32
Pediatrics
VOLUME 15 MARCH 1955 NUMBER 3
SPECIAL SECTIONS
REVIEW ARTICLE
CONGENITAL
PANCYTOPENIA
ASSOCIATED
WITH
MULTIPLE
CONGENITAL
ANOMALIES
(FANCONI
TYPE)
Review
of
the
Literature
and
Report
of
a Twenty-year-old
Female
wfth
a Ten-year
Follow-up
and
apparently
Good
Response
to
Splenectomy
By Jean P. Dawson, M.D.*
ANCONI,’ in 1926, described 3 siblings
who presented a syndrome of multiple congenital anomalies, pancytopenia, and
bone marrow hypoplasia. In reviewimmg the literature since Fanconi’s report we have
been able to find 27 additional cases. The purposes of this report are to
de-scribe a patient with this syndrome who
has survived to adulthood, to review the pertinent literature, and to discuss manage-ment of this condition.
History
CASE REPORT
CO., a 10-year-old white female, was
admitted to the Strong Memorial Hospital
May 24, 1944, because of pallor of 13 years
duration. The child had always been
umi-derweiglmt. 1mm February, 1943, there had
From time Departnimenmts of Pediatrics and
Mcdi-cue, the University of Rochester School of
Mcdi-cimme and Dentistry, amid time Pediatric and Medical
Clinics of the Strong Memorial Hospital.
0 I)avid Snmaliine Fellow in Pediatrics and
Henimatology.
ADDRESS: Children’s Hospital, 219 Bryant Street,
Buffalo 22, N.Y.
beemi a 2-week episode of swollen anmkles,
pallor, and purpura. One month later she was found to be anemic amid was treated with liver
extract and vitamins without apparent
im-provement. She was transfused amid was well until April, 1944, s’hemm she was omice mnore found to be anemic amid was referred to the
Strong Memorial Hospital.
The family history was unremarkable. Both
parents and 4 older siblings were normal. The mother’s antepartuni course was complicated
only bsr mild hyperemesis and there was mmo
history of infectiomm in the first 4 nionthms of
pregmiancy. The patiemit was born
spommtane-ously on July 15, 1933, after a 9-months’
ges-tatiomi and weighed 53 pounds. Memital ammd
motor developmemmt were normal. Sue suffered the usual childhood diseases without
coniphi-cations. No previous bleeding tendency had
been noted, and there had beemm no kimown cx-posure to toxic agemits or x-rays.
Physical Examination
Revealed a poorly developed, chronically ill, thin white female with a yellowish cast to
her skimm. Measurements were as follows:
>-0.
w
I
I.-cm C-)
>-a:
z
a:
Ui
a-C,)
U.
0
BLEEDING
TENDENCY4 3+ 2+
CC OF
RED CELLS
944 945 946 947 948 949 950 1951 952 1953
326
Fic. 1. Patient’s course from 1944 to 195.3, showing significant events and hematologic data.
moderately loud blowing systolic murmur aud-ible at the apex and along the left sternal border, which disappeared following transfu-sion therapy. There was a Sprengel’s deformity of the right scapula. Time liver was palpable 1 fingerbreadth below the right costal margin.
The spleen was not palpable. There was a
rudimentary extra thumb on the right hand.
Laboratory Data*
The hemoglobin was 5.5 gm./100 ml.,
hematocnit 12 per cent. Leukocytes were
2,200/cmm. with 60 per cent neutrophils,
:38 per cent lymphocytes, 2 per cent
mono-cytes. The red blood cells showed marked
poikilocytosis and anisocytosis with many
macrocytes, spindle cells, ovalocytes, and tar-get cells. The platelet count was 20,000/cmm.
Reticulocytes were 0.0 to 0.1 per cent. The
bleeding time was 7 minutes, clotting time
(Lee-White method) 6 minutes, prothrombin
time 7 minutes. Capillary fragility was normal.
0 Determinations were made by the clinical
iiiethods customary at the time.
