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Fanconi anemia (FA) is a genetic disorder due to mutations in any of the 22 FANC genes (FANCA – FANCW) and has high phenotypic variation. Siblings may have similar clinical outcome because they share the same variants, however, such association has not been reported. We present the detailed phenotype and clinical course of 25 sibling sets with FA from two institutions. Haematological progression significantly correlated between siblings, which was confirmed in an additional 55 sibling pairs from the International Fanconi Anemia Registry. Constitutional abnormalities were not concordant, except for a moderate degree of concordance in kidney abnormalities and microcephaly.

Objectives/Hypothesis To describe the management and outcomes of Fanconi anemia (FA) patients with head and neck squamous cell carcinoma. Study Design Cohort study. Methods Demographic information, prognostic factors, therapeutic management, and survival outcomes for FA patients enrolled in the International Fanconi Anemia Registry who developed head and neck squamous cell carcinoma (HNSCC) were analyzed. Results Thirty-five FA patients were diagnosed with HNSCC at a mean age of 32 years. The most common site of primary cancer was the oral cavity (26 of 35, 74%). Thirty patients underwent surgical resection of the cancer. Sixteen patients received radiation therapy with an average radiation dose of 5,050 cGy. The most common toxicities were high-grade mucositis (9 of 16, 56%), hematologic abnormalities (8 of 16, 50%), and dysphagia (8 of 16, 50%). Three patients received conventional chemotherapy and had significant complications, whereas three patients who received targeted chemotherapy with cetuximab had fewer toxicities. The 5-year overall survival rate was 39%, with a cause-specific survival rate of 47%. Conclusions Fanconi anemia patients have a high risk of developing aggressive HNSCC at an early age. Fanconi anemia patients can tolerate complex ablative and reconstructive surgeries, but careful postoperative care is required to reduce morbidity. The treatment of FA-associated HNSCC is difficult secondary to the poor tolerance of radiation and chemotherapy. However, radiation should be used for high-risk cancers due to the poor survival in these patients. Level of Evidence 4. Laryngoscope, 2015

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome, characterized by congenital anomalies, bone marrow failure and cancer predisposition. FA patients with mutations in FANCB exhibit X-linked inheritance pattern. FANCB patients have been frequently associated with a severe phenotype, resembling VACTERL association with hydrocephalus, although heterogeneity in these patients still exists and is not well understood. To determine the underlying pathogenesis of clinical heterogeneity, we investigated phenotype-genotype correlations in 19 patients from 16 families with FANCB pathogenic variants. We also investigated functional properties of five FANCB missense variants to determine their possible contribution to clinical manifestations. Patients were accrued at the Rockefeller University Hospital in the International Fanconi Anemia Registry. Among the 16 families with FANCB pathogenic variants, three carry nonsense variants, five have indels, two with large deletions, one has an intragenic duplication, two with canonical splice site variants that should result in aberrant splicing, and five display missense variants. One patient carried both an indel and a missense variant. Patients with variants leading to FANCB truncations (including nonsense variants, indels, large deletions/duplications, and splice variants) tend to show shorter survival and earlier hematologic onset, than patients with missense variants. However, the differences did not reach statistical significance due to small sample size. Functional properties of five missense variants were examined by overexpression of variant cDNA (HA-tagged) in FANCB-null fibroblasts, followed by assessment of FANCD2 ubiquitination, mitomycin C (MMC) sensitivity, FANCD2 foci formation and HA-FANCB localization. We found that expression of p.W479G and p.L676P FANCB variants leads to near-normal FANCD2 ubiquitination upon MMC exposure, and MMC sensitivity. Conversely, p.L43S-expressing cells behaved like FANCB-null fibroblasts. Expression of p.L329P and p.G750V resulted in low levels of FANCD2 ubiquitination upon MMC exposure and intermediate MMC sensitivity. Expression of p.L43S resulted in smaller-sized and lowest quantity of FANCD2 foci with predominant cytoplasmic localization of HA-FANCB, while other variants showed intermediate phenotype. We quantified the nuclear expression of HA-FANCB, which confirmed the lowest relative nuclear expression of p.L43S variant, suggesting a defect in nuclear localization necessary for the interstrand crosslink repair. We also assessed splicing defects in the patient primary cells by reverse transcription PCR. Majority of the transcripts in the patient carrying c.1435T>G (predicted to express p.W479G) variant showed aberrant splicing, exon 7 skipping, which should result in an out-of-frame truncated protein. Although the expression level of c.1435T>G encoding the missense variant p.W479G is lower than the splicing variant, its functional characteristics were near-normal, thus reflecting relatively milder phenotype in this patient. Overall patient survival correlated with residual function of their FANCB variants as assessed by in vitro assays described above. In summary, we report clinical course and mutation types of 19 patients with FANCB pathogenic variants. We also report that FANCB missense variants can have varying degree of residual function, which correlates with patient survival. Our data suggest that variant-level analysis may be a useful prognostic marker of patient outcome. In vitro assays evaluating the residual function of proteins with missense variants may help to predict patient outcome. Disclosures No relevant conflicts of interest to declare.

Prenatal diagnosis was performed on a fetus at risk for Fanconi anemia. A high spontaneous (0.30 breaks/cell) and diepoxybutane-induced (0.69 breaks/cell) chromosome breakage rate indicated an affected fetus and the pregnancy was terminated. The anatomic findings in the aborted fetus together with cytogenetic findings in cultured fetal skin fibroblasts confirmed the prenatal diagnosis.

