Fanconi Anemia Genetics Quiz

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Which gene exhibits X-linked recessive inheritance in Fanconi Anemia (FA)?

FANCD2

FANCC

FANCA

FANCB (correct)

What is a characteristic outcome observed in patients with FANCD2 mutations?

No associated cancer risk

Severe phenotype manifestation (correct)

Delayed onset of leukemia

Development of a mild phenotype

Which of the following proteins is NOT part of the FA core complex?

BRCA1 (correct)

FANCI

FANCB

FANCM

What diagnostic feature is associated with FA cells when exposed to DNA cross-linking agents?

High frequency of chromosomal breakage Signup and view all the answers

How do serum TGF-β levels in FA patients compare to healthy controls?

Significantly higher Signup and view all the answers

Which of the following genes is associated with a rapidly lethal cancer-prone syndrome?

FANCD1/BRCA2 Signup and view all the answers

What is the impact of biallelic mutations in BRCA2 in FA patients?

Impaired DNA repair Signup and view all the answers

What type of inheritance pattern does FANCR exhibit?

Autosomal dominant Signup and view all the answers

Which cytokines are commonly found elevated in patients with Fanconi Anemia and Shwachman-Diamond Syndrome?

IL-6 and IL-8 Signup and view all the answers

What is the hallmark feature associated with dyskeratosis congenita (DC)?

Shortening of telomere length Signup and view all the answers

What triggers the activation of the TP53/p21 axis in patients with Inherited Bone Marrow Failure Syndromes (IBMFS)?

Exogenous stimuli like UV and X-ray radiation Signup and view all the answers

Which pathway is associated with the systemic traits observed in Fanconi Anemia?

FA pathway involved in DNA repair Signup and view all the answers

Which type of cancer risk is significantly increased in patients with Fanconi Anemia during their adolescence and young adulthood?

Leukemia (MDS/AML) Signup and view all the answers

What is a common consequence of progressive hypocellularity in the bone marrow of IBMFS patients?

Bone marrow failure (BMF) Signup and view all the answers

What common feature relates oxidative stress to the pathology observed in IBMFSs?

It contributes to the shortening of telomeres. Signup and view all the answers

Which systemic trait is NOT typically associated with Fanconi Anemia?

Growth hormone deficiency Signup and view all the answers

Which inflammatory cytokine was found at higher plasma levels in FA patients?

IL-10 Signup and view all the answers

What role do TNF-α and IFN-γ play in aplastic anemia?

They may cause stress leading to bone marrow failure. Signup and view all the answers

What is indicated by a complete blood count in patients with Fanconi anemia?

Macrocytosis and increased HbF levels Signup and view all the answers

Which of the following cytokines was NOT reported to be overexpressed in lymphoblastoid cell lines from FANCA and FANCC patients?

TGF-β Signup and view all the answers

What was the result of the chromosomal breakage/stress cytogenetics test indicated for severe pancytopenia?

It is particularly indicated for patients with an absolute neutrophil count of less than 500. Signup and view all the answers

Which pathway is constitutively activated in FANCA patients leading to elevated IL-1β levels?

PI3K-AKT pathway Signup and view all the answers

What complication can arise due to the increased expression of inflammatory cytokines in FA patients?

Increased oxidative stress and DNA damage Signup and view all the answers

What clinical value does the inhibition of TGF-β by luspatercept hold for Fanconi anemia?

It may be beneficial for the anemia associated with FA. Signup and view all the answers

Which inherited bone marrow failure syndrome is characterized by a predisposition to solid tumors?

Fanconi anemia (FA) Signup and view all the answers

What is the main difference between inherited bone marrow failure syndromes (IBMFSs) and aplastic anemia?

IBMFSs arise from intrinsic defects in hematopoietic stem cells. Signup and view all the answers

Which condition has been newly described as part of the inherited bone marrow failure syndromes?

GATA2 deficiency Signup and view all the answers

Which cytokine activity is commonly dysregulated in patients with aplastic anemia and hypoplastic MDS?

Lymphocyte and cytokine activities Signup and view all the answers

What kind of genetic mutations are associated with inherited bone marrow failure syndromes?

Mutations involved in telomere maintenance and DNA repair Signup and view all the answers

Which of the following syndromes may present at any time in life?

Shwachman-Diamond syndrome (SDS) Signup and view all the answers

Which of the following conditions is characterized by the absence of amegakaryocytes?

Congenital amegakaryocytic thrombocytopenia (CAMT) Signup and view all the answers

Which of the following inherited bone marrow failure syndromes specifically presents in the neonatal period?

Diamond-Blackfan anemia (DBA) Signup and view all the answers

Study Notes

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.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

Test your knowledge on the genetic components and clinical features of Fanconi Anemia. Explore questions related to X-linked recessive inheritance, mutation impacts, and diagnostic characteristics associated with this rare disease. This quiz will challenge your understanding of the mechanisms and pathways involved in Fanconi Anemia.