Osmotic fragility of the red cells was within
normal limits. Urine was alkaline with a
spe-cific gravity of 1.005. There was no sugar,
acetone, or albumin and microscopic examina-tion was negative for red cells, white cells, or casts. Stool guaiac and blood Wassermann tests were negative. Castnic analysis revealed free acid. Decholin#{174} circulation time (arm to tongue) was 7 seconds (normal 20-25 seconds).
Total protein was 6.9 gm./100 ml., albumin
5.0 gm./100 ml., globulin 1.9 gm./100 ml.,
icterus index 6 units. Non-protein nitrogen was
24 mg./100 ml. Vitamin A absorption test was normal. A specimen of sternal marrow obtained by surgical curettage showed hypocellularity of all the blood forming elements; unfortu-nately this specimen is not available for re-view at this date.
Course
(See Fig. 1 and Table I for hematologic data during subsequent admissions.) During
the next year the child was admitted
9 times to the Strong Memorial Hospital
Date 11gb. gm/lOOm!.
Hct. %
Relics %
1I’13C/crnm.
Nentro-phil.? %
Lyrnphx %
.ilono.s %
Platelets per cmm.
May, 1944 .5.5 P2 0.1 ,20() 60 38 2() ,000
July, 194.5 7 .0 - - 3 300 .56 43 1
-July, 1948 13.0 - - 3,700 - - - 56,’25()
December, 1948 10.5 - ‘2.6 3,300 - - -
-January, 195’2 12.0 41 4,100 39 53 5 80,00(1
August, 1953 14.0 4 1.6 4,800 27 63 10
-TABLE I
Suainr OF PRINCIPAL HEMATOLOGIC DATA
3,025 ml. of red blood cells. Her fatiguabil-ity continued, and there were many episodes
of purpura and epistaxis. Various liver prepara-tions and iron failed to relieve the anemia. Thrombocytopenia and leukopenia persisted.
In the course of these admissions several
other abnormalities were found. Roentgeno-grams revealed a right scoliosis, a cervical rib
on the left and a fusion of the first two ribs on
the right (see Fig. 2).
In January, 1945, patchy brown pigment
was noted over the trunk, abdomen,
ante-cubital fossae and axillae, and the right kidney
was palpated. A film of the abdomen revealed that the right kidney shadow was en-larged and the left was absent. A sternal mar-row biopsy by surgical curettage showed a relative increase of the erythroid series with a
myeloid:erythroid ratio of 1 : 1. 1 and a
differ-ential count as follows : blasts 6.3 per cemmt; myeloblasts 11.0 per cent; juveniles 2.0 per
cent; band forms 2.3 per cent; early normo-blasts 31.0 per cent, and late normoblasts 5.3 per cent.
In July, 1945, studies revealed no evidence of a functioning left kidney, absence of left ureter and obstruction at the ureteropelvic
junction of a hydronephrotic right kidney. Non-protein nitrogen was 25 mg./100 ml. and
urea clearance was 29 per cent of normal at 2 hours. A right nephropexy#{176} was performed,
releasing numerous adhesions about the ureter
and kidney and freeing a kinked right ureter.
0 Surgery and studies were performed by Dr.
J ohn Benjamin, to whom we are indebted for the description of the findings.
Subsequent intravenous pyelograms have
shown gradual improvement of the
hydro-nephrosis (see Fig. 3). Two weeks after
nephropexy the urea clearance was 49 per cent of normal at 2 hours and the phenolsulphone-phithalein excretion was 62 per cent in 2 hours.
Three years later, in 1948, the
phenolsulphone-phthalein excretion was SO per cent in 2
hours.
In the 9 months following nephropexy time
patient reqimired only 2 transfusions although her bleeding tendency and anemia persisted.
