythroblasts.
• Specific genetic mutations (Cdani, C15ORF41) have been linked to distinct CDA types.

Congenital and Cyclical Neutropenias

• Heterogeneous disorders that include Kostmann syndrome.
• Characterized by low neutrophil counts.
• Some cases of congenital neutropenia are linked to particular genetic alterations (specifically affecting ELANE, HAX1).

Thrombocytopenia with Absent Radii (TAR)

• Autosomal recessive disorder with hypomegakaryocytic thrombocytopenia and bilateral radial aplasia.
• Presenting features often include bleeding.
• Additional skeletal and somatic abnormalities are frequently detected (e.g absent ulna, humerus and other skeletal issues).

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

• Rare disorder that presents with isolated thrombocytopenia
• Mostly characterized by a lack of megakaryocytes in the bone marrow.
• Typically presents in infancy.
• Different genetic causes exist, including a mutation in the thrombopoietin receptor (MPL) gene.

Lab Evaluation & Diagnostics

-Complete blood counts

• Serum erythropoietin levels
• Bone marrow aspiration and biopsy
• Chromosome testing
• Genetic testing
• Imaging surveys including X-rays, ultrasound, and MRI

Prenatal Evaluation

• Analysis of amniotic fluid or chorionic villi cells for chromosome abnormalities
• Serum alpha-fetoprotein testing

Summary of Inflammatory Profiles in IBMFSs

• Data from multiple sources highlights different inflammatory profiles across different IBMFS conditions.
• Some examples of cytokine/chemokine elevations/reductions are included in the chart.

Pathophysiology & Etiology

• The provided text discusses the pathophysiology of different conditions, including the specific genes involved, the impact on the body systems and clinical implications.