British Journal of Haematology, 1993, 85, 9-14

Annotation
FANCONIS ANAEMIA AND ITS VARIABILITY
characterize a condition, for which the specific pathophysiology may not yet be identified, and FA certainly belongs in
that category. The physical phenotype runs the gamut from
extremely abnormal to normal, the haematological spectrum
ranges from severe aplastic anaemia to normal, and the
malignant potential includes leukaemia, carcinomas, liver
tumours, or no malignancy.
From the diagnostic perspective, patients in any of the
above categories who have increased chromosome breakage
in the presence of DNA clastogenic agents are now considered
to have FA (Auerbach et al, 1981),while patients with any or
every symptom that is considered classic are diagnosed as
non-FA if they do not have increased chromosome breakage
(Auerbachet al, 1989b;Poole etal, 1992). In addition, efforts
to define the pathophysiology of FA have examined many
parameters with often apparently contradictory results from
different laboratories or different patients. Even at the genetic
level, evidence points to mutations on chromosome 9q in
some patients, 20q in others, and elsewhere in still others
(Strathdee et al, 1992a; Mann et al, 1991).
The current dilemma is to sort out from the syndrome
those patients who belong in specific categories, in order to
provide appropriate diagnoses (both post- and ante-natal),
counselling, and advice with regard to prognoses and
treatment options. When all of the many FA genes have been
cloned and their functions identified, the sorting will be
automatic. Until then, various efforts are underway to
categorize the patients, which will be reviewed here.

What is called acquired aplastic anaemia may in fact

represent the end result of the combination of noxious
environmental factors (drugs, chemicals, viruses) and defective genes of haematopoietic relevance (marrow failure
genes). We can now identify patients with a few of those
genes, particularly homozygotes. The most common of the
autosomal recessive marrow failure genes are for Fanconis
anaemia (FA), with an estimated heterozygote frequency of
1 / 2 0 (Swift, 1976). The current difficulty is to recognize
patients who have those genes, either after or preferably
before the development of aplastic anemia.

Historical background
Fanconis anaemia (FA) is a paradigm for aplastic anaemia,
pre-malignancy, and chromosome breakage disorders. It is
the best defined but perhaps most enigmatic of the inherited
bone marrow failure disorders. In 192 7 Fanconi described
three brothers with aplastic anaemia and congenital physical
abnormalities (Fanconi, 192 7). The phenotype was
expanded by other reports, and apparently the eponym was
applied by Naegeli in 19 3 1 (Fanconi, 19 6 7). Approximately
20 years later, Estren & Dameshek (1947) reported two
families in which several siblings had aplastic anaemia, but
whose appearances were normal (except for short stature). It
took another 3 0 years before these two syndromes, Fanconis anaemia and Estren-Dameshek Type II constitutional
aplastic anaemia (OGorman Hughes, 1966) were demonstrated to be part of the same spectrum of disease; one of the
original Estren-Dameshek families was found later to have a
relative with classical FA and diepoxybutane(DEB)-induced
chromosome breakage (Li & Potter, 1978). In fact, this
spectrum had been noted but not recognized as such, when
Dacie & Gilpin (1944)described three brothers, one each with
Fanconisanaemia, leukaemia, and paroxysmal nocturnal
haemoglobinuria. There are other case reports from the
earlier years as well, in which one sibling had apparently
classical FA, while another had aplastic anaemia without
congenital anomalies (reviewed in Alter & Young, 1992;
Young & Alter, 1993).

Physical anomalies
The first descriptions of FA were of patients with both aplastic
anaemia and a specific, albeit broad, range of physical
anomalies (Table I). Published cases were defined thus until
the last decade or so, and extensive literature reviews (e.g.
Alter & Young, 1992; Young & Alter, 1993) contain a
substantial bias, since patients for inclusion had to have both
physical and haematological manifestations. However, as
propositi were identified, and the autosomal inheritance of
FA was recognized, siblings were included in the diagnosis
who had physical anomalies without aplastic anaemia, or
aplastic anaemia or leukaemia without anomalies, or discordance with regard to the types of anomalies. There have even
been identical twins with anomalies in only one (AdlerBrecher et aZ, 1992), or with aplastic anaemia in only one,
emphasizing the importance of environmental factors.