A course of fohic acid, 100 mg. a day, was
without effect. Red cell survival studies re-vealed a normal life span of donor cells. In
J
anuary, 1946, she was found to have a left ingumnal hernia.In July, 1948, when she was 15 years old, an exploratory laparotomy, appendectomy, and hysterectomy were performedf because of a 3-year history of recurrent monthly abdominal
pain and failure to menstruate. At operation
the uterus was found to be unicornous with
atresia of the cervix, vagina, and left tube amid
ovary. One week later she suffered from
severe rectal and generalized cutaneous
bleed-ing, requiring transfusions of whole blood
totahhimig 2,650 ml.
Following discharge the patient was well.
Because of persistent timrombocytopenia a
splenectom was performed December 18,
1948 (see Table I for laboratory data). Histo-logic examination of the spleen and biopsy
specimens of the bone marrow and liver
re-vealed hemosiderosis. The bone marrow
Since splemmectomy the patient has been well. Although thrombocytopenia has persisted there
has been no bleeding tendency. Her anemia
has steadily improved and there has been no need for transfusions. In April, 1949, the
super-numerary thumb was removed without
comphi-cation (nineteenth hospitalization).
The laboratory data obtained in 1952 are
included in Table I. Osmotic fragility of the red cells showed beginnimig hemolysis at 0.44
per cent, marked at 0.32 per cent, and
corn-plete at 0.20 per cent. The red cells have never
been agglutmnable by antiglobulin serum.
She was married in 1952. When last seen imi 1953, at the age of 20 years, she was
asymp-tomatic. She had made a fairly good
ad-justment to her marriage. Her mental develop-ment appeared normal. Physical findimigs were
unchanged (see Fig. 4). Measurements taken
at that time were as follows: Height 140.5 cm.; length of legs 80 cm.; arm span 142 cm., amid
Fic. 2. Roentgenogram of the chest, showing weight 34.5 kg. Hematologic data are listed in
cervical rib on left, elevation of right scapula and Table I. The red cells were macrocytic and
fusion of first and second ribs on right. normochromic with numerous target cells and
marked variation in size and shape. There was
showed active normoblastic proliferation with an occasional polychromatophihic cell and 1
a relative decrease in myeloid elements. normoblast per 100 leukocytes. Platelets were
Megakarocytes were virtually absent. moderately reduced.
Fics. Sa and b. a. Intravenous pyelograrn, showing failure to excrete dye on left amid markedly
hydro-mmephrotic right kidney. b. Intravenous pyelogram 1 month after nephropexy, showing slight, but definite,
a wide range of congenital anomalies.
Fan-coni’s 3 cases1 were characterized by dwarf-ism, microcephaly, pigmentation,
hypogeni-tahism, strabismus, and hyper-reflexia. In Table II are listed the various anomalies encountered in reviewing the literature.
The commonest physical finding in these patients is a patchy brown pigmentation of the skin. FammconP found this to be dine to
deposition of immelaniim and this finding has been confirmed by other authors.2’ Rohr3
found subcutaneous deposits of
iron-con-taming pigment in 1 patient but these
could probably be related to previous local skimm hemorrhages.
Dwarfism also occurred frequently. Our patient was initially in the lower third
per-centile for height and at present is shorter than normal.
A large number of these patiemmts show
some form of imypogenitalism. Small testicles
or cryptorchidism have been reported 1w
TABLE II
\A1CiOUS ANOMALIES ENeonNTEnin.3n IN 30 (.ms:s
OF FmNcoNms IIyn’on’L.msTm( ANEMmA
Type J .lhnorrnulily
Fic. 4. Patient at age 20 years, showing small
stature, patchy pigmentation over buttocks,
Sprengel’s deformity of right scapula and slight
thoracic scohiosis.
Clinical Picture
DISCUSSION
This patient is characterized by severe
pammcytopenia associated with small stature, skiim pigmentation, Sprengel’s deformity,
scohiosis, a rudimentary extra thumb, a
cer-vical rib, absent left kidney and a hydro-nephrotic right kidney, a left inguinal her-im:a, and a unicornotis uterus with atresia of the cervix and vagina.
Previously reported cases have included
her
of
( uses
Pignnenmtat ionm .
