EXPERIENCE AND REASON-BRIEFLY RECORDED 455
first visit. These infants had a lesser capacity
to be sensitized, and tile likelihood of
long-continue(1 asthina was less. Only 4 of the 23
had wheezing during the tenth year.
Ratner’ has advanced the theory that
seti-sitivity to egg in an infant is a congenital
phe-llOmeilOfl due to egg protein passing the pla-cental barrier ill utero. Hill has discussed very thoroughly the positive egg test in atropic den-matitis, describing the diagnostic and prog-IlOStiC value, its presence being au indication
that the infant is highly allergic.
This relation between the degree of inherited capacity to be sensitized and the severity of
the symptoms suggests further conclusions. It
has been shown
by
Wittig alld Glaser andothers that a group of infants with bronchiolitis have a greater family history of allergy than a control group,” ‘ and that they frequently
de-velop true asthma.’ This would fit the theory
tilat some individuals with only a slightly
in-creased capacity to be sensitized react at times,
Or perhaps only once, to a respiratory illfeCtiOll
I)y
wheezing. Freeman and Todd,’ in anilium-mating discussion of wheezing during viral
infection, make the point that wheezing after the age of 18 months is more likely to be
as-sociated with allergy than it is before that age
period. By their figures, 73 of children over the age of 18 months who wheeze with certain
viral infections are demonstrably allergic. It
would seem likely that others wheeze because
of a sensitization so slight that it cannot be
(lenlonstrated.
CoNcLusIoN
Asthnla ill infants may become severe, with
a prolonged course; or it may remain mild and,
with treatment, of short duration. Recognition
of these types, often possible at the first visit, is
an important guide toward early and thorough
treatment. There is reason to believe that many
cases of so-called bronchiolitis are the response
to infection of an infant Witil a low degree of sensitization.
WILLIAM P. BUFFUM,
M.D.,
Rhode Island Hospital
Providence, Rhode I.Sl(lfld
REFERENCES
1. Buffurn, \V. P. : The prognosis of Asthma in infancy. J. Allergy, 30:155, 1959.
2. Cooke, H. A. : Allergy in Theory and Practice. Philadelphia, Saunders, 1947, p. 130.
:3. Ratner, B.: A possible causal factor of food
allergy ill certain infants. Amer. J. l)is. Child., 36:277, 1928.
4. hill, L. W. : Tile Treatment of Eczema in
In-fants and Children. St. Louis, Mosby, 1956,
p. 50.
5. Wittig, H. J., aIld Glaser, J.: The relationship
between bronchiolitis and childhood asthma.
J. Allergy, 30: 19, 1959.
6. Kohler, S., and Mai, H. : Uber das Schicksal
von Siiuglingen mit Spasticher Bronchitis,
z.
Kinderheilk., 61 :481, 1939.7. Solander, P.: Asthmatic symptoms in the first
ear of life. Acta Paediat., 49:265, 1960. 8. Freeman, C. L., and Todd, R. H. : The role of
allergy in viral respiratory tract infections, Amer. J. Dis. Child., 104:330, 1962.
9. Boesen, L. : Asthmatic bronchitis in children.
Acta Pediat., 42:87, 1953.
Nonalimentary Fructosuria
Although small amounts of fructose occur
in the urine of normal individuals ingesting a
regular diet, amounts sufficient to give a
posi-tive test for reducing sugar in the routine
ex-amination are known to occur only in essential
fructosuria, familial fructose intolerance, and
advanced liver disease.” In each of these
con-ditions there is Il abnormal fructose tolerance test, and the fructosuria is dependent on the
dietary intake of fructose and disappears
promptly when fructose is withheld from the
diet.
The present report describes fructosuria in a
boy, aged 18 months, suffering from
sickle-cell thalassemia. The fructose tolerance test
s’as normal; the fructosunia persisted after
fructose was entirely excluded from the diet,
alid had decreased markedly when the patient was seen 2 years later.
CASE REPORT
All 18-month-old Arab boy was admitted to
the American University Hospital for the study
of anemia. The patient was born at full term at
the same institution, alld the neonatal period
was not remarkable. At the age of 3 months he
was seen at the out patient clinic for an upper
respiratory infection. His liver was 3 cm below
the costa! margin, the spleen was not palpable.
