Cancer in buccal mucosa in patients with Fanconi anemia: Report of six cases.

INTRODUCTION: Fanconi anemia (FA) is a recessive hereditary disease characterized by bone marrow failure, and the treatment is hematopoietic stem cell transplantation (HSCT). Patients diagnosed with FA are more predisposed to develop oral squamous cell carcinoma (SCC), and this risk increases in transplant patients. The clinical characteristics of the oral manifestations of SCC in this group of patients do not differ from the lesions present in patients without the disease; however, they can be diagnosed in young patients and less common locations, such as, for example, in the buccal mucosa. OBJECTIVE: To report a case series of patients diagnosed with FA with oral SCC. METHOD: Included in this case series are six patients diagnosed with SCC in the buccal mucosa with similar clinical characteristics. FINAL CONSIDERATIONS: There are still difficulties in establishing the natural history of oral lesions in patients with FA. Thus, disclosing a series of cases with similar changes may be relevant to improving and refining the multidisciplinary team's clinical view of suspected SCC or oral potentially malignant disorders (OPMD), providing surveillance and timely management.

Fanconi anemia and haploidentical stem cell transplantation.

BACKGROUND: Fanconi anemia is a congenital disorder belonging to bone marrow syndromes, with a risk of developing malignancy. Hematopoietic stem cell transplantation is the only curative treatment in these cases. Here, we aimed to report our clinical experience in pediatric patients with Fanconi anemia treated with haploidentical stem cell transplantation and post-transplant cyclophosphamide, an alternative strategy. METHODS: We performed a case report based on clinical records of two patients who signed the informed consent form and were treated at Fundación Valle del Lili. RESULT: Two pediatric patients, both with reduced-intensity conditioning, prophylaxis for acute graft-versus-host disease with post-transplant cyclophosphamide. They achieved primary neutrophil/platelets engraftment, and 100% chimerism. Had grade I or II graft-versus-host disease resolved? Currently are alive and in complete remission. CONCLUSIONS: The use of mismatched related donors for haploidentical stem cell transplantation and post-transplant cyclophosphamide might be a promising option, and well-tolerated in pediatric patients. Serial chimerism can be useful during follow-up.

Transplantation for Fanconi anaemia: lessons learned from Brazil.

Fanconi anaemia is a challenging disease to manage, and haematopoietic stem-cell transplantation (HSCT) is the treatment of choice for the haematological complications related to this disease. Over these past two decades, we have observed a substantial improvement in survival outcomes after matched related and unrelated donor HSCT, even for patients living in low-income and middle-income countries. Long-term overall survival is still suboptimal because of the risk of malignancies and other disease-related complications. For patients without well matched donors, alternative donor transplantation using mismatched related donors is an option but is historically associated with a high incidence of graft failure and graft-versus-host disease (GVHD). Herein we discuss the development of a HSCT programme for Fanconi anaemia in our centre in Curitiba, Brazil. Because ex vivo, T-cell depletion is unavailable in our country, we adapted the haploidentical donor transplantation platform using post-HSCT cyclophosphamide to overcome graft failure and GVHD associated with HLA-mismatched donor transplantation. The withdrawal of pre-HSCT cyclophosphamide reduced the severity of mucositis and did not interfere with engraftment. The addition of serotherapy improved overall survival by decreasing the incidence of severe acute and chronic GVHD. Although we have improved overall survival and expanded access to HSCT for Fanconi anaemia, our patients face many challenges, especially viral reactivation and GVHD disease, that merit attention. We acknowledge that there is a learning curve to adopt the haploidentical approach for Fanconi anaemia to low-resourced settings, and this Brazilian experience might require further modifications along with national and international collaborations to be implemented in other countries.

Kidney complications in 107 Fanconi anemia patients submitted to hematopoietic cell transplantation.

Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: • Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). • Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: • Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. • CAKUT in FA patients was associated with lower kidney function and hypertension after HCT.