The syndrome of Fanconis anaemia

Fanconis anaemia should really be called Fanconis syndrome, except that that eponym is already in use to describe
a specific constellation of renal tubular dysfunction including
proteinuria and glycosuria (Fanconi, 1936). Nevertheless,
FA must really be considered as a syndrome and not a specific
disease. A syndrome is a collection of findings which

Chromosome breakage
The observation that chromosome breakage was increased in
patients with FA was made in the early 1960s by several
groups (Schroeder et al, 1964; Schmid et al. 1965;Bloom et al.
1966; German & Pugliatti Crippa. 1966; Swift & Hirschhorn,

Correspondence: Dr Blanche P. Alter, Division of Pediatric Hematology/Oncology. Childrens Hospital C3-41, University of Texas
Medical Branch, Galveston, TX 77555-0361, U.S.A.

10

Annotation
Table I. Physical abnormalities in Fanconis
anaemia,

Abnormality
Skin, pigmented
Skin, cafe au lait
Short
Upper limbs
Hypogonads male
Hypogonads female
Head abnormal
Eyes
Renal
Birth weight <2500 g
Retardation
Lower limbs
Ears
Reflexes increased
Other skeletal
Cardiopulmonary
Gastrointestinal
Other
No anomalies at all

Short and/or skin only

Patients (%)
51
23
62

50
40
3
28
27
24
13
13
9
11
8
7
7
4
6
6
8

The proportions are underestimates, since

some reports did not provide physical descriptions. Some patients had both hyperpigmented
skin and caf6 au lait spots.From Young & Alter
(1993).

1966). This test was then applied to cases with the FA

phenotype in an effort to make specific diagnoses. However,
spontaneous breakage in chromosomes from peripheral
blood lymphocytes is insensitive and non-specific, since it
may be dependent on the type of culture medium used, and
may be increased in viral illnesses as well as in non-FA
chromosome breakage syndromes (although the phenotype
of patients with xeroderma pigmentosum, Blooms syndrome, or ataxia telangiectasia is usually distinct). The next
breakthrough was achieved by the reports that breakage was
increased in a disease-specific manner with the use of DNA
crosslinkers such as mitomycin C (MMC), nitrogen mustard,
and diepoxybutane (DEB) (Sasaki & Tonomura, 1 973; Berger
et al, 1980; Auerbach & Wolman. 1976).
However, these important contributions have led to a
tautology. If FA is now diagnosed exclusively in patients
whose chromosomes have increased breakage with a clastogen, independent of the physical or haematological findings,
we have a dilemma: we do not know whether Fanconis
original patients in fact had FA. What do we do with patients
who have the physical findings, but whose chromosomes do
not break with DEB? One option is to state that these patients
must have other syndromes (Poole et al, 1992). In fact, a
discriminant function has been proposed which assigns
points for the various physical and haematological features
(Auerbach et al, 1989b). However, this proposal has not
eliminated the tautology, since the discriminant function was
initially determined using DEB testing.

