scholarly journals Biallelic variants in BRCA1 gene cause a recognisable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency

2020 ◽  
pp. jmedgenet-2020-107198
Author(s):  
Adela Chirita-Emandi ◽  
Nicoleta Andreescu ◽  
Cristina Popa ◽  
Alexandra Mihailescu ◽  
Anca-Lelia Riza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Medical Management ◽  
Chromosomal Instability ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
Growth Failure ◽  
Brca1 Gene ◽  
Fanconi Anaemia ◽  
Facial Dysmorphism

Pathogenic variants in BRCA1 gene in heterozygous state are known to be associated with breast-ovarian cancer susceptibility; however, biallelic variants cause a phenotype recognised as Fanconi anaemia complementation group S. Due to its rarity, medical management and preventive screening measures are insufficiently understood. Here, we present nine individuals (one new and eight previously presented) with biallelic variants in BRCA1 gene, to delineate clinical features in comparison with other chromosome instability syndromes and understand the patients’ health risk. Features seen in these 9 individuals (7 females/2 males) include prenatal and postnatal growth failure (9/9), microcephaly (9/9), hypo/hyperpigmented lesions (9/9), facial dysmorphism (9/9), mild developmental delay (8/9) and early-onset solid tumours (5/9). None presented bone marrow failure or immunodeficiency. Individuals with biallelic variants in BRCA1 also showed chromosomal instability by mitomycin and diepoxybutane test. The phenotype caused by biallelic BRCA1 variants is best framed between Fanconi anaemia and Nijmegen syndrome, yet distinct due to lack of bone marrow failure and immunodeficiency. We hypothesise that disease class should be reframed and medical management in people with biallelic variants in BRCA1 should emphasise on detection of solid tumour development and avoiding exposure to ionising radiation.

scholarly journals Genetic background and diagnosis of Fanconi anemia

2020 ◽  
Vol 74 ◽  
pp. 589-600
Author(s):  
Anna Repczyńska ◽  
Olga Haus
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Cell Cycle Control ◽  
Skin Pigmentation ◽  
Chromosome Instability ◽  
Molecular Techniques ◽  
Genetic Diagnostics ◽  
Risk Of Cancer

Fanconi anemia (FA) is a rare genetic disease caused by mutations in genes whose protein products are involved in important cell processes such as replication, cell cycle control and repair of DNA damage. FA is characterized by congenital malformations, bone marrow failure and high risk of cancer. Phenotypic symptoms, present in about 75% of patients, most often include such abnormalities as short stature, microcephaly, thumb and radial side of the limb defects, abnormal skin pigmentation, gastrointestinal and genitourinary defects. Progressive bone marrow failure occurs in the first decade of life, often initially with leukopenia or thrombocytopenia. The most common cancers occurring in patients with FA are myelodysplastic syndromes and acute myeloid leukemia, as well as solid tumors of the head and neck, skin, gastrointestinal system and genitourinary system. So far, 22 genes of Fanconi anemia (FANC) have been identified, which are located on the autosomal chromosomes, except for FANCB, which is located on the X chromosome. Protein products of FANC genes are the elements of Fanconi anemia pathway, which regulates DNA damage repair systems. Genetic diagnostics of Fanconi anemia should start by testing crosslinking agents: mitomycin C (MMC) or diepoxybutane (DEB) assuring differential diagnosis of chromosome instability syndromes. In patients with Fanconi anemia, an increased number of chromosomal gaps and breaks as well as specific radial structures are observed. In order to detect a mutation underlying Fanconi anemia, molecular techniques should be used, preferentially next generation sequencing (NGS).

scholarly journals CDK-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity

2020 ◽  
Author(s):  
Juan A. Cantres-Velez ◽  
Justin L. Blaize ◽  
David A. Vierra ◽  
Rebecca A. Boisvert ◽  
Jada M. Garzon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Disease ◽  
Regulatory Mechanism ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
S Phase ◽  
Rare Genetic Disease ◽  
Increased Risk

AbstractFanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins under conditions of cellular stress and during S-phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a CDK regulatory phospho-site (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by LC-MS/MS and by immunoblotting with a S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during S-phase. Furthermore, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.Author SummaryFanconi anemia (FA) is a rare genetic disease characterized by high risk for bone marrow failure and cancer. FA has strong genetic and biochemical links to hereditary breast and ovarian cancer. The FA proteins function to repair DNA damage and to maintain genome stability. The FANCD2 protein functions at a critical stage of the FA pathway and its posttranslational modification is defective in >90% of FA patients. However, the function, and regulation of FANCD2, particularly under unperturbed cellular conditions, remains remarkably poorly characterized. In this study, we describe a novel mechanism of regulation of the FANCD2 protein during S-phase of the cell cycle. CDK-mediated phosphorylation of FANCD2 on S592 promotes the ubiquitination of FANCD2 during S-phase. Disruption of this phospho-regulatory mechanism results in compromised mitotic fidelity and an increase in mitotic chromosome instability.

scholarly journals Cancer in dyskeratosis congenita

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6549-6557 ◽  
Author(s):  
Blanche P. Alter ◽  
Neelam Giri ◽  
Sharon A. Savage ◽  
Philip S. Rosenberg
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Cancer Susceptibility ◽  
Tongue Cancer ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Anorectal Cancer ◽  
Telomere Biology

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder of telomere biology has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumors were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The ratio of observed to expected cancers (O/E ratio) in the NCI cohort was 11-fold compared with the general population (P < .05). Significantly elevated O/E ratios were 1154 for tongue cancer and 195 for acute myeloid leukemia. Survival after bone marrow transplantation for aplastic anemia or leukemia was poor in both cohorts. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse hematologic and neoplastic events, and patients with these diseases should be counseled and monitored similarly.