Eighteen consecutive patients aged 5.5-24 years with Fanconi anaemia and diagnoses of aplastic anaemia (n = 8), myelodysplastic syndrome (n = 4), acute myeloid leukaemia (n = 6), received allogeneic haematopoietic stem cell transplants from alternative donors. All patients had been transfused, 13 had previously been treated with androgens and 14 had a history of infection. Donors were related human leucocyte antigen (HLA) mismatched for eight patients, unrelated HLA mismatched for seven patients and unrelated HLA matched for three patients. Cytoreduction included single dose total body irradiation (450 cGy), fludarabine (150 mg/m(2)) and cyclophosphamide (40 mg/kg). Immunosuppression included antithymocyte globulin and tacrolimus. Grafts were granulocyte colony-stimulating factor-mobilized, CD34+ T-cell-depleted peripheral blood stem cells in 15 patients and T-cell-depleted marrows in three. All 18 patients engrafted with 100% donor chimaerism; only one patient developed graft-versus-host disease (GVHD). With a median follow-up of 4.2 years, 13/18 patients were alive, 12 of these were disease-free. Five-year overall survival and disease-free survival were 72.2% and 66.6% respectively. Immune reconstitution was achieved at approximately 6 months post-transplant for most patients. These are encouraging results of T-cell-depleted transplants from alternative donors using fludarabine-based cytoreduction in 18 high-risk patients with Fanconi anaemia, with no evidence of rejection and minimal GVHD.

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1–2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1–5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles. [Cancer Res 2007;67(19):9591–6]

Fanconi anemia (FA) is a genetic disorder characterized bycongenital abnormalities, cancer predisposition, and progressivepancytopenia. The cellular phenotype of FA is characterized byincreasedsensitivitytoDNAcross-linkingoralkylatingagentsthatblock DNA replication and RNA transcription. FA patients have avery high risk of developing bone marrow failure along with anincreased risk of development of malignancies. The most frequentmalignancy in FA is acute myeloid leukemia (AML) with acumulative incidence of 33% by 40 years of age [1]. Themanagement of FA patients who develop myelodysplastic syn-drome (MDS) or leukemia is challenging. Sensitivity to DNA-damaging agents limits therapy that can be administered to FApatients.Severetoxicityandmarrowaplasiawithouthematologicalrecovery have been described in single patient case reports [2,3].Currently, the only definitive treatment for patients with FA andmyeloidmalignancyisstemcelltransplantation(SCT)andthereareno data to indicate whether cytoreduction with chemotherapy isbeneficial prior to SCTin these patients. However, bulky leukemiamay reduce the success of SCT. In addition, leukemia may need tobe controlled while waiting for a transplant donor search.The literature regarding conventional chemotherapy in FApatients with leukemia is limited, consisting of single case reports.Verbeek et al. [4] reported an adult AML patient with FA whoseinduction chemotherapy, consisting of sequential high-dose cyto-sine arabinoside (Ara-C) and mitoxantrone resulted in a completebut temporary hematological remission. Recently, Ikeda et al. [5]reported their experience of treating a 2-year-old boy with 100 mg1-b-D-arabinofuranosylcytosine/m

Expert curation and complete collection of mutations in genes that affect human health is essential for proper genetic healthcare and research. Expert curation is given by the curators of gene-specific mutation databases or locus-specific databases (LSDBs). While there are over 700 such databases, they vary in their content, completeness, time available for curation, and the expertise of the curator. Curation and LSDBs have been discussed, written about, and protocols have been provided for over 10 years, but there have been no formal recommendations for the ideal form of these entities. This work initiates a discussion on this topic to assist future efforts in human genetics. Further discussion is welcome.

Fanconi anemia (FA) is an autosomal recessive syndrome characterized by progressive pancytopenia and a high risk of malignancies, particularly acute myelogenous leukemia (AML). Diepoxybutane (DEB) analysis is the preferred test for FA because other agents have higher rates of false-positive and false-negative results. Basic Protocol in this unit applies the DEB test to rule out a diagnosis of FA using a peripheral blood sample from the patient. Support Protocol 1 provides instructions for working with DEB. Support Protocol 2 describes staining slides for chromosome-breakage analysis that is performed on unbanded metaphase preparations. Alternate Protocol 1 provides a detailed method for applying the DEB test to cultured fibroblasts that grow as a monolayer attached to the bottom of the flask. Alternate Protocol 2 outlines methods for using the DEB test for prenatal diagnosis of FA, utilizing fetal cells obtained by chorionic villus sampling (CVS), amniocentesis, or fetal blood sampling.Fanconi anemia (FA) is an autosomal recessive syndrome characterized by progressive pancytopenia and a high risk of malignanci.

Bone marrow transplantation (BMT) is the only known cure for the hematologic manifestations of Fanconi anemia (FA). Potential benefits of unrelated donor BMT for FA, however, have been severely limited by graft rejection and treatment-related mortality with resultant poor survival. Therefore, we evaluated the impact of potential prognostic factors on hematopoietic recovery, graft-versus-host disease (GVHD), and mortality in 98 recipients of unrelated donor BMT who received transplants between 1990 and 2003. Probabilities of neutrophil (89% vs 69%; P = .02) and platelet (74% vs 23%; P < .001) recovery were higher after fludarabine-containing regimens than nonfludarabine-containing regimens. Risks of acute GVHD (relative risk [RR], 4.29; P < .001) were higher with non–T-cell–depleted grafts. The day-100 mortality rate was significantly higher after nonfludarabine-containing regimens than fludarabine-containing regimens (65% vs 24%, respectively; P < .001). Corresponding 3-year adjusted overall survival rates were 13% versus 52% (P < .001). In addition, mortality was higher in recipients who were older (> 10 years), who were cytomegalovirus (CMV) seropositive, and who received more than 20 blood product transfusions before BMT. Based on these results, significant practice changes are suggested: use of a fludarabine-containing conditioning regimen in the context of T-cell–depleted marrow allografts, and earlier referral for transplantation prior to excessive transfusions in patients with marrow failure.