Snnall stature 16
Sniall head 1 1
Hypogenntalisnni 13
trnl)isnmnus 10
.\nonnmalies of thunnnbs I (1
Renal anonnahes 9
Mental retardation 7
Hyper-reflexia 6
Microphthalnmia .5
Anomnalies of ears and deafnmess .5
Deformities of forearm 4
Congenital dislocationn of hips 3
Syndactyly 3
Ptosis of eyelids
Nystagnmnmns ‘2
Gynecomastia ‘2
Congenital heart disease ‘2
Vascular anomalies ‘2
Hernia, sacrococcygeal sinus, pigeon breast,
vocal cord paralysis, hydrocephalus, asynni-nnetric skull, club foot, “pseudonneuritis,’
DAWSON CONGENITAL PANCYTOPENIA
Fanconi,1 Baumann,2’ Rohr,5 Uehlinger,#{176}
van Leeuwen,7 %Veil,5 Hjorth,9 Diamond,1#{176} and Kunz.” Structural malformations of
time female genitalia have not been noted
previously to our knowledge. Silver et
(,/,12 amid Estren et aiim noted
gynecomas-tia and Silver’s patient. a female, was said
to have hypogenitahism. Our patient’s uter-inc and vaginal anomalies seem to have
been of developmeimtal origin.
Skeletal abnormalities are commomi in this syndrome. We have been unable to find
a previous report of Sprengel’s deformity
or cervical rib. As in our patient, 10 previous
cases have had anomalies of the thumbs.
Other skeletal anomalies observed include clubfoot (Hjorth9), anomalies of the radius and ulna,bo 11, 13-15 syndactyly,1012 and
con-gemmital dislocation of the hips.5’ 15 16
Renal anomalies have been noted in nine of the previously reported
cases.4’ 6, 7, 10, 11, 1619 The management of
our patient’s renal anomalies was a major
problem. The degree of hydronephrosis was
extreme and renal function was markedly
diminished. It is of interest that following
nephropexy there was partial improvement in the severity of her anemia and less need
for transfusions. However, the leukopemmia and thrombocytopenia did not respond
simi-larly and major bleeding episodes continued to occur.
The central nervous system is frequently
affected in these patients. Our patient was of normal mentality and no neurological
abnormalities were noted. Common findings include small head size, mental retardation,
strabismus, hyper-reflexia, deafness,
mi-crophthalmia and ptosis of the lids. Kunzmm described a patient with a large head and
paralysis of the vocal cords. Reinhold’s
pa-tient18 was noted to have nystagmus. Levy19
found ghiosis of the cortex in one of the siblings he described.
Anemia was first detected in our patient
at the age of 9 years. In most of the previ-ously reported patients hematologic abnor-mahities were first detected between the
ages of 4 and 12 years. Kunzm1 reports a
pa-tient in whom pancytopenia appeared at the
age of 2% years. Baumann’s patient,2’ :mwho
died at the age of 5 years, was noted to have pallor at 4 months and purpura at 13 months of age. These are the youngest reported
pa-tients to our knowledge. Rohr5 reported 2
brothers in whom symptoms of hematologic
disorder appeared at the ages of 19 and 20
years and were associated with
pigmenta-tion in both and, in one, feminine hahitu
and a small head. To our knowledge these are the only 2 patients in which the symp-toms of pancytopenia appeared in
adult-hood.
Laboratory Findings
The basic hematologic studies in Our case
revealed a marked anemia, leukopenia, and thrombocytopenia. The red blood cell
mor-phology, characterized by the presence of macrocytes and target cells, was similar to that seen in previous cases. Reticulocytes were, generally, only slightly increased in
number and this finding was consistent with that seen in previous cases. Leukopenia has persisted to the present and the white cell count has been below 4,000/cmm. on most occasions. Although the bleeding tendency
has disappeared since splenectomy there is still a moderate thrombocytopenia.
