Body proportions in fanconi anemia heterozygotes

To study the anthropometric ratios in parents (heterozygotes) of children withFanconi anemia. The study was carried out in the Department of Hematology, Institute of Child Health & Hospital for Children, Chennai. Parents of children with Fanconi anemia were the subjects of the study. Applying standard instruments and methods, various body measurements were recorded. 31 fathers and 37 mothers were included in the study. A hundred male and female controls of the same ethnic group were also studied for the same parameters. The ratios were calculated and statistically analyzed. It was observed that fathers (male heterozygotes) had shorter forearms, the ratio of upper arm: forearm was significantly increased compared to male controls. In mothers (female heterozygotes) the inter-pupillary distance was increased, the ratio of head circumference to inter-pupillary distance was decreased compared to female controls.     

Successful treatment of secondary graft failure following unrelated cord blood transplant with hematopoietic growth factors in a pediatric patient with Fanconi anemia

Graft failure following allogeneic HCT in Fanconi anemia is associated with significant mortality. Retransplantation may be considered; however, the limited toxicity profile of HGFs also makes them an option for the treatment of graft failure. We describe a five‐yr‐old female diagnosed with Fanconi anemia and marrow failure treated with HCT. The course was complicated by secondary graft failure treated successfully with HGFs including G‐CSF, EPO, and romiplostim. The outcome could be related to the intervention, but could also be the natural course of recovery, including recovering from a recent CMV infection treated with ganciclovir. We found the use of HGFs to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of retransplantation.     

Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor

Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred. Pediatr Blood Cancer 2009;53:1140–1142. © 2009 Wiley‐Liss, Inc.     

范可尼贫血临床特征的新认识

范可尼贫血(FA)表现极大的临床异质性,尽管FA相关基因的识别拓宽了人们对于FA发病机制的认识,但除少数病例外,这些基因型与临床表现型之间缺少严格的对应性.对于同一基因型FA患者而言,突变类型对临床表现型影响似乎更为重要,修饰基因、环境因素差异等也可致FA患者临床表现明显不同.与基因型和临床表现型多样性不同,FA细胞表现型更具特征性,是诊断FA最重要的依据.     

Metachronous manifestations of Sweet's syndrome in a neutropenic patient with Fanconi anemia

Sweet's syndrome (SS) is an acute, febrile neutrophilic dermatosis that frequently presents with leukocytosis and erythematous plaques. Lesions show neutrophilic infiltration of the dermis and rarely other organs. We report the case of an adolescent male with chronic pancytopenia secondary to Fanconi anemia (FA) who presented with acute respiratory distress. Despite an exhaustive and ultimately unrevealing work-up, the diagnosis of pulmonary SS was not made until he developed characteristic cutaneous lesions 4 months later. Comprehensive review of pathological specimens revealed metachronous SS manifestations with infiltrates in lung parenchyma, dermis, and subcutis in this neutropenic patient.     

Fanconi Syndrome Secondary to Deferasirox in Diamond–Blackfan Anemia: Case Series and Recommendations for Early Diagnosis

Deferasirox is an oral iron chelator used to treat patients with transfusion‐related iron overload. We report, from two institutions, two children with Diamond–Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life‐threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy.     

The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations

Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group.     

Hyperbaric oxygen should not be used in the management of hemorrhagic cystitis in patients with Fanconi anemia

Hemorrhagic cystitis (HC) is a common complication after stem cell transplantation (SCT) that occurs more frequently in patients with Fanconi anemia (FA) because of hypersensitivity of their cells to the agents used in the preparation for SCT (chemo and radiation). Many HC cases respond to therapy with hyperhydration and maintenance of adequate platelet counts, but refractory cases may require additional measures such as the use of prostaglandins, alum, or hyperbaric oxygen (HBO). We report here an unusual complication to HBO therapy in a FA patient consisting of generalized edema mimicking capillary leak syndrome but with no pulmonary edema or ascites.     

Microcephalus, medulloblastoma and excessive toxicity from chemotherapy: an unusual presentation of Fanconi anaemia

Fanconi anaemia is a genetically and phenotypically heterogeneous disorder with different forms of clinical presentation. In this case the patient had suffered from microcephalus and delayed motor development from birth, but extensive investigation did not disclose any aetiology. At 3.5 y she developed a cerebellar medulloblastoma which was treated with surgery and chemotherapy. Following chemotherapy with alkylating agents she suffered from severe bone marrow aplasia which caused life-threatening infections, feeding problems and impaired kidney function. Fanconi anaemia was suspected, but it took 2 mo before the chromosome fragility test came out positive. From the moment diagnosis of Fanconi anaemia was made, no further active treatment was given. The patient's condition improved for some time, but she relapsed and died exactly 1 y after the first diagnosis of brain tumour. CONCLUSION: Fanconi anaemia must always be suspected in patients who experience excessive toxicity from chemotherapy regardless of the type of malignancy and congenital malformations.     