Fanconi anemia and hematopoietic stem cell transplant as risk factors for oral squamous cell carcinoma: A case report with a 12-year follow-up.

Fanconi anemia is a rare disorder resulting from defects in genes responsible for DNA damage responses. It is characterized by congenital anomalies, aplastic anemia, and a predisposition to cancer. Currently, hematopoietic stem cell transplant (HSCT) is the only curative treatment available for bone marrow failure; however, HSCT increases oral squamous cell carcinoma (OSCC) risk. Here we report the case of a patient diagnosed with Fanconi anemia in childhood who was treated with HSCT and later diagnosed with multiple OSCCs during a 12-year follow-up. Despite multiple surgical interventions and radiotherapy regimens, the patient`s health deteriorated. Management of individuals with Fanconi anemia is challenging and must be provided by a multidisciplinary healthcare team to ensure better staging, treatment planning, and coordination.

Ocular Manifestations in Patients with Fanconi Anemia: A Single-Center Experience Including 106 Patients.

OBJECTIVES: To describe the prevalence of acquired ocular manifestations in patients with Fanconi anemia (FA) and to describe and correlate the congenital ocular malformations with the genetic subtypes of the disease. STUDY DESIGN: This is a cross-sectional observational study of 106 consecutive patients with confirmed diagnosis of FA who were followed at the Hematopoietic Stem Cell Transplantation (HSCT) Service at the Federal University of Paraná, Curitiba, Parana, Brazil. Participants underwent a complete ophthalmologic evaluation and 84 patients underwent ocular ultrasound examination. This study was conducted between November 2014 and August 2017. RESULTS: The patients ranged in age from 6 months to 43 years of age. Microphthalmia was the most common congenital ocular abnormality (95.2%). A decrease in anthropometric measurements was observed, including palpebral fissure length (78/103 patients [76.5%]), microcornea (48/103 patients [46.6%]), and ptosis (31/103 patients [30.1%]). We identified a new ophthalmic condition in 15 patients with FA, that is, epiretinal tissue on the optic disc. The genetic subtype was identified in 78 patients (79.6%), the FA-A subtype was most prevalent (50%). The most common acquired ocular manifestation (non-graft-versus-host disease [GVHD] related) in patients who did not undergo HSCT (n = 44) was limbal neovascularization (13.6%), whereas in patients who underwent HSCT (n = 62), the GVHD-related manifestation was ocular GVHD (51.6%). The most frequent symptom of ocular GVHD was keratoconjunctivitis sicca (29%). CONCLUSIONS: Several ocular manifestations were identified in patients with FA.

Nursing diagnosis after hematopoietic stem cell transplant due to Fanconi anemia.

OBJECTIVES: to identify nursing diagnoses in patients who underwent hematopoietic stem-cell transplants due to Fanconi anemia, according to the NANDA-I taxonomy. METHODS: exploratory study using a retrospective analysis of 85 records from patients who underwent hematopoietic stem-cell transplants due to Fanconi anemia, developed in a specialize transplant center in the South of Brazil. The results were analyzed using descriptive statistics. RESULTS: 73 different diagnoses were found in 9 out of the 13 domains from the NANDA-I taxonomy. From these, 22 were in 50% or more of the patients investigated, and most of them are related to the domain Safety/Protection. CONCLUSIONS: it was possible to identify the nursing diagnosis in the patients who underwent hematopoietic stem cell transplants due to Fanconi anemia, contributing to design a plan for the care of these patients. The same was true for those with other syndromes of chromosomal instability that need to undergo this transplant.

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences.

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.

Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia.

Fanconi anemia (FA) is a rare inherited genetic condition that may lead to bone marrow failure, leukemia, and/or solid tumors. It is caused by the loss of function of at least 1 gene of the FA/BRCA pathway, which is necessary for DNA repair. Patients with FA have a 200-fold to 1000-fold risk of developing head and neck cancer, mainly oral squamous cell carcinoma (OSCC), and of doing so at a much younger age than individuals within the general population. Also, patients who have FA with OSCC have poor overall survival rates, reinforcing the necessity to detect OSCC early. The scope of the current review is to provide an update on OSCC in patients with FA.