At the ages of 1 1, 12, and 13 months he was
seen again at the outpatient clinic for colds,
poor development, and pallor. His spleen was
palpated 3 cm below the costal margin. Since
the patient failed to improve on iron therapy
‘FABLE I
OuA1 FR((TOSE TolEltANcF: ‘1’EiT
Time after Fructose J,.gestion Fasting I hour hours Shours
iflood Fructose (mg 1(W) ml)
Patient
Jan. (‘ontrol i
12, l!5() 196C
3.1 3.7 1.7
8.5 Ii 6.7
st 3t 9.4
1.8 .3 3.6
Essential Fructo-tuna, Adult 34 48
Total urine volume
(3 hours) 13 45 . . 156
Total urine
fructose (mg) 34 183 . . 6,670
456 NONALIMENTARY FRUCTOSURIA
The patient was pale, irritable, had a
dis-tended abdomen, and was too weak to stand.
He weighed 8.4 kg (below 3rd percentile) and
was 79 cm long (10th percentile). The liver
and spleen were 3 cm below the costal margin,
both were soft and non-tender. The physical
examination was otherwise within normal
limits.
The hemoglobin concentration was 6.5 gm/
100 ml; the erythrocyte count was 3,200,000/
mm’; leukocytes, 8,500/mm’; neutrophils, 50%;
lymphocytes, 48%; monocytes, 2%; platelets,
105,000/mm’; and reticulocytes, 4%. The
pe-ripheral blood smear showed anisocytosis,
poiki-locytosis and hypochromia. Fetal hemoglobin
was 13.4% of the total. Paper electnophoresis
showed mainly S hemoglobin. The
hematolo-gist’s diagnosis was sickle-cell thalassemia.
The fasting blood sugar was 71 mg/100 ml
(glucose oxidase method), total bilinubin 0.8,
and direct reacting bilinubin 0.3 mg/100 ml,
serum iron 124 p.g/100 ml. The oral glucose
tolerance test was normal.
The urine persistently gave a positive
Bene-diets qualitative test, but otherwise was normal.
The patient’s parents were first cousins. His
father was in good health and had a normal
erythrocyte count and a positive sickling test.
His mother, aged 34 years suffered from
sickle-thalassemia. She had had four abortions at 2
to 3 months, and had three living children
be-side the patient. A son and a daughter had
sickle-cell anemia, and one daughter had the
thalassemia trait.
The urine gave positive Benedict and
Seli-wanoff tests and was negative to glucose
oxi-dase paper. The osazone was identified as
fruc-tosazone by crystal shape, melting point and
mixed melting point vith P#{176}’ fructosazone.
Chromatography’ in ?l-I)lltanol-d(etic acid and
pyridine-n-butanol-water gave a single spot
with the same Rf and staining )roperties
(ani-line, orcinol) as fructose. Quantitative
deter-minations of fructose in serum and urine were
made by the method of Roe.’ The patient was
placed on a diet completely free of fructose and
sucrose for ten days in the hospital. Daily urine
samples all contained fructose at a
concentra-tion of 84 to 118 mg/100 ml. Corresponding
values for 10 controls from the pediatric ward and laboratory personnel all ingesting a regular
diet were 5 to 20 mg/ 100 ml.
Three days after the fructose-free diet was
begun, an oral fructose tolerance test was
made by feeding the patient 2 gm of fructose
kg body weight. Table I shows the results of
this test 011 the patient, a control, and an adult
patient with essential fructosuria given 50 gm
fructose by mouth. At this time the parents
refused further tests, and the child was
dis-charged and could not be obtained for
follow-up.
Two years later the patient was readmitted
to the Eye service for study of a corneal scar
following a conjuctivitis. His general health
had been satisfactory in the interval and he
had not needed transfusions. His hemoglobin
was 9 gm/100 ml. The urine was negative to
Benedicts’s test, and the urinary fructose on a
fructose-free diet was 23 mg” 100 ml. An oral
fructose tolerance test (two gm of fructose/kg body weight) and an intravenous fructose
to!-erance test (1 gm of fructose/kg body weight
over 30 minutes) were made with the results
shown in Tables I and II respectively.