Wilms tumor,AML and medulloblastoma in a child with cancer prone syndrome of total premature chromatid separation and Fanconi anemia

Wilms tumor (WT) is the most common primary renal tumor in childhood. The occurrence of WT in patients with growth retardation, mental retardation and central nervous system abnormalities in association with premature chromatid separation (PCS) and mosaic variegated aneuploidy has been previously described in only 10 patients. Here we report the very rare occurrence of WT with two other malignancies, acute myeloid leukemia and medulloblastoma in association with chromosomal instability. This is a novel presentation of Fanconi anemia with this cytogenetic abnormality. Pediatr Blood Cancer 2009;53:208–210. © 2009 Wiley‐Liss, Inc.     

κ light chain — myeloma associated with adult Fanconi syndrome: Response of the nephropathy to treatment of myeloma

The association of Bence Jones proteinuria with adult Fanconi syndrome has been reported in a small number of patients. The nephropathy and the Bence Jones proteinuria often precede by several years the diagnosis of frank myeloma. A 39-year-old woman developed renal glucosuria 2.5 years prior to the diagnosis of a plasma cell disease characterized by k Bence Jones proteinuria, osteolytic lesions, and histologically proven plasmacytomas. Serum phosphorus of 1.1–2.1 mg/dl and uric acid of 1.3–1.6 mg/dl were compatible with Fanconi syndrome. Glucosuria was constantly present, while the glucose tolerance test was normal. Urinary β₂ microglobulin (β₂M) excretion was up to 135 mg/24 hours (normal less than 0.14 mg), indicating failure of tubular absorption of this protein. Amino-aciduria was noted. The patient's myeloma responded to irradiation followed by melphalan plus prednisone and vincristine; the result was a marked reduction of the Bence Jones proteinuria. Some of the manifestations of the Fanconi syndrome disappeared, while the others were markedly reduced; this included disappearance of the glucosuria, elevation of the serum phosphorus and uric acid to normal, decrease of the urinary amino acid excretion to the normal range in 11 of the 14 amino acids tested, and decrease in the β₂ M excretion to 5.4 mg/24 hours. The response of the Fanconi syndrome to the treatment of myeloma supports the view that the nephropathy is due to the myeloma process, probably through renal tubular injury induced by Bence Jones proteinuria.     

Screening of the FANCA gene mutational hotspots in the Pakistani fanconi anemia patients revealed 19 sequence variations

Fanconi anemia (FA) is a recessive disorder that predispose to bone marrow failure and multiple congenital anomalies in affected individuals worldwide. To date, 22 FA genes are known to harbor sequence variations in disease phenotype. Among these, mutations in the FANCA gene are associated with 60% to 70% of FA cases. The aim of the present study was to screen FA cases belonging to consanguineous Pakistani families for selected exons of FANCA gene which are known mutational hotspots for Asian populations. Blood samples were collected from 20 FA cases and 20 controls. RNA was extracted and cDNA was synthesized from blood samples of cases. DNA was extracted from blood samples of cases and ethnically matched healthy controls. Sanger's sequencing of the nine selected exons of FANCA gene in FA cases revealed 19 genetic alterations of which 15 were single nucleotide variants, three were insertions and one was microdeletion. Of the total 19 sequence changes, 13 were novel and six were previously reported. All identified variants were evaluated by computational programs including SIFT, PolyPhen-2 and Mutation taster. Seven out of 20 analyzed patients were carrying homozygous novel sequence variations, predicted to be associated with FA. These disease associated novel variants were not detected in ethnically matched controls and depict genetic heterogeneity of disease.     

Medulloblastoma as a first presentation of fanconi anemia

Fanconi anemia is a chromosomal instability syndrome associated with certain congenital abnormalities, defective hemopoiesis, and an increased risk of developing acute myeloid leukemia and some solid tumors. The diagnosis can be made at birth if congenital abnormalities are present but is often made in childhood when hematologic complications develop. The authors report a case of Fanconi anemia diagnosed in a child with no congenital abnormalities and normal bone marrow who first presented with a cerebellar medulloblastoma. The authors discuss diagnostic and therapeutic implications for such malignancies in Fanconi anemia.     

Allogeneic hematopoietic stem cell transplantation of patients with FA and high risk features using fludarabine without radiation

Several factors unique to Fanconi anemia (FA) limit the success of allogeneic hematopoietic stem cell transplantation (HSCT) in this population. In this report, we describe a multi‐center pilot study of five consecutive FA patients with high‐risk features for transplant prepared with fludarabine, without radiation. Four patients engrafted quickly, experienced minimal toxicity and are well at 43–65 months post‐transplant. One patient had a C‐mismatched unrelated donor transplant and had unsustained engraftment. This fludarabine based regimen without radiation was safe and effective for four high‐risk patients, suggesting that eliminating radiation should be further studied as an approach to HSCT in children with FA. Pediatr Blood Cancer 2009;52:683–685. © 2009 Wiley‐Liss, Inc.     