Salivary lactate dehydrogenase (LDH) as a tool for early diagnosis of oral cancer in individuals with Fanconi anemia.

Currently one of the greater challenges is the diagnosis and treatment of cancer. Many studies address the genetic and metabolic aspects to support in early diagnosis and increase the survival of individuals at high risk. Individuals with Fanconi anemia can be included in this high risk group because they have a predisposition to develop head and neck cancer. The use of salivary enzymes as biomarkers to detect the changes in oral tissue at the initial phase seems viable, because saliva is easy to obtain, it moisture oral mucosa and cells metabolic compounds can be found on it. Due to the metabolic characteristics of the cancer cell, an increase in Lactate Dehydrogenase (LDH) may indicate a carcinogenesis process. The hypothesis of this study is to use of salivary LDH as a tool in the early diagnosis of oral cancer on a high risk group such as Fanconi anemia's patients.

Fanconi Anemia and Laron Syndrome.

BACKGROUND: Fanconi anemia (FA) is a condition characterized by genetic instability and short stature, which is due to growth hormone (GH) deficiency in most cases. However, no apparent relationships have been identified between FA complementation group genes and GH. In this study, we thereby considered an association between FA and Laron syndrome (LS) (insulin-like growth factor 1 [IGF-1] deficiency). METHODS: A 21-year-old female Mexican patient with a genetic diagnosis of FA was referred to our research department for an evaluation of her short stature. Upon admission to our facility, her phenotype led to a suspicion of LS; accordingly, serum levels of IGF-1 and IGF binding protein 3 were analyzed and a GH stimulation test was performed. In addition, we used a next-generation sequencing approach for a molecular evaluation of FA disease-causing mutations and genes involved in the GH-IGF signaling pathway. RESULTS: Tests revealed low levels of IGF-1 and IGF binding protein 3 that remained within normal ranges, as well as a lack of response to GH stimulation. Sequencing confirmed a defect in the GH receptor signaling pathway. CONCLUSIONS: To the best of our knowledge, this study is the first to suggest an association between FA and LS. We propose that IGF-1 administration might improve some FA complications and functions based upon IGF-1 beneficial actions observed in animal, cell and indirect clinical models: erythropoiesis modulation, immune function improvement and metabolic regulation.

Mouth examination performance by children's parents and by adolescents in Fanconi anemia.

BACKGROUND: Fanconi anemia (FA) is a rare genetic syndrome characterized by increased risk of developing malignant neoplasms, particularly oral squamous cell carcinoma. This study aims to ascertain the extent to which adolescents and guardians/parents of children with FA are aware of their oral cancer risks and assess their ability to perform mouth examination (ME). PROCEDURE: A cross-sectional study was conducted among patients with FA (between 6 and 16 years) and their parents. A total of 45 patients, 19 children and 26 adolescents, participated in the study. Among children less than 12 years of age, caregivers performed ME and adolescents between 12 and 16 years of age performed mouth self-examination (MSE). All parents were given a self-reporting questionnaire to collect sociodemographic data, information about health-related behaviors, and oral cancer awareness. Performance was evaluated using criteria for mucosal visualization and retracting ability. Subsequently, a dentist clinically examined all patient participants. RESULTS: Performance evaluation indicated that the examination quality was unsatisfactory in both groups. Statistical significance was found between ability to perform ME by marital status (P < 0.036), where divorced parents had more difficulty performing ME than nondivorced parents. CONCLUSION: Oral mucosa surveillance performed by parents and adolescents seems to be inaccurate. However, as an oral examination is a relatively inexpensive form of secondary prevention, it merits attention to teaching the technique to patients with FA and their caregivers.