scholarly journals Pregnancy in fanconi anaemia with bone marrow failure: a case report and review of the literature

2017 ◽  
Vol 17 (1) ◽  
Author(s):  
Flavia Sorbi ◽  
Federico Mecacci ◽  
Alessandro Di Filippo ◽  
Massimiliano Fambrini
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Bone Marrow Failure ◽  
Fanconi Anaemia ◽  
Review Of The Literature

scholarly journals Clinical approach to marrow failure

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 329-337 ◽  
Author(s):  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Medical Management ◽  
Bone Marrow Failure ◽  
Clinical History ◽  
Clinical Approach ◽  
Careful Attention ◽  
Bone Marrow Failure Syndrome ◽  
Bone Marrow Failure Syndromes ◽  
Molecular Pathophysiology

Abstract The treatment and medical management of aplastic anemia fundamentally differ between patients with inherited versus acquired marrow failure; however, the diagnosis of an inherited bone marrow failure syndrome is frequently obscure. Recent exciting advances in our understanding of the molecular pathophysiology of the inherited bone marrow failure syndromes have resulted in a profusion of new tests to aid in diagnosis. This in turn has raised questions regarding the appropriate choice of testing for the patient presenting with aplastic anemia. Important clues to the diagnosis of an inherited marrow failure syndrome may be gleaned from careful attention to the clinical history, physical exam, and laboratory workup.

A case report on Fanconi anaemia in pregnancy

2021 ◽  
pp. 1753495X2110119
Author(s):  
Peter Akinlade Adeleke ◽  
Etienne Ciantar
Keyword(s):  
Chromosomal Instability ◽  
Autosomal Recessive ◽  
Bone Marrow Failure ◽  
Fanconi Anaemia ◽  
Successful Pregnancy ◽  
Spontaneous Conception ◽  
Skeletal Defects ◽  
Anaemia In Pregnancy ◽  
In Pregnancy ◽  
Increased Susceptibility

Fanconi anaemia is a rare autosomal recessive chromosomal instability syndrome characterised by progressive bone marrow failure, skeletal defects, reduced fertility and increased susceptibility to malignancy. Successful pregnancy in both transplanted and non-transplanted patients have been recorded. In this paper, we present a woman diagnosed with Fanconi anaemia and who had a spontaneous conception at the age of 25 years with an uneventful delivery at 38 weeks of pregnancy.

scholarly journals Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1528
Author(s):  
Benilde García-de-Teresa ◽  
Alfredo Rodríguez ◽  
Sara Frias
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Chromosomal Instability ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
Premature Aging ◽  
Dna Double Strand Breaks ◽  
Interstrand Crosslinks ◽  
Pathogenic Variants ◽  
Extreme Risk

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.

scholarly journals Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita

2008 ◽  
Vol 29 (1) ◽  
pp. 229-240 ◽  
Author(s):  
Hua He ◽  
Yang Wang ◽  
Xiaolan Guo ◽  
Sonal Ramchandani ◽  
Jin Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
Premature Death ◽  
Dyskeratosis Congenita ◽  
Damage Response ◽  
Survival Potential

ABSTRACT The Protection of telomeres 1 (POT1) protein is a single-stranded telomere binding protein that is essential for proper maintenance of telomere length. Disruption of POT1 function leads to chromosome instability and loss of cellular viability. Here, we show that targeted deletion of the mouse Pot1b gene results in increased apoptosis in highly proliferative tissues. In the setting of telomerase haploinsufficiency, loss of Pot1b results in depletion of germ cells and complete bone marrow failure due to increased apoptosis, culminating in premature death. Pot1b −/ − mTR +/ − hematopoietic progenitor and stem cells display markedly reduced survival potential in vitro. Accelerated telomere shortening, increased G overhang and elevated number of chromosome end-to-end fusions that initiate an ATR-dependent DNA damage response were also observed. These results indicate an essential role for Pot1b in the maintenance of genome integrity and the long-term viability of proliferative tissues in the setting of telomerase deficiency. Interestingly, these phenotypes closely resemble those found in the human disease dyskeratosis congenita (DC), an inherited syndrome characterized by bone marrow failure, hyperpigmentation, and nail dystrophy. We anticipate that this mouse will serve as a useful model to further understand the pathophysiology of DC.

scholarly journals When to worry about inherited bone marrow failure and myeloid malignancy predisposition syndromes in the setting of a hypocellular marrow

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 153-156
Author(s):  
Anupama Narla
Keyword(s):  
Bone Marrow ◽  
Differential Diagnosis ◽  
Family Planning ◽  
Cancer Screening ◽  
Myelodysplastic Syndrome ◽  
Medical Management ◽  
Bone Marrow Failure ◽  
Correct Diagnosis ◽  
Myeloid Malignancy ◽  
Phenotypic Spectrum

Abstract With our increasing understanding of inherited marrow failure and myeloid malignancy predisposition syndromes, it has become clear that there is a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of both children and adults with unexplained defects in hematopoiesis. Moreover, these conditions are not as rare as previously believed and may present as aplastic anemia, myelodysplastic syndrome, or malignancy over a range of ages. Establishing the correct diagnosis is essential because it has implications for treatment, medical management, cancer screening, and family planning. Our goal is to highlight insights into the pathophysiology of these diseases, review cryptic presentations of these syndromes, and provide useful references for the practicing hematologist.

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