Survival analysis encompasses investigation of time to event data. In most clinical studies, estimating the cumulative incidence function (or the probability of experiencing an event by a given time) is of primary interest. When the data consist of patients who experience an event and censored individuals, a nonparametric estimate of the cumulative incidence can be obtained using the Kaplan-Meier method. Under this approach, the censoring mechanism is assumed to be noninformative. In other words, the survival time of an individual (or the time at which a subject experiences an event) is assumed to be independent of a mechanism that would cause the patient to be censored. Often times, a patient may experience an event other than the one of interest which alters the probability of experiencing the event of interest. Such events are known as competing risk events. In this setting, it would often be of interest to calculate the cumulative incidence of a specific event of interest. Any subject who does not experience the event of interest can be treated as censored. However, a patient experiencing a competing risk event is censored in an informative manner. Hence, the Kaplan-Meier estimation procedure may not be directly applicable. The cumulative incidence function for an event of interest must be calculated by appropriately accounting for the presence of competing risk events. In this paper, we illustrate nonparametric estimation of the cumulative incidence function for an event of interest in the presence of competing risk events using two published data sets. We compare the resulting estimates with those obtained using the Kaplan-Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCCmutations (P = .007) and hematopoietic stem cell transplantation (P =

Objectives.1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group.Study Design.Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1–31.9 years, with the mean age at assessment 8.6 years.Results.Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal.Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of theFANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C.Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: −2.35 ± 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA.Conclusion.Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.

We have studied a 38-year-old man with a prior diagnosis of Holt-Oram syndrome, who presented with diabetes mellitus. He had recently taken prednisone for idiopathic interstitial lung disease and trimethoprim-sulfamethoxazole for sinusitis. Thrombocytopenia progressed to pancytopenia. The patient had skeletal, cardiac, renal, cutaneous, endocrine, hepatic, neurologic, and hematologic manifestations of Fanconi anemia (FA). Chest radiographs showed increased interstitial markings at age 25, dyspnea began in his late 20s, and he stopped smoking at age 32. At age 38, computerized tomography showed bilateral upper lobe fibrosis, lower lobe honeycombing, and bronchiectasis. Pulmonary function tests, compromised at age 29, showed a moderately severe obstructive and restrictive pattern by age 38. Serum alpha-1 antitrypsin level was 224 (normal 85-213) mg/dL and PI phenotype was M1. Karyotype was 46,XY with a marked increase in chromosome aberrations induced in vitro by diepoxybutane. The early onset and degree of pulmonary disease in this patient cannot be fully explained by environmental or known genetic causes. The International Fanconi Anemia Registry (IFAR) contains no example of a similar pulmonary presentation. Gene-environment (ecogenetic) interactions in FA seem evident in the final phenotype. The pathogenic mechanism of lung involvement in FA may relate to oxidative injury and cytokine anomalies.

Data were analyzed from 419 Fanconi anemia (FA) patients enrolled in the American Registry of the International Fanconi Anemia Registry (IFAR) to determine whether Fanconi anemia (FA) patients without major congenital malformations (CM) have distinguishing characteristics that can lead to an earlier diagnosis. These included 377 patients reported by physicians to the IFAR and 42 patients examined by us. The number of FA patients in each group without CM was 128 and 16, respectively; one third of all patients lacked CM. We found that height, weight, and head circumference were < or = 5th centile in 26.6%, 18.0%, and 8.6% of FA patients without CM referred to the IFAR, and in 43.8%, 25.0%, and 43.8% of FA patients without CM examined by us. Minor anomalies were reported in 9.4% of FA patients without CM referred to the IFAR and 100% of FA patients without CM examined by us. Most FA patients without CM have alterations in growth parameters, skin pigmentation abnormalities, or microphthalmia. Increased awareness of the complete spectrum of FA by clinicians will enable an earlier diagnosis to be made.

Fanconi anemia is a rare genetic disorder that leads to bone marrow failure. Hematopoietic cell transplantation (HCT) is currently the only treatment option with curative potential. When a suitable HLA-matched sibling donor is not available, patients are often treated with androgenic steroids before considering HCT. Such androgen treatments can lead to the development of hepatic adenomas, which usually regress upon stopping androgen therapy. A patient with Fanconi anemia is described who underwent an unrelated umbilical cord blood transplant with a history of a hepatic adenoma related to androgen therapy. No adenomas were detected on an ultrasound examination prior to HCT. Soon after HCT, he died due to sudden rupture and hemorrhage of a hepatic adenoma. This case illustrates the need for extra vigilance in the detection and management of hepatic adenomas in patients treated with androgens, especially prior to HCT.

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.

(95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure ANCON1 ANEMIA is an autosomal recessive disease characterized by aplastic anemia and congenital abnormalities.’ Hypersensitivity to DNA cross-linking agents, like diepoxybutane (DEB), is often used as a diagnostic test.’ DEB testing allows diagnosis of Fanconi anemia in persons with diverse clinical features including those without clinically detectable congenital abn~rmalities.~ Complementation studies suggest that the genetic bases of Fanconi anemia are heterogeneo~s.~.~ Abnormalities in at least four genes, defined by complementation groups A, B, C, and D, result in increased DNA cross-linking sensitivity’ that characterizes Fanconi anemia. Group C complementing gene (FACC) was recently cloned! Mutation analysis suggests a correlation between genetic and clinical features in persons with abnormalities in this gene.7 Although hematologic abnormalities are common in persons with Fanconi a~~emia,~,~ their natural history is uncertain. Most studies are of small numbers of subjects with brief follow-up. We analyzed hematologic abnormalities in 388 persons with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). F

Summary There have only been a few reports documenting the use of umbilical cord blood as a source of stem cells for haemopoietic reconstitution. We report our experience with a child with Fanconi anaemia (FA) who underwent a stem cell transplant using umbilical cord blood cells from his HLA matched sibling. Although the engraftment was somewhat slow, it was complete and comparable to other transplants performed in FA patients using HLA matched sibling marrow. There was no graft-versus-host disease. The post-transplant period was uncomplicated and, at a follow-up of 36 months, this child is well with normal blood counts and immune function.