The Salivary Microbiome and Oral Cancer Risk: a Pilot Study in Fanconi Anemia.

Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability and impaired DNA damage repair. FA patients develop oral squamous cell carcinoma (OSCC) earlier and more frequently than the general population, especially after hematopoietic stem cell transplantation (HSCT). Although evidence of an etiological role of the local microbiome and carcinogenesis has been mounting, no information exists regarding the oral microbiome of FA patients. The aim of this study was to explore the salivary microbiome of 61 FA patients regarding their oral health status and OSCC risk factors. After answering a questionnaire and receiving clinical examination, saliva samples were collected and analyzed using 16S rRNA sequencing of the V3-V4 hypervariable region. The microbial profiles associated with medical and clinical parameters were analyzed using general linear models. Patients were young (mean age, 22 y) and most had received HSCT ( n = 53). The most abundant phyla were Firmicutes [mean relative abundance (SD), 42.1% (10.1%)] and Bacteroidetes [(25.4% (11.4%)]. A history of graft-versus-host disease (GVHD) ( n = 27) was associated with higher proportions of Firmicutes (43.8% × 38.5%, P = 0.05). High levels of gingival bleeding were associated with the genera Prevotella (22.25% × 20%), Streptococcus (19.83% × 17.61%), Porphyromonas (3.63% × 1.42%, P = 0.03), Treponema (1.02% × 0.28%, P = 0.009), Parvimonas (0.28% × 0.07%, P = 0.02) and Dialister (0.27% × 0.10%, P = 0.04). Finally, participants transplanted over 11 y ago showed the highest levels of Streptococcus (18.4%), Haemophilus (12.7%) and Neisseria (6.8%). In conclusion, FA patients that showed poor oral hygiene harbored higher proportions of the genera of bacteria compatible with gingival disease. Specific microbial differences were associated with a history of oral GVHD and a history of oral mucositis.

Oral health status in children and adolescents with Fanconi anemia.

OBJECTIVE: The aim of the study was to investigate the caries experience, dental care level, and oral hygiene in children and adolescents with Fanconi anemia. METHODS: Decay-missing-filled teeth index, restorative index and simplified oral hygiene index were examined in two groups of children and adolescents: FA, diagnosed with Fanconi anemia (n = 35) and a healthy control group, non-FA (n = 35). Oral hygiene habits were assessed through questionnaires completed by parents. RESULTS: FA group presents higher decay-missing-filled teeth index values, dental care index, oral hygiene index. Nevertheless, no statistical difference was observed between the groups. Frequency of visits to the dentist was higher in the non-FA group. Frequency of tooth brushing was higher in FA group and it was performed by the subjects without the help of their parents. CONCLUSIONS: No difference was observed in caries experience, dental care level, and oral hygiene in children and adolescents with FA when compare with non-FA.

Oral leukoplakia in patients with Fanconi anaemia without hematopoietic stem cell transplantation.

BACKGROUND: Fanconi anaemia is a genetic disease characterized by congenital abnormalities, progressive bone marrow failure, and a higher predisposition of oral squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of oral mucosa lesions in patients with Fanconi anaemia without hematopoietic stem cell transplantation (HSCT). PROCEDURE: Patients with Fanconi anaemia who had not undergone HSCT was cross-sectional evaluated for the presence of oral lesions. RESULTS: The sample was composed of 78 male and 60 female patients, with a median age of 9 years. Of the 138 patients, approximately 45% manifested at least one oral mucosa abnormality: 35 patients (25%) presented with traumatic injuries, and 16 (12%) exhibited leukoplakia. The following lesions were observed in low prevalence: aphthous ulcers, atrophic tongue, petechiae and hematomas, gingival hyperplasia, mucoceles, herpes, hyperpigmentation, haemangioma, non-neoplastic proliferative lesions, neutropenic ulcers, papilloma, and candidiasis. CONCLUSION: There was a high prevalence of oral leukoplakias in patients with Fanconi anaemia who had not undergone HSCT. It highlights the need of regular oral screenings in this cohort of concern for head and neck malignancies and suggests that oral leukoplakias should be further investigated as part of the syndrome phenotype.