There may be additional problems with basing FA diagnosis on a specific chromosome breakage test. There are some
patients whose breakage rate varies with time, and others in
whom breakage is clonal, i.e. only a small percentage of cells
may show breaks at a given time (Auerbach et al, 1989b;
Arwert & Kwee, 1989; Schroeder-Kurth et al, 1989; Kwee et
d,1983;Hajianpour et al, 1992). One might then extend this
variation to the extreme: what if an FA patient is demonstrating that variation at the time of study, and the results are
normal! That patient will be labelled non-FA. Another
source of variation is the choice of clastogenic agent, since the
mechanisms of action and cellular bioavailability are not
identical. Which one is to be the gold standard?
Genetic variability
It is clear that the molecular biological approach is the only
way to resolve many of these dilemmas. One of the FA genes
has already been cloned and localized to chromosome 9q, the
gene for FACC (Fanconi Anaemia Complementation group C)
(Strathdee et al, 1992b). Complementation groups were
assigned based on the correction of chromosome breakage in
hybrid cells formed from different groups; hybrid cells of the
same complementation group still demonstrate breakage
(Duckworth-Rysiecki et al, 198 5). The initial complementation studies identified cell lines as A and non-A, i.e. B. More
recently it was found that B actually consists of groups B, C
and D (Strathdee & Buchwald, 1992). The protein product of
the FACC gene is novel and does not resemble anything in the
databank, and thus the role of this gene in normal development or in FA remains to be elucidated. Another FA gene, for
complementation group A, was suggested by linkage analysis
to be located on 20q (Mann et al, 1991;Mathew et nl, 1991),
but this gene and its product have not yet been identified.
There are at least two additional complementation groups (B
and D); their genes are presumably on neither 9q nor 20q
(Strathdee et al, 1992a). Only after all (four or more) genes
are cloned will we be able to determine the specificity of
chromosome breakage tests for FA. If patients with increased
breakage do not have mutations in any of those genes, we will
conclude that there are more FA genes. If patients with the
FA phenotype without increased breakage have mutations in
any of the FA genes, we will learn that the breakage test is not
completely sensitive. And if normal individuals who have no
known FA relatives have mutant FA genes, we may finally
get a better estimate of the frequency of the FA gene(s).
The putative proximal cause of aplastic anaemia can vary
from no known cause, to infections with hepatitis or other
viruses, mycoplasma or tuberculosis, as well as drugs such as
chloramphenicol. In some families the affected siblings
developed aplastic anaemia at the same time, suggesting a
common environmental relationship. while in others the
onset of aplasia was concurrent for the age of the patient;
these variations indicate that the relative roles of genes and
environment are not consistent.
Clinical heterogeneity
The type and degree of haematologic involvement are highly
variable, and Table I1 summarizes our attempt to classify the
patients (Alter et al, 1991b). Some patients demonstrate the

Annotation

11

Table 11. Clinical classification of Fanconi's anaemia.

Group

Transfusions

Androgens

Status

Yes

No

Severe aplastic anaemia, failed or never

received androgens

Yes

Yes

Severe aplastic anaemia, currently on but

not responding to androgens

No

Yes

Responding to androgens, previously

severe or moderate aplasia

No

No

Severe or moderate aplastic anaemia.

needs treatment

No

No

Stable,with some sign of marrow failure,

e.g. mild anaemia, mild neutropenia,
thrombocytopenia,high MCV, high Hb F

No

No

Normal haematology, f normal Hb F

MCV, mean cell volume. Hb F. fetal haemoglobin. From Alter et a1 (1991b). 'Yes' under
transfusions or androgens means currently receiving regularly.

continual change from group 6 (normal blood counts), to 5

(some signs of marrow dysfunction, such as mild-moderate
cytopenias, macrocytosis, fetal haemoglobin), to 4 (needing
treatment), to 3 (responding to treatment), to 2 (failing), to 1
(failed). Others will be in any of the groups less than 6 at
presentation. There are families with children i n more than
one group.
Bone marrow examinations contribute to the concept of
variability, and except for patients i n groups 1and 2, may not
correlate well with the clinical group. Marrows may be
severely aplastic, even in patients in group 5 , or may be
normal, myelodysplastic, or even hypercellular. Although

clonal cytogenetic abnormalities have been noted in FA

marrows, the clinical significance of this clonality awaits
long-term prospective studies (Alter, 1992).

Outcome
Another example of clinical heterogeneity relates to outcome.
Although >90% of FA patients are presumed to develop
aplastic anaemia a t some point, many have leukaemia and/
or solid tumours, and many of those patients may not have
had or never get aplastic anaemia (Table 111). There seems to
be a temporal continuum, whereby aplasia occurs early, with
leukaemia later, and tumours even later. Those who escape

Table 111. Complications in Fanconi's anaemia.