Researchers and clinicians ideally need instant access to all the variation in their gene/locus of interest to efficiently conduct their research and genetic healthcare to the highest standards. Currently much key data resides in the laboratory books or patient records around the world, as there are many impediments to submitting this data. It would be ideal therefore if a semiautomated pathway was available, with a minimum of effort, to make the deidentified data publicly available for others to use. The Human Variome Project (HVP) meeting listed 96 recommendations to work toward this situation. This article is planned to initiate a strategy to enhance the collection of phenotype and genotype data from the clinician/diagnostic laboratory nexus. Thus, the aim is to develop universally applicable forms that people can use when investigating patients for each inherited disease, to assist in satisfying many of the recommendations of the HVP Meeting [Cotton et al., 2007]. We call for comment and collaboration in this article. Hum Mutat 28(10), 931–932, 2007. © 2007 Wiley-Liss, Inc.

Summary Our results for 18 patients undergoing matched sibling donor stem cell transplant for Fanconi anaemia at Cincinnati Children's Hospital Medical Center were published in 1994. The present report updates our results in 35 consecutive patients. Thirty patients transplanted for marrow aplasia received cyclophosphamide 5 mg/kg for 4 d and 400 cGy thoraco-abdominal irradiation. Five patients with clones involving chromosome 7, myelodysplastic syndrome or leukaemia received a more aggressive regimen with total body irradiation. Horse antithymocyte globulin was administered in the pretransplant period to promote engraftment and in the post-transplant period for additional graft-versus-host disease (GVHD) prophylaxis. The median age at bone marrow transplantation was 7·6 years. Median day of engraftment was day +12 (range 9–49), eight patients developed acute GVHD and four chronic GVHD, one limited and three extensive. Twenty-nine of 35 patients (89% actuarial survival at 10 years) had survived with a median follow up of 10·2 years; two children had developed secondary malignancy. All surviving patients had normal blood counts with full donor engraftment. These data indicate excellent long-term outcomes and serve as a reference for newer radiation-free preparative regimes that may reduce the risk of late secondary malignancy.

Background To potentially reduce late effects of malignancy, chronic graft-versus-host disease (GVHD), endocrinopathy, and infertility in patients with Fanconi anemia (FA) undergoing HLA-matched related donor hematopoietic cell transplantation (HCT), we developed a regimen using fludarabine (FLU), cyclophosphamide (CY), and anti-thymocyte globulin (ATG) followed by infusion of T-cell depleted (TCD) bone marrow (BM) or unmanipulated umbilical cord blood (UCB). GVHD prophylaxis consisted of cyclosporine and short course methylprednisolone. Procedure Between April 2000 and June 2003, 11 patients (10 aplastic anemia (AA), 1 myelodysplastic syndrome (MDS)) underwent HCT using this regimen. Stem cell sources were BM and UCB in eight and three patients, respectively. Results All patients demonstrated primary engraftment. Median days to neutrophil and platelet engraftment were 11 days (range 9–21) and 38 days (range 19–381), respectively. No patient developed GVHD after primary HCT. The patient with MDS relapsed with AML and a maternal donor recipient experienced secondary graft failure. For the nine FA patients with AA who underwent HLA-identical sibling donor HCT, the Kaplan–Meier estimates of overall survival and event-free survival (EFS) at 2 years are 100% and 82%, respectively, at a median follow-up of 2.9 years (range 1.9–4.8). Conclusions In summary, a FLU-based, non-irradiation approach is effective for FA patients with AA undergoing HLA-identical sibling donor HCT. © 2005 Wiley-Liss, Inc.

Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between proteins that comprise the transcription factor complex TFIIH raises the possibility that nucleotide excision repair, RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes, xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in Bloom syndrome (BLM) and Werner syndrome (WRN) show that both are DNA and RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and infertility. Although the first Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.

Thrombocytopenia may be the presenting finding for both Wiskott-Aldrich syndrome and Fanconi anemia. We examined a sibship of four boys who had features of both of these hematologic disorders. Peripheral blood lymphocytes from three of the boys demonstrated DNA instability when cultured with diepoxybutane, confirming the diagnosis of Fanconi anemia in these patients. However, results of linkage analysis and X chromosome inactivation studies were consistent with the diagnosis of Wiskott-Aldrich syndrome in two of the boys, including one of the boys with Fanconi anemia. These findings could be attributed to the occurrence of two rare genetic disorders in a single family or to an unusual variant of Fanconi anemia. The recent identification of the Wiskott-Aldrich gene permitted us to address this question directly. Epstein-Barr virus-transformed cell lines from the two boys thought to have Wiskott-Aldrich syndrome on the basis of linkage analysis failed to express transcripts for the Wiskott-Aldrich gene. Genomic DNA from these two patients demonstrated a G insertion in the tenth exon of the Wiskott-Aldrich gene, resulting in a frameshift and a premature stop codon. Surprisingly, the patient with Fanconi anemia and a null mutation in the Wiskott-Aldrich gene had typical Fanconi anemia but mild Wiskott-Aldrich syndrome.