There has been no evidence of a hemo-lytic process at any time. The osmotic
fra-gihity of the red cells was slightly decreased
on one occasion, perhaps reflecting the
pres-ence of target cells in the peripheal blood smear. Rohr,5 and Gasser2#{176} both reported patients in whom the red cells were weakly agglutinable by antiglobuhin serum (posi-tive Coombs test). Sucim was not the case
with our patient. Dacie and Gilpin’7
re-ported a case of Fanconi’s hypoplastic anemia associated with paroxysmal
hemo-globinuria and a positive acid hemolysin test. There has been no evidence of
hemo-giobmnuria in our patient. Donor red cell sur-vival was measured in our patient and proved to be normal.#{176}
0 Our patient has been referred to in 2 previous
papers by Young et. al., in which spleen
Our patient’s initial sternal marrow
bi-opsy showed a generally hypoplastic
mar-row with depression of all hematopoietic
elements. Two subsequent biopsies, one
prior to nephropexy and the other
simul-taneous with splenectomy, revealed a
nor-mally cellular marrow with a relative
in-crease in erythropoietic elements and marked decrease in megakaryocytes. Fan-coni,’ and Uehlinger6 first described the marrow at autopsy; they found a generally
fatty marrow organ containing islets of
hematopoietic tissue. Several authors have reported marrow biopsies which were either
normally cellular or hypercellular and which exhibited a relative erythroid hyper-plasia.5 17 One of Weil’s patients exhibited
a generally hypoplastic marrow which
sub-sequently became hyperplastic.8 Silver
et al.’2 reported a hypocellular marrow with
a relative increase in erythropoiesis. It is
possible that the variability of the bone nmar-raw findings may represent uneven
distri-bution of hematopoietic tissue throughout the marrow organ, as was originally
de-scribed by Fanconi and Uehlinger. Thus the findings of a normal or hyperplastic bone marrow might represent a chance
bi-opsy of one of the islets of hematopoiesis.
Van Leeuwen7 believed that the peripheral
blood picture represented a marrow of nor-mal morphology that was present in diimmin-ished amount. It is also possible that the total composition varies from time to time.
Incidence
The disease appears to be commoner in males than in females. To our knowledge 21 cases have occurred in males and 9 in
females.
There appears to be no racial or geo-graphic preponderance and cases have been reported in France,8 England,168 Switzer-land,1’ 20 South Africa,4 Greece,14 Japan,15
and Scandinavia.9 Estren et al.’3 described
the first case in the U.S.A. in 1947. Since then 4 additional cases have been described
in America,11’ 12, 19 including a child of
Italian ancestry and 2 brothers of Jewish
parentage.
Fanconi’s first 3 cases were siblings.1
Six-teen of the cases reported iii the literature represented 7 families. Kunz, Higashmi
Ct al.,15 and Cassimos and Zannos’4 each
reported cases of Fanconi’s hypoplastic
anemia who were known to have siblings
with congenital defects but no
pancyto-penia. Hjorth9 reported a family in which 2
siblings were affected with Fanconi’s
anemia and 3 exhibited only multiple
con-genital defects. Fourteen of the previously reported cases were believed to be sporadic
with no evidence of inheritance of either
congenital defects or pancytopenia. This ap-pears to be the case in our patient, who has 4 normal siblings.
Etiology and Pathogenesis
The etiology of this diseases is unknown.
Because of the strong familial incidence it
is generally thought to be hereditary. Four
of the cases were the products of first cousin
marriages.15’ 16. 19 Reinhold’8 analyzed the
literature to 1952 and presented evidence
that the conditioim was due to a recessive
gene. However, it is possible that the
spo-radic cases might be due to a spontaneous gene mutation. There also seems to be some
variability in the severity of the syndrome.
As mentioned previously, siblings of
pa-tients with the complete syndrome may
have congenital anomalies without
hema-tologic disorder. Baumann,2’ found that a
cousin of his patient exhibited
agranulocv-tosis. Estren and Dameshek’3 reported 2
families in which 8 members were affected
by severe hypoplastic anemia without
asso-ciated congenital anomalies. The number and severity of associated congenital
anoma-lies is also highly variable. It seems possible that this syndrome is subject to variable gene expressivity.
