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Phenotypic features of Fanconi anemia (FA). (A) Hypoplastic thumbs in an 11-year-old. (B) Hypopigmented (white arrow) and hyperpigmented (black arrows) skin lesions on the trunk of an adolescent. Photograph courtesy of Susan J. Bayliss, MD. (C) Progressive aplastic anemia in a 20-year-old with FA. Most of the marrow space is occupied by fat.
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The inherited bone marrow failure syndromes are a diverse group of genetic diseases associated with inadequate production of one or more blood cell lineages. Examples include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, thrombocytopenia absent radii syndrome, severe congenital neutropenia, and Shwachman-Diamond syndrome. The man...
Context in source publication
Context 1
... anemia (FA) is a genetically and phenotypically het- erogeneous disorder characterized by birth defects, progressive bone marrow failure (BMF), and a predisposition for cancer ( Figure 1). Originally, the diagnosis of FA was based on the Annals of Medicine, 2014;46: 353-363 © 2014Informa UK, Ltd. ...
Similar publications
Inherited bone marrow failure syndromes are experiments of nature characterized by impaired hematopoiesis with cancer and leukemia predisposition. The mutations associated with inherited bone marrow failure syndromes affect fundamental cellular pathways, such as DNA repair, telomere maintenance, or proteostasis. How these disturbed pathways fail to...
Citations
... Fanconi anemia (FA) is a rare genetic disorder that is generally characterized by physical abnormalities, inherited bone marrow failure (BMF), and an increased susceptibility to malignancies [1,2]. FA is caused by pathogenic variants in the genes making up the FA/BRCA DNA repair pathway, which consists of 22 proteins, organized into complementation groups based on their position in the FA pathway [3]. ...
... Esophageal polyps (1) Simple renal cyst (1) Adnexal cyst (1) Renal cyst (1) Breast cyst (1) Kidney nephroblastic proliferation (1) Breast tubular adenoma (1) sun-exposed areas, including the scalp and face. NMSC is known as the most common type of cancer in the general population, but usually does not occur until later in life. ...
Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study “Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study” (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11–64 and 0–56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.
... Patients with FA exhibit a diverse range of clinical presentations, typically diagnosed around the age of 7 years (5, 6). These individuals often display congenital malformations, skin abnormalities, BMF, and an increased susceptibility to malignancies (5,7). ...
Background
Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT).
Procedure
: A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study “Etiologic investigation of cancer susceptibility in IBMFS: A Natural History Study” (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous cell carcinoma or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group.
Results
Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11–64 and 0–56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations.
Conclusion
Early onset NMSC emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing heightened cancer risk.
... 4 The most important treatment for these patients is hematopoietic stem cell transplantation (HSCT), which is the only current option capable of prolonging the patients' lives. 1,[5][6][7] Graft-versus-host disease (GVHD) is an immune-mediated reaction that causes high morbidity and mortality, and its main determinant in allogeneic HSCT is human leukocyte antigen incompatibility. [8][9][10][11][12][13][14][15] This disease generates direct cytotoxicity to some organs, especially the skin, gastrointestinal tract, eyes, and liver. ...
Objective:
The aim of this study was to elaborate a specific protocol for the assessment and early identification of skin lesions in pediatric patients with Fanconi anemia undergoing hematopoietic stem cell transplantation.
Methods:
This is a longitudinal, retrospective, and descriptive study. The medical records of 136 pediatric patients with Fanconi anemia who underwent hematopoietic stem cell transplantation between 2008 and 2018 at the Clinical Hospital of the Federal University of Paraná were reviewed. A specific protocol was created for data collection, which included age, sex, skin color, age at diagnosis of Fanconi anemia, transplantation data, family history of consanguinity, and pre- and post-transplant complications. In addition, the data included the presence of graft-versus-host disease of the skin and other organs, its classification, type of lesion, location, and also skin lesions not related to graft-versus-host disease.
