Esmer Et Al-2004-American Journal of Medical Genetics Part A

8/18/2019 Esmer Et Al-2004-American Journal of Medical Genetics Part A

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American Journal of Medical Genetics 124A:35 – 39 (2004)

DEB Test for Fanconi Anemia Detectionin Patients With Atypical Phenotypes

Carmen Esmer, Silvia Sánchez, Sandra Ramos, Bertha Molina, Sara Frias, and Alessandra Carnevale*

Department of Research in Human Genetics, National Institute of Pediatrics, Mexico City, DF, Mexico

Pancytopenia, hyperpigmentation, smallstature, congenital abnormalities, and pre-dispositiontoneoplasiacharacterizeFanconianemia (FA). The clinical phenotype is ex-tremely variable, therefore the diagnosis isfrequently delayed until the pancytopenia

appears, making diagnosis difficult on the basis of clinical manifestationsalone. Hyper-sensitivity of FA cells to theclastogenic effectof diepoxybutane (DEB) provides a uniquemarker for the diagnosis before the begin-ning of hematological manifestations. Ouraim in this study was to detect FA in childrenwith atypical manifestations to define whichconditions should be routinely included inthe DEB test screening. We performed thechromosomal breakage test in 34 patientswith probable FA and 83 patients with clini-cal conditions that could suggest FA, butare not usually screened by the DEB test:

20 patients with aplastic anemia, 20 patientswith VACTERL association, 20 with radialray abnormalities, 7 with tracheo-esophagealfistulae, 12 with anal atresia, and 4 withmyelodysplastic syndrome. We found 18 DEB-positive patients: 12 were in the group of probable FA and 6 in the other groups.

Among the last ones: three were included because of aplastic anemia, without any other sign of FA, however when re-examined,other anomalies were detected. The thirdpatient had anal atresia, renal hypoplasia,pre-axial polydactyly, and normal blood cellcounts and was diagnosed as having VAC-

TERL association. The other two patients

lacking physical or hematological signs wereidentified among the group of radial ray abnormalities. Thus, our results highlightthe need to increase the number of abnorm-alities indicating need for a DEB test. Delay in the diagnosis of FA may have serious con-

sequences for the patients and their family members. 2003 Wiley-Liss, Inc.

KEY WORDS: Fanconi anemia; chromo-some breakage; diepoxybu-tane test; congenitalanomalies; VACTERL

INTRODUCTION

Fanconi anemia (FA) was first described in 1927[Gordon and Rutherford, 1989]. It is an autosomalrecessive disorder with prevalence between 1/26,000and 1/476,000 in different geographic regions [Macdougall

et al., 1994; Altay et al., 1997]. Until 1992, approxi-mately 1,000 patients had been reported.

Among the most constant clinical characteristics are:pancytopenia, growth delay, and skin hyperpigmenta-tion present in over 60% of patients [Alter, 1993]. Themost frequent associated malformations are those of theskeletal system, mainly of the radius and thumb. Lessthan 50% have renal, genital, ocular, hearing, or heartabnormalities [Alter, 1992; Porteus et al., 1992]. Thepresence of malformations such as anal atresia, cardiacdefects, tracheo-esophageal fistula in FA patients maylead to confusion with other entities such as the

VACTERL association or the Baller– Gerold syndrome[Porteus et al., 1992; Rossbach et al., 1996; Perel et al.,

1998]. Approximately 20% of patients develop sometype of neoplasia, mainly hematological (leukemias) andcarcinomas, particularly liver cancer [D’Andrea andGrompe, 1997]. Generally, a FA patient has 15,000times greater risk of developing cancer in pediatric ages[Gordon and Rutherford, 1989; Alter, 1993], and it hasbeen reported that in 24% of FA patients developing leukemia,this is the first symptom. Thetypeof leukemiaseen with greatest frequency is acute myeloid leukemiapreceded or not by a myelodysplasic syndrome [Alter,1996]. The FA clinical picture is extremely variable, upto 37% of patients does not have associated congenitalmalformations [Giampietro et al., 1997] and in such

Grant sponsor: CONACYT; Grant numbers: 29140-M, 3388-M;Grant sponsor: CONACYT (to C.E.); Grant number: 91769.