To the Editor: We have several comments on the Image in Clinical Medicine entitled “Some Features of Fanconi's Anemia” (Oct. 14 issue)1. It is gratifying that efforts are being made to increase phy...

Objective To describe the complications and adverse effects of postoperative radiotherapy in patients with Fanconi anemia (FA). Design Cohort study. Setting Patients with FA treated at community and tertiary care hospitals throughout the United States. Patients The study included patients with FA who were enrolled in the International FA Registry (IFAR) and who developed head and neck squamous cell carcinoma and received postoperative radiotherapy. Main Outcome Measures Demographics of patients with FA and adverse effects and dosages of radiotherapy. Results Twelve patients with FA (7 men and 5 women) were identified. They developed cancers at a mean age of 35.5 years (age range, 20-48 years). The sites of primary cancer were the oral cavity (n = 8), larynx (n = 2), pharynx (n = 1), and unknown (n = 1). The median radiation dose was 5590 cGy (range, 2500-7020 cGy). The most common adverse effects were mucositis (n = 9), dysphagia (n = 8), and pancytopenia (n = 6). Other complications included esophageal stenosis, laryngeal edema, and wound breakdown. Radiotherapy could not be completed in 5 cases. Overall, 8 patients died, 4 during the course of radiotherapy. The postoperative disease-free survival time ranged from 0 to 55 months. Conclusions Patients with FA have a high rate of complications from radiotherapy. Common adverse effects, particularly mucositis, are especially prevalent and difficult to manage in this population. Pancytopenia is common and may lead to further complications, particularly bleeding and infection. Overall survival is poor. Further study of the response to radiotherapy in patients with FA should be attempted to establish appropriate dosages to balance treating disease while limiting adverse effects.

Monozygotic (MZ) twin girls, diagnosed at birth to have Fanconi anemia (FA) on the basis of multiple anomalies and an apparently increased baseline chromosomal breakage frequency in one twin, have been followed prospectively for 13 years. They have not developed aplastic anemia or other hematologic manifestations of FA. There was no evidence for increased baseline or diepoxybutane (DEB)-induced chromosomal breakage in either twin when the studies were repeated in Denver as well as in New York. Since the cellular phenotype must be considered in establishing the diagnosis of FA, these MZ twins should not be classified as affected with FA. Using the scoring system for FA diagnosis developed by Auerbach et al. [1989], the probability coefficients of their having FA based solely on clinical findings, prior to DEB testing, were .75 and .92, respectively. When the combination of their anomalies are taken together, their FA probability coefficient is .98. Through the International FA Registry, 15 additional patients have been identified with an FA probability score of .75 or greater, but who have not developed aplastic anemia and who are DEB negative. These patients, as well as the twins described in this report, are most likely a heterogeneous group and may represent other syndromes like Holt-Oram, VATER, VACTERL and IVIC, with genetic as well as nongenetic etiologies. These cases demonstrate the importance of testing with DEB or other DNA crosslinking agent in order to discriminate between FA and other syndromes with a similar phenotype.

We have identified six new cases of Fanconi's anaemia (FA) who had pregnancies, and reviewed 11 others from the literature. At least 110 FA females have reached 16 years of age or more, of whom 15% became pregnant. There were a total of 26 pregnancies, resulting in 19 births and 18 surviving children. Anaemia and/or thrombocytopenia worsened during pregnancy in 10 patients, but five subsequently improved: seven had no haematological problems. Seven of the FA patients who had pregnancies died subsequently from cancer, and two from thrombocytopenic bleeding 3 and 20 years later. There were no peripartum deaths. Pregnancy in FA is clearly possible, with increased risks that are manageable from both the haematological and the obstetric aspects.

The diagnosis of aplastic anemia is based on the presence of pancytopenia combined with bone marrow hypocellularity. Aplastic anemia may be acquired or constitutional; in either case its occurrence may be indicative of a preleukemic condition.

Determination of the degree of somatic mosaicism providing functional correction of Fanconi anemia (FA) hematopoiesis has direct implications for gene therapy for FA: it may help assess the percentage of FA hematopoietic cells corrected by gene therapy approaches that are needed to achieve clinically meaningful effects. Hypersensitivity to DNA interstrand cross-linking agents, such as diepoxybutane (DEB) and mitomycin C (MMC), is a cellular marker for diagnosis of FA. However, in some FA patients a population of DEB-resistant PHA-stimulated lymphoblasts (PHA-L) was observed, and this population sometimes varied over time. To assess the significance of this finding on hematopoietic function, we evaluated the MMC sensitivity of bone marrow mononuclear cells (BMMC) and DEB sensitivity of PHA-L and cultured lymphoblastoid cell lines (LCL) in 42 consecutive FA patients referred to the University of Minnesota. In cases where LCL were DEB-resistant, cultured fibroblasts were also studied. BMMC were cultured in the presence of increasing concentrations of MMC. PHA-L and LCL were cultured in DEB at 0.1 mcg/ml. Wild type BM progenitors (N = 17 subjects) proliferated regardless of increasing MMC concentrations (albeit at decreased efficiency at the highest concentrations) as follows: 0 MMC (normalized to 100%), 5 nM MMC (99% [standard deviation, SD, 16%]), 10 nM MMC (90% [SD 22%]), 25 nM MMC (77% [SD21%]), and 50 nM MMC (44% [SD 30%]). Of the 42 FA patients, BMMC failed to proliferate at 0 nM MMC in 10 patients and at 5 nM MMC in 20 patients. Twelve FA patients had MMC resistant BMMC: cells cultured in 5, 10, 25 and 50 nM MMC grew 44% (SD 28%), 35% (SD 24%), 24% (SD 30%) and 17% (SD 32%) of colony numbers in MMC free culture, respectively. Six of these 12 subjects were PHA-L mosaics as determined by DEB sensitivity testing. Four patients with no growth of BMMC at 0 or 5 nM MMC were also somatic mosaics in their PHA-L and LCL. Thus there was no clear correlation between somatic mosaicism as demonstrated by DEB testing in peripheral blood and sensitivity of BMMC to growth in MMC. Clinically, two patients with hematopoietic somatic mosaicism developed severe marrow aplasia, one of which received hematopoietic stem cell transplantation. Four of the mosaic patients had normal or near normal peripheral blood counts with one patient having clonal hematopoiesis by HUMARA assay and only low levels of metaphases with multiple breaks in multiple DEB studies. While patients with hematopoietic somatic mosaicism had mixed populations of DEB sensitive cells in their peripheral blood, all their fibroblast cultures were DEB sensitive. In summary, these data show that the presence of somatic mosaicism per se does not necessarily prevent bone marrow failure. Moreover, the data suggest that patients with stigmata of FA may have chromosomal breakage studies showing few cells (or no cells) with the characteristic changes of FA; in these cases, skin fibroblasts should be tested as well.