范可尼贫血患者临床转归与基因突变关系分析

目的初步探讨范可尼贫血(FA)基因突变与临床转归的关系。方法回顾性分析临床严重程度及治疗均相同的6例FA患者的临床资料,均采用单细胞凝胶电泳及丝裂霉素C(MMC)诱导的染色体断裂试验进行诊断,并采用先天性骨髓衰竭性疾病的基因检测试剂盒或互补实验进行基因分型,最后综合分析FA患者治疗3、6、9、12个月的临床转归与基因突变的关系。结果 6例FA患者中,5例为FANCA型、1例为FANCM型,4例患者携带2种及以上FA基因突变。临床严重程度相同的FA患者中,携带FA突变基因较多的患者发病年龄较小,对药物反应较差,更易发展为重型。结论同时携带两种以上FA突变基因的患者临床预后较差,应尽早进行造血干细胞移植。     

Differentiation of Fanconi anemia from idiopathic aplastic anemia by induced chromosomal breakage study using mitomycin-C (MMC)

This study was conducted to differentiate between Fanconi anemia (FA) and "idiopathic" aplastic anemia on the basis of induced chromosomal breakage study with mitomycin C (MMC). MMC-stress test was conducted on peripheral blood lymphocytes from 29 patients with aplastic anemia. Ten patients with very high percentage of chromosomal breakage and four patients exhibiting somatic mosaicism were diagnosed as FA on the basis of chromosomal breakage study. Six of these patients exhibited congenital anomalies at presentation while another eight lacked such anomalies or had minor physical problems.The present study illustrates that MMC stress test provides an unequivocal means of differentiation between Fanconi anemia and 'idiopathic' aplastic anemia. Further, the study, first of its kind from India, stresses on the need for conducting this test in all aplastic anemia cases, even those without congenital anomalies, for accurate and timely diagnosis of Fanconi anemia to implement appropriate therapy.     

Pseudotumor cerebri in a Turkish boy with Fanconi anemia

Pseudotumor cerebri (PC) is a clinical syndrome characterized by increased intracranial pressure with a normal cerebrospinal fluid cell count and protein level in the absence of a space-occupying lesion or apparent obstruction to the cerebrospinal fluid pathway. Although PC is described in patients with various hematological diseases including iron-deficiency anemia, megaloblastic anemia, acquired aplastic anemia, hemolytic anemia, sickle cell disease, and paroxysmal nocturnal hemoglobinuria, there is no case of PC with Fanconi anemia in the English literature. Here, we report a first case of PC in an 11-year-old boy with a diagnosis of Fanconi anemia.     

Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML

Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management. Pediatr Blood Cancer 2012; 59: 922-924. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.     

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??Objective??To analyze the clinical characteristics of children with Fanconi anemia??FA?? and their responses to different drug treatments??and to study the clinical outcomes of different drug treatments. Methods??A total of 43 children with definite diagnosis of FA in Institute of Hematology and Blood Diseases Hospital??Chinese Academy of Medical Sciences & Peking Union Medical College??From October 2003 to December 2014?? were included. Fisher’s exact test was used to analyze the potential difference of different treatments. Results??Of 43 cases??the median age of onset was 5 years??50 days to 14 years????and there were 23 male cases??53.5%?? and 20 female cases??46.5%??. The male to female ratio was 1.15??1. There were 30 cases??69.8%?? of malformation??and the incidence of hand deformity was the highest??34.3%??. No family history was observed in 27 cases??62.8%??. The most common first symptoms were anemia and thrombocytopenia. The authors further analyzed the efficacy of cases with the follow-up time≥6 months??and found that there was significant efficacy difference between the androgen +/-glucocorticoid/rabbit anti-human thymocyte immunoglobulin??ATG??+cyclosporin A group and androgen group as well as androgen+glucocorticoid groups??P??0.05??. Conclusion??The incidence of malformations in children with FA is inconsistent with some other international reports. The deformity or family history does not exist in all children with FA. The poor clinical prognosis and progression of FA are associated with the treatment of cyclosporin A.     

Therapy‐related leukemia associated with alkylating agents*

The leukemogenic potential of alkylating agents has been known for many years and almost all alkylating agents in clinical use have been shown to increase the risk of leukemia. With these drugs the risk of leukemia appears to increase with increasing patient age, as does the risk of de novo myeloid leukemia in the population. Susceptibility to alkylating agent‐associated leukemia is influenced by the genetic constitution of the patient, and by the nature of the exposure. To illustrate the importance of these factors in etiology of leukemia, this paper discusses the contribution of disorders such as Fanconi anemia and neurofibromatosis to susceptibility to alkylating agent‐associated leukemia. This paper also discusses the contribution of alkylkating agents and other therapeutic exposures in the etiology of leukemias occurring after autologous bone marrow transplant. Med. Pediatr. Oncol. 36:536–540, 2001. © 2001 Wiley‐Liss, Inc.