*Correspondence to: Dr. Alessandra Carnevale, Department of Research in Human Genetics, National Institute of Pediatrics,Insurgentes Sur 3700-C, 04530, Mexico.E-mail: [email protected]

Received 12 September 2002; Accepted 8 April 2003

DOI 10.1002/ajmg.a.20327

2003 Wiley-Liss, Inc.


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cases the diagnosis is not made until the onset of pancytopenia. This hematological manifestation, whichis present in 90% of cases, also behaves variably, is seenin several degrees of severity, and starts at variableages [Gordon and Rutherford, 1989]. Although most of patients are diagnosed between 3 to 7 years of age based

on thepresence of pancytopenia, in 10%, the diagnosis ismade after the age of 16. The age range for diagnosisvaries between 0 and 38 years and the most fre-quent initial hematological manifestation is thrombo-cytopenia. It may be said that the clinical picture has acontinuous spectrum of manifestations. Some patientshave a relatively mild condition with normal skeletaldevelopment, subclinical hematopoietic abnormalities,surviving until the fourth or fifth decade of life. On theother end of the scale, there are patients with severephenotype, multipleskeletal abnormalities, andan earlyonset of aplastic anemia and/or cancer. There are alsoatypical clinical conditions without anemia, of late onset[Auerbach et al., 1989; Giampietro et al., 1997], or withinitial conditions that may be confused with other syn-dromes, as those mentioned earlier.

The definite diagnosis of FA is established when theperipheral blood lymphocytes show a response to mito-mycin C or diepoxybutane (DEB) 3–10 times greaterthan a normal control. Comparative studies show thattheDEB test provides a highly sensitive and specific testgiven that the chromosomal response of FA patientscannotbe confused with the response of a normalcontrol[Schroeder et al., 1964; Sasaki and Tonomura, 1973;Frias et al., 1986; Auerbach et al., 1989; Auerbach,1993].

Although the DEB test is highly effective in dis-criminating FA from other conditions, it remains un-derutilized mainly because there are some clinical

conditions in which FA is not usually suspected. Thepurpose of this study was to screen patients withmanifestations related to the FA phenotype using theDEB test that are not usually screened, in order todetect FA patientsin this group of children with atypicalmanifestations and to define which conditions shouldbe included in the routine screening of the disease.

MATERIALS AND METHODS

Patients

Patients were referred to the Cytogenetics Laboratoryfrom the Outpatient Clinic at the National Institute

of Pediatrics in Mexico City, and from three othermedical centers on the basis of the clinical character-istics established for each of five groups, as follows:

1. Probable FA: patients with aplastic anemia, shortstature, hyperpigmentation, and typical congenitalabnormalities;

2. Aplastic anemia: patients with aplastic anemiawithout any other finding;

3. VACTERL association: patients with 2 malforma-tions such as vertebral or radial ray abnormalities,anal atresia, tracheo-esophageal atresia, congenitalcardiovascular malformations;

4. Radial ray abnormalities, anal atresia, or tracheo-esophagealatresia:patientswithoneoftheseisolatedcongenital anomalies;

5. Myelod abnormalities: patients with myelodysplasicsyndrome or myeloid leukemia.

Chromosome Breakage Studies

Blood samples were obtained from each patient forchromosomal instability studies, including testing forhypersensitivity to the clastogenic effect of the DNA cross-linking agent DEB. The cytogenetic diagnosis wasconventionally made in peripheral blood lymphocytesstimulated with phytohemagglutinin in 72 hr cultures[Frias et al., 1986; Auerbach, 1993], 0.5 ml of hepar-inized blood added to 5 ml of medium. Cultures werepaired for DEBstudies, with a replicate set of cultures toserve as untreated controls. DEB, at a final concentra-tion inthe mediumof 0.1 mg/ml, was addedto thetreatedcultures; dilutions were prepared just before addition of