Results:
Among the skin manifestations in pre-transplant period, café-au-lait spots stood out (32.4%). At least one organ was affected by graft-versus-host disease in 55.1% of patients; the most common involvement being the mouth, followed by the skin. Rash and erythema were the most frequently observed cutaneous manifestations of graft-versus-host disease.
Conclusion:
A high prevalence of cutaneous manifestations of the disease was observed, as well as cutaneous manifestations of graft-versus-host disease. The protocol developed gathers relevant and standardized information for the follow-up of patients with Fanconi anemia undergoing hematopoietic stem cell transplantation, ensuring greater reliability of the information, and its implementation will allow the prospective evaluation of patients.
... The most common congenital disorders (1), eithercause pancytopenia such as Fanconi anemia (4) and dyskeratosis congenita (5) or primary affect one lineage such as Shwachman-Diamond syndrome (6), Diamond-Blackfan anemia (7), Kostmann syndrome and congenital amegakaryocytic thrombocytopenia (8). They also feature a predisposition for congenital malformations and progression to myelodysplasia, acute leukemias and solid tumors (9). Due to presentation variability increased awareness and continuous follow-up are always needed, even though acquired BMF syndromes are more frequent in both adults and children (10). ...
Bone marrow failure (BMF) syndromes are a group of various hematological diseases with cytopenia as a main common characteristic. Given their rarity and continuous progress in the field, we aim to provide data considering the efficiency and safety of the therapeutic methods, focusing on the treatment of aplastic anemia(AA) and paroxysmal nocturnal hemoglobinuria (PNH). We enrolled consecutive patients diagnosed with BMF in two referral centers of Northern Greece from 2008 to 2020. We studied 43 patients with AA (37 adults and 6 children/adolescents) and 6 with classical PNH. Regarding classical PNH, 4 patients have received eculizumab treatment with 1/4 presenting extravascular hemolysis. Among 43 patients with aplastic anemia, PNH clones were detected in 11. Regarding patients that did not receive alloHCT (n=15), 14/15 were treated with ATG and cyclosporine as first line, with the addition of eltrombopag in patients treated after its approval (n=9). With a median follow-up of 16.7 (1.8-56.2) months from diagnosis, 12/14 (85.7%) are alive (4-year OS: 85.1%). AlloHCT was performed in 28 patients. Five patients developed TA-TMA which did not resolve in 3/5 (all with a pre-transplant PNH clone). With the follow-up among survivors reaching 86.3 (6.3-262.4) months, 10-year OS was 56.9%, independently associated with PNH clones after adjusting for age (p=0.024). In conclusion, our real-world experience confirms that novel treatments are changing the field of BMF syndromes. Nevertheless, there is still an unmet need to personalize algorithms in this field.
... Inherited bone marrow failure (IBMF) syndromes are genetically heterogeneous hematopoietic stem cell disorders that impede the adequate production of one or more blood cell lineages and consequently predispose affected individuals to the development of myelodysplastic syndromes (MDS) as well as myeloid malignancies (1)(2)(3). The responsible genetic defects often produce recognizable syndromes, whose main features are microcephaly, growth retardation as well as inconsistent other physical malformations and organ abnormalities. ...
... The responsible genetic defects often produce recognizable syndromes, whose main features are microcephaly, growth retardation as well as inconsistent other physical malformations and organ abnormalities. Such germline alterations comprise pathogenic variants in genes that encode for transcription factors such as GATA2, RUNX1 and ETV6, products that are involved in telomere maintenance (dyskeratosis congenita), ribosomal biogenesis (Blackfan-Diamond anemia) and maturation (Shwachman-Diamond syndrome; SDS), DNA maintenance and repair (Fanconi anemia), protein folding and trafficking (severe congenital neutropenia) as well as in the regulation of cell proliferation and apoptosis (SAMD9/9L) (3)(4)(5)(6)(7)(8)(9). In many instances characteristic clinical, laboratory and hematologic parameters alone will already suffice to identify the respective syndrome. ...