Cases

All
leukaemia

Other
cancer

Liver
disease

No. of cases

838

73

42

36

Per cent of total

100

1.3

0.4

1.6

Male :female

1.3

Age at diagnosisof FA (years)

Mean
Median
Range

8.4
7
0-48

Age at complication (years)

Mean
Median
Range
No. without pancytopenia

10.6
9
0.1-28

14.5
14
0.1-29

13.9
14
0.3-32

9.1
6
1-48
15.8
13
2.5-48

41 (5%)
548 (65%)

17 (23%)

No. without androgens

33 (45%)

2 (6%)

No. reported deceased

343 (47%)

59 (81%)

31 (86%)

1(3%)

Some patients had more than one complication;they are listed here in all relevant
categories. Without androgens or pancytopenia means never received androgens or
never developed pancytopenia. From Young & Alter (1993).

12

Annotation
Table IV. Complementation groups.
Feature

Group A

Group B

Spontaneous chromosome breakage

MMC-induced chromosome breakage
Growth inhibition by MMC
Recovery of DNA synthesis after 8-MOP/UVA
Cross-link repair
Incision of interstrand cross-links
Endonuclease which repairs interstrand cross-links
Incision of monoadducts
Endonuclease which recognizes monoadducts
DNA double-strand break repair
DNA ligase activity
ADPRT activity
ADPRT activity
Thymine-dimer excision
Correction by coculture with mouse
Correction of breakage by mouse DNA
Correction of MMC killing by mouse DNA
Mutation on chromosome 20q
Mutation on 9q

High
High
Yes
No
Deficient
Decreased
Decreased

Less high
Moderate

Reduced
Reduced
Reduced
Normal
Normal
Yes
Yes
No
Yes
No

Yes
Efficient

Decreased
Decreased
Normal

Normal
No
No
Yes
No
Yes (group C)

The terminology was often slightly different, although the mechanisms being examined
may be similar, and thus there are multiple topic listings. Group B is now known to include
groups C and D (see text). MMC, mitomycin C: S-MOP/UVA, 8-methoxypsoralenl
ultraviolet: ADPRT, ADP-ribosyl transferase. Each line represents a different study. Adapted
from Young & Alter (1993).

early aplastic anaemia remain at risk of the later complications, and the probability of their occurrence increases with
age. It is the rare FA patient who has none of those problems,
but it may be that FA is not diagnosed until one of those
events occurs. For example, many FA patients even with
typical physical anomalies are not diagnosed until haematological changes develop (Alter, 1991). Although the median
survival for FA patients is now approximately 2 5 years of age
(Young & Alter, 1993; Auerbach et al, 1989a), there are
patients who are not even diagnosed until they are older than
30 (Liu et al, 1991), and several survivors into their 30s and
40s. Only population surveys with molecular probes for FA
mutations will provide the correct data with regard to life
expectancy.
There is variation even among FA patients with aplastic
anaemia, in terms of age of onset, and response to conventional treatment with androgens. Approximately 50% of
patients respond to androgens, although the duration of
response can vary from a few months to >20 years.
Response is related to marrow status as might be expected:
those whose marrow still has some residual haematopoietic
activity and who are only moderately pancytopenic seem to
respond better. Most patients seem to require their androgens
continuously, but a few patients in the literature and in our
own experience who improve on treatment are able to
maintain their blood counts after discontinuation of the
androgens (McDonald & Mibashan, 1968).
The types of leukaemia which do occur in FA are primarily
within the spectrum of nonlymphocytic leukaemias