Fanconi anemia (FA) patients have a 33% cumulative incidence of AML by 40 years of age (Kutler et al, 2003). Chemotherapy treatment of FA patients with MDS or AML is challenging because of constitutional sensitivity to DNA-damaging agents. Severe toxicity and marrow aplasia without hematological recovery have been described, largely in case reports of children given chemotherapy prior to diagnosis of FA. The definitive treatment for hematological malignancy in FA is stem cell transplant (SCT). However, transplant in patients with overt AML has a poor prognosis and also a donor may not be immediately available. Relapse post-SCT is usually fatal. Between 2002 and 2005 we treated 6 children with FA and AML or hypercellular MDS with monosomy 7, referred to the Fanconi Anemia Comprehensive Care Clinic at Cincinnati Children’s Hospital, with a uniform chemotherapy protocol (“mini-FLAG”). Figure Figure Clinical characteristics of patients, toxicity and efficacy of mini-FLAG are shown below: 3 patients belonged to complementation group A and one each to group D1, J and F. Overall, mini-FLAG was well tolerated with no mucositis or organ toxicity. Two of the three patients with leukemia achieved clearance of blasts and cytoreduction was attained in those with MDS. In all cases, patients proceeded to SCT once cytoreduction was achieved so reconstitution of normal hematopoiesis and durability of response could not be assessed. Table 1 Pt # Age / Gender Marrow cytogenetics Toxicity of mini-FLAG Marrow morphology pre-mini-FLAG Marrow morphology after mini-FLAG 1 16.3yrs/M 45,XY, t(2;3) No organ toxicity AML; 51% blasts No residual blasts; markedly hypocellular marrow 2 14.2yrs/F 47,XX, t(6;11) No organ toxicity AML; 80% blasts Hypoplastic; Three children survive; one died of relapsed leukemia 4 months post-SCT and 2 of complications of SCT. These data show that mini-FLAG can be used with minimal toxicity and significant but heterogeneous responses in children with FA. A future prospective multi-center study is needed to optimize use of chemotherapy in FA and determine the effect of pre-transplant chemotherapy on outcomes of SCT.

Between 05/98 and 06/04, 15 consecutive patients with FA received hematopoietic stem cell transplants (SCT) from alternative donors at our Center. There were 7 males and 8 females aged 5 to 24 years (median 11.5). Hematologic diagnoses included aplastic anemia (AA) (N=5), myelodysplastic syndrome (MDS) in RAEB (N=4), RAEBT (N=1) or acute myelogenous leukemia (AML) (N=5). High risk features included: Age > 20 years (n=4), prior multiple transfusions (n=11), prior androgen treatment (n=12), prior infections (n=10), or advanced MDS or AML (n=9). Eight pts had related mismatched donors transplants with respective matching at 3/6 (6/10), 4/6 (6/10), 4/6 (7/10) (n=2)), 5/6 (8/10) (n=3) and 5/6 (9/10) HLA-antigens. Seven pts had unrelated donors transplants with respective matching at 5/6 (7/10), 5/6 (8/10) (n=2), 5/6 (9/10) and 6/6 (10/10) (n=3) HLA-antigens. Cytoreduction included single dose total body irradiation (SDTBI) (450 cGy), fludarabine (Flu) (30 mg/m2 x 5) and cyclophosphamide (Cy) (10 mg/Kg x 4). Immunosuppression included rabbit anti-thymocyte globulin (Thymoglobulin) and tacrolimus for all patients. Grafts were G-CSF mobilized CD34+ and E-rosette negative (E-) peripheral blood stem cell transplants for 12 pts and soybean agglutinin negative (SBA-) and E-rosette negative marrow transplants for 3 pts. Cell doses of the grafts were 1.5 – 29.6 x 106 CD34 cells/Kg and 0 – 26 x 103 CD3 cells/Kg. As evidenced by RFLP or FISH, all 15 evaluable pts were fully engrafted and complete chimeras. Fourteen pts were evaluable for graft-versus-host disease (GvHD). GvHD of the skin and of the gut was suspected in two pts but resolved completely prior to immunosuppressive treatment. With a median follow-up of 2.5 years (range 0.2–6), 13 of 15 pts are alive and 11 of 15 are alive disease-free. There were two deaths: one pt died from sepsis/ARDS at 2 months post SCT and one pt from pneumonitis/ARDS and EBV-infection 6 months post SCT. Three pts relapsed (MDS-RAEB x 1 – AML x 2): One pt relapsed 7 months post transplant, received a 2nd transplant from the same donor following busulfan and Flu and is alive, disease-free 18 months post SCT, while the other two pts are awaiting a second SCT. In summary, this cytoreductive regimen used with T-cell depleted stem cell transplants from unrelated or HLA-mismatched related donors for the treatment of high risk patients with Fanconi anemia, results in rapid hematopoietic engraftment and lymphohematopoietic reconstitution with minimal GVHD and a high disease-free survival.