DEB to cell cultures. Untreated cultures were set andprocessed under the same conditions. In addition, foreach patient, a unmatched control was studied with thesame methodology. Control subjets were phenotypicallynormal individuals of both sexes ranging in age from 21to 28 years, free of drugs, alcohol, or smoking habits whosigned the informed consent to voluntarily participatein the study. Slides were prepared and codified for theblind analysis of chromosome aberrations. Analysiswas performed on 50 Giemsa-stained metaphases, eachcell was scored for chromosome number and for thenumbers and types of structural abnormalities. Achro-matic areas, less than a chromatid in width, wereexcluded in the calculation of chromosome breakagefrequencies, while exchange configurations, transloca-tions, dicentric and ring chromosomes were scored asone chromosomal aberration. A patient was diagnosedas having FA when the frequency of breaks/cell was atleast six times the frequency in the control lymphocyteculture.

RESULTS

One hundred and seventeen patients were studied:34 in Group 1 with probable FA; 20 in Group 2 withonly aplastic anemia; 20 in Group 3 with VACTERLassociation; 39 patients in Group 4: 20 with radial rayabnormalities, 7 with tracheo-esophageal atresia orfistula, and 12 with anal atresia; and in Group 5, four

patients with myeloid abnormalities. Among the 34 patients (Group 1) referred because

they had some clinical findings consistent with FA,12 were diagnosed as affected based on the DEB test(Table I). Table II shows the most frequent findings inFA and non-FA patients in this group. The main clinicalmanifestation in this group’s FA patients was aplasticanemia in all of the patients, associated with otherfindings such as hyperpigmentation (83%) and sug-gestive FA facial anomalies (66%), as contrasted withthe non-FA group where only 77% of patients hadanemia and 18% had hyperpigmentation or the minoranomalies. Short stature was seen with the same

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frequency in both groups. FA patients had four ormore abnormalities, while non-FA subjects had three of them. In Group 2, including 20 patients with aplasticanemia, 3 were diagnosed as having FA (Table III).Two were 12- and 8-year-old boy patients, one with arenal anomaly, and the other had hypoplasia of the firstmetacarpal bone. The third was a 6-year-old girl withaplastic anemia and short stature. Among the patientswith VACTERL association (Group 3), one with analatresia, polydactyly, and renal hypoplasia was DEB

positive (Table IV). On physical examination, performedafter the diagnosis, hyperpigmentation, minor facialanomalies, and short stature were also found. Thepatient was not anemic at the time of the study but a

year later started with thrombocytopenia.

TABLE II. Clinical Manifestations of Group 1 Patients According to the Diagnosis (FA and Non-FA)

Characteristics FA (n¼12) (%)Non-FA

(n¼22) (%)

Aplastic anemia 12 (100) 17 (77)Short stature 11 (91) 20 (90)Hyperpigmentation 10 (83) 4 (18)Suggestive facies 8 (66) 4 (18)Radial ray abnormalities 7 (58) 15 (68)Renal malformation 2 (16) 5 (22)

TABLE III. Chromosomal Aberration in Peripheral BloodLymphocytes From Group 2 Patients With Aplastic Anemia

Patients

Spontaneous(breaks/cell) DEB (breaks/cell)

Patient Control Patient Control

AA1 0.04 0.04 0.0 0.0 AA2 0.0 0.0 0.2 0.2 AA3 0.0 0.0 0.12 0.04 AA4 0.08 0.12 0.04 0.04 AA5 0.0 0.04 0.04 0.08 AA6 0.48 0.04 0.04 0.0 AA7 0.08 0.04 0.04 0.04 AA8 0.0 0.0 0.04 0.0 AA9 0.04 0.12 0.0 0.04 AA10a 0.12 0.04 4.5 0.0 AA11a 0.24 0.0 4.32 0.0 AA12 0.0 0.08 0.12 0.08 AA13 0.04 0.0 0.12 0.04 AA14b 0.12 0.16 1.32 0.36 AA15 0.16 0.2 0.16 0.04 AA16 0.08 0.04 0.04 0.08