We report the case of a male Pakistani patient with a pathogenic homozygous loss of function variant in the non-homologous end-joining factor 1 (NHEJ1) gene. The growth retarded and microcephalic boy with clinodactyly of both hands and hyperpigmentation of the skin suffered from recurrent respiratory infections. He was five and a half years old when he came to our attention with refractory cytopenia and monosomy 7. Hematopoietic stem cell transplantation was considered but not feasible because there was no suitable donor available. Monosomy 7 was not detected anymore in subsequent bone marrow biopsies that were repeated in yearly intervals. Instead, seven and a half years later, a novel clone with a del(20q) appeared and steadily increased thereafter. In parallel, the patient’s blood count, which had remained stable for over 20 years without necessitating any specific therapeutic interventions, improved gradually and the erythropoiesis-associated dysplasia resolved.
... Patients were assigned diagnostic groups using standard diagnostic criteria. [19][20][21] Clinical data were abstracted from the electronic medical record. AA diagnosis was completed by standard criteria, including a bone marrow biopsy examination and metaphase cytogenetic analysis, with fluorescence in situ hybridization performed in case of poor cytogenetic culture growth, followed by systematic exclusion of other disorders and etiologies that mimic AA. 6,20 AA severity was classified using the modified Camitta criteria. ...
... IBMFSs were diagnosed using a combination of clinical diagnoses and syndrome-specific tests, including telomere-length measurement by fluorescence in situ hybridization and flow cytometry for DC, chromosome breakage analysis on lymphocytes or skin fibroblasts for FA, and syndrome-specific genetic testing (supplemental Table 2). 21,26 Patients with other inherited disorders, including inherited hematologic diseases associated with mutations in GATA1 (n 5 1), GATA2 (n 5 2), SAMD9 (n 5 2), SAMD9L (n 5 1), and MYH9 (n 5 1), as well as Noonan syndrome (n 5 1), X-linked agammaglobulinemia (n 5 1), hereditary xerocytosis (n 5 1), sideroblastic anemia (n 5 7), congenital dyserythropoietic anemia (n 5 2), glycogen storage disease type I (n 5 1), pyruvate kinase deficiency (n 5 2), and others (n 5 16), were classified as other inherited. ...
Acquired aplastic anemia (AA) is a life-threatening bone marrow aplasia caused by the autoimmune destruction of hematopoietic stem and progenitor cells. There are no existing diagnostic tests that definitively establish AA, and diagnosis is currently made via systematic exclusion of various alternative etiologies, including inherited bone marrow failure syndromes (IBMFSs). The exclusion of IBMFSs, which requires syndrome-specific functional and genetic testing, can substantially delay treatment. AA and IBMFSs can have mimicking clinical presentations, and their distinction has significant implications for treatment and family planning, making accurate and prompt diagnosis imperative to optimal patient outcomes. We hypothesized that AA could be distinguished from IBMFSs using 3 laboratory findings specific to the autoimmune pathogenesis of AA: paroxysmal nocturnal hemoglobinuria (PNH) clones, copy-number–neutral loss of heterozygosity in chromosome arm 6p (6p CN-LOH), and clonal T-cell receptor (TCR) γ gene (TRG) rearrangement. To test our hypothesis, we determined the prevalence of PNH, acquired 6p CN-LOH, and clonal TRG rearrangement in 454 consecutive pediatric and adult patients diagnosed with AA, IBMFSs, and other hematologic diseases. Our results indicated that PNH and acquired 6p CN-LOH clones encompassing HLA genes have ∽100% positive predictive value for AA, and they can facilitate diagnosis in approximately one-half of AA patients. In contrast, clonal TRG rearrangement is not specific for AA. Our analysis demonstrates that PNH and 6p CN-LOH clones effectively distinguish AA from IBMFSs, and both measures should be incorporated early in the diagnostic evaluation of suspected AA using the included Bayesian nomogram to inform clinical application.
... IBMFS are a heterogeneous cluster of disorders manifested by an ineffective blood production and concurrent cytopenias that eventually result in a hypoplastic bone marrow (BM). These syndromes constitute an increased propensity to develop hematological malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (Dokal and Vulliamy, 2010;Wilson et al., 2014;Cook, 2018). Mutations in GATA2 are the most common genetic defects in pediatric MDS (Spinner et al., 2014). ...