Fanconi anemia patients with biallelic BRCA2 mutations have an exceptionally high risk of developing hematological malignancies, Wilms tumors and medulloblastoma at a very young age. We report on the hematopoietic cell transplant (HCT) results of 6 patients from 4 kindreds, all of whom have biallelic BRCA2 mutations. Two patients (800/2 and 984/2) were found to have a Wilms tumor at time of work-up for HCT despite normal previous renal ultrasounds. One was a stage 1 favorable histology, the second a stage II poorly differentiated tumor with diffuse anaplasia. In each case, the patient underwent nephrectomy and proceeded to HCT 3 weeks later. All unrelated or mismatched related donor marrow grafts were T cell depleted either by elutriation in patient 632/1, or CD34 selection with Isolex in the remaining cases. Five of 6 patients achieved neutrophil engraftment. Only one patient developed severe regimen related toxicity and one patient GVHD. Two of 6 patients are alive and well after HCT, both whom had T-cell ALL, which is uncommon in FA patients. Patient and Transplant Characteristics | Kindred, IFAR No. | Age/Gender | Clinical Hx | Donor | Preparative Rx | Day to ANC>500 | Toxicity, GVHD | Outcome | |:----------------- | ---------- | ------------------------------------------------------------------------------------------------ | -------------- | --------------------------------------- | ------------------ | ---------------------- | ------------------------------------------------------ | | 1, 632/1 | 3.7 yr/F | AML at 36 mo, chemotherapy refractory | 6/6 URD BM x 2 | CY, TBI, ATG, CSA, MP; CY, ATG, MP, CSA | graft failure; +31 | None | AML relapse after both HCT, died day +76 after 2nd HCT | | 1, 632/2 | 1.9 yr/F | AML at 21 mo, chemotherapy refractory | 6/6 MSD BM | CY, TBI, FLU, ATG, CSA, MP | Engrafted | None | AML relapse, died day +288 | | 2, 800/1 | 1.8 yr/M | AML at 11 mo, chemotherapy refractory | 6/6 URD TCD BM | CY, TBI, ATG, CSA, MP | +11 | Grade II aGVHD | AML relapse day +110, died day +124 | | 2, 800/2 | 0.8 yr/M | Neutropenia at 5 mo, Wilms tumor at 9 mo | 6/6 URD TCD BM | CY, TBI, FLU, ATG, CSA, MP | +9 | Resp and renal failure | Died day +60 from pulmonary hemorrhage | | 3, 900/1 | 4.9 yr/M | T cell ALL at 5.2 yr, CR after chemotherapy | 5/6 Mat TCD BM | BU, CY, FLU, ATG, CSA, MP | +10 | None | Alive and well 19 mo after HCT | | 4, 900/2 | 6.7 yr/F | T cell ALL at 4.9 yr, remission with chemotherapy, relapse with AML 17 mo later, Wilms at 6.6 yr | 6/6 URD UCB | BU, CY, FLU, ATG, CSA, MP | +13 | None | Alive and well 3 mo after HCT | In summary, HCT has limited effectiveness after the onset of leukemia in patients with Fanconi anemia. While these patients have tolerated chemoradiotherapy well in most cases, refractoriness of the leukemia is the principle obstacle to success. Therefore, patients with biallelic BRCA2 mutations should be screened for solid tumors and referred for HCT as soon as possible, prior to the onset of leukemia. In addition, these patients require routine screening for solid tumors after HCT, the incidence of which remains to be determined.

Background: Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by a high degree of genomic instability and predisposition to cancer development. Recent evidence suggests that the incidence of head and neck squamous cell carcinoma (HNSCC) may be increased in patients with FA. Objective: To determine the cumulative incidence, tumor distribution, and outcome of HNSCC in patients with FA. Design and Setting: We analyzed data from 754 subjects from the International Fanconi Anemia Registry, a prospectively collected database of patients with FA. Main Outcome Measures: Cumulative incidence of HNSCC and 2-year overall, relapse-free and diseasespecific survival. Results: Of the 754 patients in the International FanconiAnemiaRegistry,19(3%)hadHNSCC.ThisisasignificantlyhigherincidenceofHNSCCcomparedwiththat observed in the general population (standardized incidence ratio, 500; 95% confidence interval, 300-781) (P.001). The patients’ age ranged from 15 to 49 years (median, 31 years), and there was a 2:1 female predominance.Surgicaltreatmentwaswelltolerated(n=17);however, radiation therapy and chemotherapy were associated with significant morbidity and mortality. Of the 19 patients, 10 (53%) developed locoregional recurrences within a median of 16 months from diagnosis. The median follow-up was 29 months. The 2-year diseasespecific,overall,andrelapse-freesurvivalrateswere49%, 49%, and 42%, respectively. The cumulative incidence of relapse by the age of 40 years was 50%. Conclusions: In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity. An increased understanding of FA-associated malignancies is not only important in the clinical management of patients with FA but can also elucidate the role of chromosomal instability in the development of HNSCC in general.

We report a family with a dominantly transmitted syndrome resembling Fanconi's anemia and spanning two generations. This syndrome was characterized by an ill-defined hematologic stem cell disorder, immune dysfunction, poor dentition, hyperpigmented skin, warts, and multiple second trimester spontaneous abortions and included one case of acute myelomonocytic leukemia (acute non-lymphocytic leukemia, M4). This family lacks the characteristic chromosomal aberrations of Fanconi's anemia. We believe this constellation of findings represents an entity not previously described.