AA17 0.0 0.04 0.08 0.24 AA18 0.16 0.04 0.08 0.12 AA19 0.08 0.04 0.04 0.12 AA20 0.08 0.0 0.08 0.08

On the DEB test the FA patient shows exchange configurations andchromosomal breaks while control only shows chromosomal breaks.aDEB positive patients.b Additional MMC test was performed: 3.84 ab/cell (patient) vs. 0.12 ab/cell(control).

TABLE IV. Lymphocyte Chromosomal Aberration in Group 3Patient’s With VACTERL Association

Patients



V1 0.0 0.0 0.08 0.0 V2 0.0 0.04 0.04 0.08 V3 0.04 0.08 0.0 0.08 V4 0.08 0.0 0.04 0.08 V5 0.0 0.0 0.2 0.0 V6 0.04 0.0 0.08 0.04 V7 0.0 0.04 0.0 0.08 V8 0.04 0.08 0.0 0.0 V9a 0.28 0.04 4.4 0.04 V10 0.12 0.0 0.04 0.0 V11 0.08 0.04 0.32 0.16 V12 0.04 0.0 0.12 0.12 V13 0.0 0.04 0.04 0.04 V14 0.12 0.08 0.08 0.24 V15 0.0 0.04 0.04 0.08 V16 0.2 0.04 0.28 0.12 V17 0.16 0.12 0.08 0.04 V18 0.04 0.04 0.04 0.04 V19 0.04 0.0 0.12 0.12 V20 0.12 0.0 0.16 0.0

aDEB positive.

TABLE I. Chromosomal Breakage in Peripheral BloodLymphocytes of Group 1 Patient’s With Probable FA

Patients



AF1 0.04 0.04 0.12 0.08 AF2a 0.33 0.04 3.17 0.0 AF3a 0.76 0.04 5.72 0.08 AF4a 0.12 0.0 4.32 0.0 AF5 0.0 0.04 0.0 0.0 AF6 0.0 0.0 0.04 0.04 AF7a 0.28 0.0 2.84 0.0 AF8a 0.24 0.0 5.86 0.08 AF9a 0.32 0.0 3.2 0.04 AF10a 0.32 0.04 2.84 0.08F11 0.04 0.04 0.04 0.12

AF12 0.08 0.0 0.0 0.08 AF13 0.12 0.0 0.12 0.0 AF14a 0.22 0.0 2.44 0.08 AF15 0.08 0.04 0.08 0.08 AF16 0.0 0.04 0.0 0.08

AF17 0.08 0.08 0.04 0.04 AF18 0.02 0.0 0.12 0.0 AF19 0.04 0.08 0.12 0.04 AF20 0.12 0.0 0.04 0.08 AF21 0.28 0.04 0.04 0.08 AF22 0.20 0.04 0.32 0.0 AF23 0.12 0.0 0.2 0.12 AF24 0.0 0.24 0.0 0.24 AF25 0.0 0.0 0.04 0.04 AF26 0.0 0.0 0.08 0.0 AF27a 0.04 0.0 2.84 0.08 AF28 0.0 0.0 0.04 0.12 AF29 0.12 0.08 0.08 0.16 AF30a 0.04 0.04 1.68 0.04 AF31a 0.24 0.04 1.39 0.04 AF32 0.0 0.0 0.08 0.08 AF33 0.0 0.08 0.0 0.12

AF34a

0.32 0.04 3.44 0.04aDEB positive patients.