(although two lymphoblastic have been reported), but

include all of the types of myetoid leukaemias from M 1 to M6.
The only somewhat consistent element of leukaemia in FA is
that it is generally very difficult to treat, and survival has been
very poor. The defect in DNA repair leads to increased
sensitivity to chemotherapy, and thus patients are either
vulnerable to treatment toxicity, or may receive inadequate
treatment. Nevertheless, more than one FA patient with
leukaemia has had a long-term remission (Kwee et al, 1983:
Auerbach et al, 1983).
The types of tumour are quite varied, although they
generally involve either the gynaecologic or gastrointestinal
systems. They occur more frequently in females (because of
the gynaecologic prevalence), and are the major risk for the
older patient (Table 111). Most of the tumours are squamous
carcinomas. However, hepatic tumours are a separate category, occurring primarily but not exclusively in patients who
have received androgens. Although most of the liver tumours
are stated to be hepatocellular carcinomas, they are rarely
metastatic, and the pathologic distinction between adenoma
and carcinoma is not always clear, and may indicate cellular
dysploidy in the liver (as is seen in the bone marrow) rather
than a true malignancy.
As we become aware of FA patients reaching adulthood,
we have paid more attention to their fertility. Females have
late menarche, irregular menses, early menopause, and
gynaecological malignancies. and yet fertility is not as
reduced as might have been expected (Alter et al, 1991a).
Males do have hypogonadism and hypospermia (Bargman et

Annotation
al, 1977), and yet fatherhood has been reported, albeit in a
very small number of patients (Schroeder et al, 1 976;Alter rt
al, 1991a; Liu et al, 1991).

Laboratory heterogeneity
Table TV outlines some of the heterogeneous laboratory
results which have been obtained in efforts to identify thr
primary defect in FA. These often contradictory results were
initially puzzling, but might be at least partly explained by the
fact that there are several different complementation groups
in FA (Strathdee 81Buchwald, 1992). The general consensus
is that patients with FA have a defect in DNA repair, but the
precise localization in the repair pathway has not been
elucidated, and each mutation may be of a different repair
enzyme.
The role of toxicity from oxygen-free radicals is another
controversial area. Decreased levels of antioxidants such a s
superoxide dismutase (SOD) were found in some but not
other patients, but it seems clear now that some of the
variable data may be due to variations among patients with
different mutations, and not necessarily to interlaboratory
variation (Okahata et al, 1980; Yoshimitsu et al, 1984). In a
preliminary test of SOD in vivo, a few patients did have a
decrease in the degree of chromosome breakage (J. Liu and
N. Young, unpublished observation).
Despite the pleiotropic effects of defective DNA repair, the
initial and still major problem in FA is haematologic. In most
cases the numbers of haematopoietic progenitor cells are
decreased, although we did find some correlation of in vitro
colony formation with clinical classification, in that there
was better colony growth from patients in clinical group 6, 5
or 3 in that order (Alter et al, 1991b. 1992). In vitro cultures
from FA patients grew better in low oxygen, but so did
cultures from normal controls. Erythroid colony growth was
improved with the addition of stem cell factor, and the degree
of improvement correlated with the clinical group (Alter et al,
1992). In studies from other laboratories and other patients,
however, stem cell factor did not augment erythroid colony
growth (Bagnara et al, 1992). Those experiments used
enriched progenitor cells depleted of potential accessory cells,
while ours used total mononuclear cells, and the interaction
of accessory cells with progenitors may be important.
Technical differences aside, it is clear that haematopoietic
progenitors are decreased in at least many FA patients, and
the in vitro responses to haematopoietic growth factors are
somewhat variable. In vivo response to haematopoietic
growth factors (GM-CSF or IL-3) has been restricted to the
myeloid lineage, and did not correlate with the in vitro results
(Guinan et al, 1991; Gillio et a!, unpublished observation).
Conclusion

As stated at the outset, Fanconis anaemia is really a

syndrome, with at least four genetic mutations. Phenotypic
variation can be explained on the basis of the multiple FA
genes, as well as variable intrinsic and extrinsic environments. The primary defect(s) is (are) not haematopoietic or
dermatological or orthopaedic, but presumably relate in
some as yet undefined manner to DNA repair. Definition of
the relevant mutated molecular pathways will provide

13

understanding with regard to DNA damage in general, and

may help to explain the wide but specific variety of physical,
haematological and malignant problems in FA patients. It is
hoped that this knowledge will permit prevention and/or
specific treatment of the complications of FA.

ACKNOWLEDGMENTS
This work was supported in part by the March of Dimes/Birth
Defects Foundation and the American Cancer Society.
Division of Pediatric HematologyJOncology.
University of Texas Medical Branch,

B. P. ALTER

Galveston. Texas

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