Fanconi anemia (FA) is characterized clinically by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, study of cellular sensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) has been used to facilitate the diagnosis. Data from DEB-induced chromosomal breakage studies of 328 peripheral blood specimens from patients considered at risk for FA were analyzed using a stepwise multivariate logistic regression, in order to determine which method of representing the data best discriminated between DEB-sensitive (DEB+) and DEB-insensitive (DEB-) cases. Similar methods were applied to the data from the International Fanconi Anemia Registry (IFAR) to determine whether DEB+ and DEB- cases may be considered as distinct clinical entities, and if so, which variables provide the best discrimination between the two groups. We conclude that hypersensitivity to the clastogenic effect of DEB is a useful discriminator for FA. A simplified scoring method for classifying patients on the basis of eight clinical manifestations that are the best predictors for FA is presented. Our data indicate that the clinical diversity in FA is more widespread than previously recognized.

Progress has been made in the elucidation of the basic mechanisms that underlie both developmental abnormalities and malignancy through careful studies of heritable diseases that predispose persons to these problems. Fanconi anemia (FA), ataxia-telangiectasia, xeroderma pigmentosum, and Bloom syndrome are a few examples of such rare disorders, which are of interest in their own right but have even more significance because of their relevance to cancer predisposition and the interaction of genetic and environmental factors in cancer risk. Registries for surveillance of cancers have been established for Bloom syndrome (German et al. 1984), ataxia-telangiectasia (Spector et al. 1978) and xeroderma pigmentosum (Lambert 1987). In order to study a large number of FA patients with the full spectrum of the diverse features of the disease, the International Fanconi Anemia Registry (IFAR) was established at The Rockefeller University in 1982. The registry serves as a central repository for clinical, hematologic, and genetic information on FA patients. The large clinical database generated by the IFAR and cellular material stored from IFAR patients and their families provide an important resource which should enable us to better define the disorder.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

We report our experience, since 1978, with prenatal diagnosis in fetuses at risk for Fanconi anemia. Amniotic fluid cells from 30 fetuses from 24 families were monitored for baseline and diepoxybutane-induced chromosomal breakage. Seven of the fetuses at risk were diagnosed as affected; baseline and diepoxybutane-induced breakage ranged from 0.18 to 0.45 and 0.69 to 0.96 breaks per cell, respectively. The range of baseline and diepoxybutane-induced chromosomal breakage in amniocytes from the 23 pregnancies at risk that were diagnosed prenatally as unaffected ranged from 0 to 0.08 and 0 to 0.13 breaks per cell, respectively. Four of these cases were also diagnosed as normal on the basis of chromosomal breakage studies in cells obtained by chorionic villus sampling. The range of baseline and diepoxybutane-induced breakage in cells from five control fetuses was 0 to 0.05 and 0 to 0.10 breaks per cell, respectively. Of the pregnancies diagnosed as affected, two were carried to term, whereas five were terminated. One newborn and two abortuses had congenital malformations including abnormalities of the thumb and radius. The other affected live-born infant, now 5½ years old, has severe growth retardation and pancytopenia. No Fanconi anemia-associated malformations were found in any of the other fetuses or newborns studied. In all cases in which tissue was available for study, diagnoses were confirmed by chromosome breakage studies. This method thus permits reliable detection of Fanconi anemia.

Fanconi anemia is an inherited disease characterized by bone marrow failure, congenital malformations, and predisposition to cancer. The breast cancer susceptibility gene BRCA2 was recently found to be associated with Fanconi anemia complementation group D1 (FA-D1). We examined four kindreds afflicted with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred, of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and had Fanconi anemia and brain tumors. In another kindred of Ashkenazi Jewish and Lithuanian Catholic ancestry, a child with Fanconi anemia and a medulloblastoma was a BRCA2*6174delT/886delGT compound heterozygote. Two other kindreds each contained a Fanconi anemia-afflicted child who developed medulloblastoma; one child was of Latin American ancestry and a compound heterozygote for BRCA2*I2490T/ 5301insA and the other was African American and a compound heterozygote for BRCA2*Q3066X/E1308X. Median age of the Fanconi anemia-afflicted children at brain tumor diagnosis was 3.5 years. The co-occurrence of brain tumors, Fanconi anemia, and breast cancer observed in one of these kindreds constitutes a new syndromic association. Individuals who carry a germline BRCA2 mutation and who plan to have children with a partner of Ashkenazi Jewish descent should consider undergoing genetic counseling.

The clinical manifestations of Fanconi’s anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi’s anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7]. We report here on hematopoietic reconstitution in a boy with severe Fanconi’s anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9,10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling. This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

To the Editor.— In the December 1979Archives(115:1437-1439), Mills et al described two brothers with dyskeratosis congenita (DC) who also had massive intracranial calcifications detected on skull roentgenograms. The authors stated that this finding had not been previously described in patients with this syndrome, although only a small number of pertinent negative statements could be found in the literature. Report of Cases.— We have recently observed two West Indian brothers, aged 21 and 15 years, with DC. Both of them have the characteristic reticulated cutaneous hyperpigmentation and dystrophy of the nails. Neither of them has leukoplakia, although the younger brother has splotchy hyperpigmentation of the oral cavity. Both have mild anemia (hematocrit readings, 37.1% and 37.7%), leukopenia (leukocyte levels, 3,300 and 3,000/cu mm), and thrombocytopenia (platelet levels, 20,000 and 45,000/cu mm). There has been no evidence of malignant neoplasms to date. Neither brother has had any neurologic disorders, although