AF in Patients With Atypical Phenotypes 37


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In Groups 4 and 5, where patients with only oneanomaly (renal, radial, anorrectal, or myeloid) wereincluded, two FA newborn patientswere detected among those with isolated radial ray abnormalities, they haveabsence of thumbs and low birth weight and normalblood cell counts (Tables V, VI).

Therefore among the 117 patients included, we found18 with chromosomal instability exhibiting a higherfrequency of breaks after DEB exposure. Analysis of baseline chromosomal breakage in theFA group showedthat the patient’s frequency differs from that found innormal controls or in the non-FA group. The range of breakage in untreated cells was 0.04–1.6 breaks/cell(mean 0.30) for the FA patients and 0 –0.48 breaks/cell(mean 0.07) for the non-FA group. There were no signi-ficant differences in the baseline breakage frequencies

for these two groups. The mean DEB-induced chromo-somal breakage in the FA group was 3.39 breaks/cell(range 1.32–5.86), while the mean breakage frequencyfor the non-FA patients was 0.09 breaks/cell (range 0 – 1.44). As expected, differences between FA vs. non-FA or controls were statistically significant (Table VII).

DISCUSSION

FA is one of several disorders that have in commonthe presence of increased chromosomal fragility orcellular hypersensitivity to mutagenic chemicals, asso-ciated with developmental defects. Cells from FA pa-tients are uniquely hypersensitive to the clastogeniceffect of DNA cross-linking agentssuch as DEB, andcanthus be distinguished from cells of the patients withother syndromes on this basis.

Clinical diagnosis of FA is complicated because of other disorders, both genetic and non-genetic, are char-acterized by many of the clinical manifestations seenin FA. Familial associations of various combinations of radial, renal, cardiac, hearing, growth, skin pigmenta-

tion, and hematologic abnormalities have been welldocumented, and a number of different syndromesdelineated. Among these are dyskeratosis congenita,TAR syndrome, Holt–Oram syndrome, Aase syndrome,

WT syndrome, Shwachman syndrome, IVIC syndrome,and the VACTERL association. Thumb abnorma-lities have been reported in a number of patients withBlackfan– Diamond anemia. The extreme phenotypicdiversity associated with FA makes the availability of adiagnostic laboratory test especially valuable.

In the present study we found 12/34 (30%) FA patientsamong cases suspected of having FA on the basis of anemia characteristic facial appearence, short stature,hyperpigmentation, renal or radial ray anomalies. This

result coincides with that reported by Auerbach et al.[1989], who found 104/328 (29%) patients with these

TABLE V. Chromosomal Breakage in Peripheral BloodLymphocytes in Group 4 Patient’s With Single

Congenital Malformations

Patients

Spontaneous (breaks/cell) DEB (breaks/cell)


Esophageal atresia AE1 0.0 0.0 0.04 0.16 AE2 0.04 0.0 0.08 0.04 AE3 0.2 0.0 0.0 0.0 AE4 0.0 0.0 0.0 0.0 AE5 0.08 0.08 0.2 0.28 AE6 0.04 0.08 0.16 0.28 AE7 0.04 0.0 0.08 0.04

Radial ray abnormalityR1 0.0 0.0 0.02 0.12R2 0.04 0.02 0.08 0.16R3 0.08 0.0 0.0 0.0

R4 0.08 0.0 0.08 0.12R5 0.24 0.0 0.24 0.24R6 0.0 0.0 1.44 1.68R7a 0.16 0.0 3.84 0.04R8 0.04 0.08 0.04 0.04R9 0.12 0.04 0.17 0.0R10 0.16 0.04 0.08 0.2R11 0.40 0.04 0.72 0.0R12 0.04 0.04 0.0 0.12R13 0.04 0.0 0.0 0.0R14 0.0 0.0 0.08 0.20R15 0.04 0.04 0.04 0.20R16 0.2 0.04 0.0 0.12R17 0.08 0.04 0.08 0.0R18 0.04 0.04 0.04 0.04R19 0.04 0.04 0.10 0.0R20a 1.60 0.12 3.0 0.0