Mouth self-examination as a screening tool for oral cancer in a high-risk group of patients with Fanconi anemia.

OBJECTIVE: Oral cancer usually occurs at accessible sites, enabling early detection by visual inspection. Fanconi anemia (FA) is a recessive disorder associated with a high risk of developing head and neck solid tumors. The aim of this study was to assess the ability to perform mouth self-examination (MSE) in these patients. STUDY DESIGN: A total of 44 patients with FA, aged ≥ 18 years, were given a self-reported questionnaire to collect sociodemographic data and information about health-related behaviors and oral cancer awareness. They were asked to perform MSE, which was evaluated using criteria for mucosal visualization and retracting ability. Subsequently, an oral medicine specialist clinically examined all participants, and these findings were considered to be the gold standard. RESULTS: The sensitivity and specificity values of MSE were 43% and 44%, respectively. The MSE accuracy was 43%. Most patients (73%) reported that MSE was easy or very easy, although 75% showed insufficient performance. CONCLUSIONS: The accuracy of MSE alone is not sufficient to indicate whether MSE should be recommended as a strategy to prevent oral cancer in patients with FA. Nevertheless, the present results indicate that this inexpensive technique could be used as a tool for early detection of cancer in these patients.

A study of facial pattern in patients with fanconi anemia.

OBJECTIVE: This study is aimed to evaluate craniofacial features in patients with Fanconi anemia (FA) through cephalometric analysis and to classify the facial growth pattern to observe possible facial discrepancies. DESIGN: This is a cross-sectional study which employed a quantitative approach to compare linear and angular measurements of cephalometric analysis in lateral teleradiographic images of a clinical type sample of patients with FA. A retrospective cephalometric study was performed using cephalometric analyses of Ricketts and Steiner; growth patterns according to Ricketts' vertical growth pattern (VERT index) were also analyzed. PATIENTS: Fifty patients diagnosed with FA who were undergoing anti-aplasia treatment at the outpatient Hematology service at the Federal University of Paraná, Curitiba, Brazil were included in the study. INTERVENTIONS: The patients were evaluated in the School of Dentistry of the Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil. Exclusion criteria included patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. MAIN OUTCOME MEASURES: Cephalometric points were plotted in order to set up linear and angular cephalometric measurements. Angular and linear measurements from 17 factors proposed by Ricketts' cephalometric analysis were assessed. RESULTS: Dolicofacial appearance was observed in 52% of individuals; braquifacial in 28%, and mesofacial in 20%. Significant maxillary/mandibular discrepancy was observed. It was concluded that upon anteroposterior evaluation of facial bone structures, the FA sample presented smaller median measurements in most variables evaluated; it also presented mandibular micrognathism and mainly dolicofacial vertical growth pattern. These findings, together with other features such as skin pigmentation and microphthalmia, may lead to a possible recognition of a FA condition from a patient's facial features.

Oral squamous cell carcinoma in two siblings with Fanconi anemia after allogeneic bone marrow transplantation.

Fanconi Anemia patients are a high risk group for solid and hematologic malignancies. The risk seems to be influenced by age, chronic graft versus host disease and immunosuppressive drug regimens. Reports of oral malignant transformation in Fanconi Anemia after hematopoietic stem cell transplantation (HSCT) are increasing probably because of longer survival rates. This is the report of an 18- and her 28-year old sister who developed a post-HSCT oral squamous cell carcinoma. There were significant differences regarding time to malignant transformation, marrow donor characteristics and graft versus host disease evolution and treatment. The report reinforce the need for a routine head and neck screening for cancer in this particular syndrome and suggest that familial history should also be considered in Fanconi anemia patients at risk for oral malignancy after HSCT.