Inherited bone marrow failure syndromes (IBMFS) are monogenetic disorders that result in a reduction of mature blood cell formation and predisposition to leukemia. In children with myeloid leukemia the gene most often mutated is Gata binding protein 2 (GATA2) and 80% of patients with GATA2 mutations develop myeloid malignancy before the age of forty. Although GATA2 is established as one of the key regulators of embryonic and adult hematopoiesis, the mechanisms behind the leukemia predisposition in GATA2 haploinsufficiencies is ambiguous. The only curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-SCT). However, allo-SCT can only be applied at a relatively late stage of the disease as its applicability is compromised by treatment related morbidity and mortality (TRM). Alternatively, autologous hematopoietic stem cell transplantation (auto-SCT), which is associated with significantly less TRM, might become a treatment option if repaired hematopoietic stem cells would be available. Here we discuss the recent literature on leukemia predisposition syndromes caused by GATA2 mutations, current knowledge on the function of GATA2 in the hematopoietic system and advantages and pitfalls of potential treatment options provided by genome editing.
... Informed consent from the patient was obtained in accordance with the Declaration of Helsinki. The diagnosis of aplastic anemia was established using standard criteria (International Agranulocytosis and Aplastic Anemia Study 1987; Wilson et al. 2014). ...
Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a mutation in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-kappa B signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.
... Dyskeratosis congenita (DC) is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and neck, and oral leukoplakia. 1 Patients with DC present at early age with short telomeres, and bone marrow failure represents the major cause of morbidity. 2 Treatment is challenging and tailored to the individual. 3 Hematopoietic stem cell transplantation remains the only curative treatment of bone marrow failure in these patients but historically has had poor long-term efficacy. ...
Dyskeratosis congenita (DC) is a pediatric bone marrow failure syndrome caused by germline mutations in telomere biology genes. Mutations in DKC1 (the most commonly mutated gene in DC), the 3′ region of TERC, and poly(A)-specific ribonuclease (PARN) cause reduced levels of the telomerase RNA component (TERC) by reducing its stability and accelerating TERC degradation. We have previously shown that depleting wild-type DKC1 levels by RNA interference or expression of the disease-associated A353V mutation in the DKC1 gene leads to decay of TERC, modulated by 3′-end oligoadenylation by noncanonical poly(A) polymerase 5 (PAPD5) followed by 3′ to 5′ degradation by EXOSC10. Furthermore, the constitutive genetic silencing of PAPD5 is sufficient to rescue TERC levels, restore telomerase function, and elongate telomeres in DKC1_A353V mutant human embryonic stem cells (hESCs). Here, we tested a novel PAPD5/7 inhibitor (RG7834), which was originally discovered in screens against hepatitis B viral loads in hepatic cells. We found that treatment with RG7834 rescues TERC levels, restores correct telomerase localization in DKC1 and PARN-depleted cells, and is sufficient to elongate telomeres in DKC1_A353V hESCs. Finally, treatment with RG7834 significantly improved definitive hematopoietic potential from DKC1_A353V hESCs, indicating that the chemical inhibition of PAPD5 is a potential therapy for patients with DC and reduced TERC levels.
... The diagnosis of AA was determined by standard criteria. [11][12][13] Peripheral blood (PB) mononuclear cells, stained for CD3, CD4, CD8, CD27, CD45RA, CCR7, CD95, CD127, FoxP3, and TCRVB19 (VB17 using older nomenclature), were analyzed on a BD LSR II flow cytometer. The TCR-b chain repertoire was analyzed by nextgeneration sequencing (NGS) of the TCR Vb gene rearrangements on bulk bone marrow or sorted PB mononuclear cells. ...
Key Points
Acquired aplastic anemia is a T-cell–mediated autoimmune bone marrow aplasia, without a known etiologic trigger. Clonal expansion of CD8+ effector T lymphocytes can occur following vaccination and accompany graft dysfunction or aplastic anemia relapse.