Anorectal malformation AR1 0.12 0.0 0.04 0.0 AR2 0.0 0.04 0.04 0.04 AR3 0.12 0.04 0.0 0.0 AR4 0.08 0.32 0.04 0.16 AR5 0.08 0.12 0.12 0.04 AR6 0.04 0.0 0.08 0.04 AR7 0.24 0.24 0.0 0.24 AR8 0.0 0.16 0.04 0.2 AR9 0.04 0.08 0.24 0.08 AR10 0.2 0.08 0.04 0.08 AR11 0.0 0.12 0.16 0.16 AR12 0.16 0.12 0.04 0.16

aDEB positive patients.

TABLE VI. Chromosomal Breakage in Periferal BloodLymphocytes in Group 5 Patient’s With Myeloid Abnormalities

Patients



M1 0.12 0.0 0.04 0.04M2 0.08 0.0 0.04 0.0M3 0.04 0.0 0.04 0.0M4 0.0 0.28 0.04 0.08

TABLE VII. Mean Chromosomal Breaks Among Controls, FA,and Non-FA Patients

Spontaneous(breaks/cell)

Induced with DEB(breaks/cell)

Control (n¼117) 0.04 0.09FA (n¼18) 0.30 3.39Non-FA (n¼99) 0.07 0.10

Control vs. spontaneous FA; P ¼0.006 (Mann–Whitney test).Control vs. FA DEB 0.64; P ¼0.000 (Mann–Whitney test).

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manifestations. Also, we found six FA patients among groups that are not usually tested for chromosomalbreakage: three hadaplastic anemianot associated withother manifestation, agreeing with the expected 10%reported by Auerbach et al. [1989]. One FA patient wasfound among those with VACTERL association. The

frequency of FA in patients with VACTERL criteriawithout aplastic anemia is still unknown, although 10%of FA patients meet three of the disease’s criteria and20% meet two. Two newborn patients with isolatedradial ray malformation, were diagnosed as having FA,which was particularly important both for geneticfamily counseling, as well as for establishing surveil-lance on hematological manifestations. None out of 19 patients with a gastrointestinal abnormality wereaffected, although 5.1% of the FA patients have ano-rectal anomalies and 3.5% have tracheal-esophagealfistula as part of their clinical manifestations [Perelet al., 1998]. No patients were affected in Group 5, butthe number should be increased, since it is knownthat there are patients in which hematologic neoplasmsare the disease’s initial manifestation, and that thereare variants in the FANCC sequence in patients withacute myeloid leukemia [Awan et al., 1998].

Our results emphasize the importance of routinelyconducting a diagnostic test in patients with aplasticanemia, with criteria of VACTERL association, or with aradial ray anomaly without any other anomaly. On thecontrary, we suggest that patients with isolated intest-inal abnormalities do not need the test. An accuratediagnosis will influence the choice of therapy, consider-ing that FA patients have a high response rate to treat-ment using androgens. Information regarding DEBsensitivity is also extremely important in patients tobe treated with bone marrow transplantation or che-

motherapy. Since FA patients are hypersensitive toall DNA cross-linking agents, they require a modifiedpre-transplantation conditioning regimen, with a lowerthan usual dose of cyclophosphamide or lower doses of chemotherapeutic agents [Alter, 1996; D’Andrea andGrompe, 1997].

In conclusion, the results of this study indicate thatFA patients are probably underdiagnosed and thattesting for hypersensitivity to the clastogenic effect of DEB is a useful method for pinpointing FA cases from

other patients manifesting some of the clinical featuresof the syndrome.

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Giampietro PF, Verlander PC, Davis JG, Auerbach AD. 1997. Diagnosis of Fanconi anemia patients without congenital malformations: An Inter-national Fanconi Anemia Registry Study. Am J Med Genet 68:58–61.

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AF in Patients With Atypical Phenotypes 39

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