The symptoms due to the pancytopeimia
do not appear until the patient is several years old. The reason for this finding is not
clear.
Higashi et al.11 recently made
was interpreted as reflecting some
constitu-tional defect in the red cell precursors.
Our patient’s urimme was examined for the presence of abnormal tryptophane meta-bohites as found by Altman and Miller imm
cases of congenital hypoplastic anemia.’4 None was found.
We know of no documentation of expo-sure to x-rays, irradiation, or noxiotms drugs
iii previous cases. Also, with the exception of Silver’s case,’3 there has been imo evidence of maternal antenatal virus infection in the
reporte(l cases.
Course of the Disease
The previously reported cases have had aim almost uniformly fatal course. Eighteemm patients had died before the case reports were published. Three cases had not been followed for more than a few months but
were living at the time of the reports. In
3 additional cases we do not know the
out-come of the disease.’#{176}’25 Only 6 cases were
alive 3 or more years after the onset of
symnptoms secondary to the
pancyto-penia.” 6, 1G18 Ten patients died within 2
years of the onset of 12, 19 The
course of the disease has usually been one of severe bleeding tendency and progres-sive anemia. Repeated transfusions have been necessary and severe infections have
been frequent. Death has usually been due to hemorrhage into the brain or
gastrointes-timmal tract.
Our patient is remarkably well at present. It is 10% years since her hematological
dis-ease manifested itself. She is asymptomatic and has been married for over a year. She
is no longer aimemic but the
thrombocyto-penia and leukopenia persist. However, she has no bleedimmg tendency at present and does not appear to be unusually susceptible to infections.
Treatment
Treatment of the reported cases has been
mainly supportive. Multiple transfusions
have been necessary for the relief of anemia.
This was the case with our patieimt iii the first 2 years of her disease. Antibiotics would
be of importance in controlling immtercurrent infections. It would also seem that surgical
correction of genito-urinary anomalies would be important if renal function were significantly impaired. Our patient seemed to show definite clinical improvement
fol-lowing nephropexy.
Our patieimt was subjected to splenectomy in the fifth year of her hematologic illness
in the hope that it would decrease the
severity of her thrombocytopenia and bleed-big tendency. Althougim there has beeim no significant increase in the number of plate-lets, the bleeding tendency seems to have
been controlled. Splenectomy in previous patients has yielded variable results. Seven patients have been splenectomized. Four patients did not improve and of these 3 died
soon after splenectomy. One patient’
im-proved temporarily but subsequently
be-came worse. Dacie,1’ and Estren’7 both re-ported good results following splenectomy. Dacie’s patient was alive 10 years after op-eration. The physiologic effect of this proce-dure is not clearly understood hut it is
thought that splenectomy might release the bone marrow from the inhibitory effect of the spleen. Reinhold’8 felt that splenectomy
should be undertaken only when there is evidence of erythropoiesis in the bone
mar-row.
Kessel and Cohen’ attempted a course of
therapy with ACTH in their patient. No
beneficial results were observed and the pa-tient subsequently died.
Attempts at therapy with iron, liver preparations, and folic acid were all
unsuc-cessful in relieving our patient’s anemia.
SUMMARY
1) A case of hypoplastic aimernia with
multiple congenital anomalies (Fanconi’s
type) is reported. The patient exhibited
pancytopenia associated with skin
2) The literature is reviewed and the characteristics of the disease discussed.
3) Management and therapy are
dis-cussed.
ACKNOWLEDGMENTS
The author wishes to acknowledge time
constructive suggestions offered by Drs. Lawrence E. Young and Gerald Miller, and to thank Dr. Young for permission to
pub-lish this case report.
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pernizio-saartige An#{228}mie (pernizioses Blutbild
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3. Baurnann, T.: Ammn. paediat., 177:142, 1951.
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