Urine samples from the father and mother
were negative to the Benedict and Selivanoff
tests On several occa5ions. The urine samples
from the brother and the two sisters of the
patient showed intermittelit fructosuria, the
urinary level of the sugar varying between
5 and 60 mg100 ml. The eldest sister, an
11-year-old girl, was studied in the outpatient de-partment. Both oral and intravenous fructose tolerance tests gave results entirely within nor-mal limits. Ingestion of glucose or lactose and
a mixture of glucose and fructose did not
pro-duce fructosuria.
COMMENT
The identification of the urinary sugar as
TABLE II
INTRAVENOUS FlturrosE TolE1tANcE TKiT*
EXPERIENCE AND REASON-BRIEFLY RECORDED 457
several samples of urine from the patient
pro-vided conclusive evidence for fructosuria. The
possii)ihtv of conversion of glucose to fructose
in alkaline urine was excluded since all urine
samples had a pH below 7.
The persistence of the fructosuria on a
rigidly controlled fructose free diet as well as
the entirely normal fructose tolerance tests presented evidence against the diagnoses of
es-sential ffllctostlria, fructose intolerance and
fructosuria due to liver disease. We were
there-fore confronted with a hitherto undeseribed
condition of an endogenous, nonalimentary
fructosuria. The mechanism of this fructosuria
remains obscure. The co-existence of fetal
hemogloi)inemia and fructosuria as well as the
subsequent decline in the level of urinary sugor
raises the interesting speculation that the fruc-tosuria may be caused by a delay in fetal
en-zvme maturation resulting in a high i)asal level
of serum fructose alld overflow fructosuria.
Fructose is found in substantial amounts in
the blood of many species and there is enough
evidence to indicate its presence in small
amounts ill the human fetal blood.’
Fructo-suria in the first 10 (lays of life has been
re-ported III l)rem;lttlre llld full term infants.’ In
our laboratory, using concentrates of the zinc
llydroXide filtrates of 1)100(1, ve found the level
of iion-glucose resorcinol-reacting substances to
vary i)etweeu 1.5 and 3 nlg/100 ml in nine
adults, and 0.5 to 6 mg’lOO ml in seven
urn-i)iliCal cord i)lOods. Although our ptiel1t had
fasting levels of serum fructose slightly above
the control values the interpretation of this
finding is ilazardous l)ecause of the relativel
large error in the determination of serum
fruc-tose at the low fasting levels.
The iresetice of intermittent fructosuria in
the three siblings of the patietit suggests a
fa-milial nature of the condition. However the
de-crease in the fructosuria ill our patient at the age
of 3i years makes the interpretation of urinary
findings in his elder siblings and parents
dif-ficult, 011(1 I)recltlles COllCltlSiOllS about the
1)055i11e mode of inheritance.
SUMMARY
Fructosuria iii an 18-month-old boy’
suffer-ing from sickle-cell thalassemia is reported.
The fructosuria persisted after the I)atiellt was
place(l Oil a fructose-free diet. Oral and intra-venous tolerance tests were normal. The
fructo-Blood Fruet ose (mg/lOt) ml)
Patient Control
Fasting minutes after endofinlusion
60 ‘““““ Ulo “““““ 3.0 5.8 4 10.0 4.7
Total fructose excretion in
4 hours (mg) 766 I ,Q00
* One gram per kilogram of hody weight injected over 30 minutes
(patient 13 gm, control .50 gm)
suria had diminished by the age of 33 years.
The mechanism of the fructosuria is uncertain.
A delay in enzyme maturation is suggested.
AVEDIS
K.
KHACHADURIAN,M.D.
Department of Biochemistry
American University of Beirut
Beirut, Lebanon
Acknowledgment. I wish to thank Dr. Calvin
\v. \Voodruff, Professor of Pediatrics, for referring
this patient and for helpful suggestion in the
preparation of the manuscript; Dr. Salim Firzhi for
making available the hematologic data on the
family; afl(l tile pediatric house staff for their
co-ol)eration in the studies carried on this patient.
Thanks are also due to Dr. Alfred E. Diab,
Pro-fessor of Ophthalmology, for studies carried out
while the patient was hospitalized in his
depart-ment; to %Ir. M. Kemelian for his research as-sistance and to Miss K. Bajakian for her technical assistance.
REFERENCES
1. Krane, M. S. : Fructosuria, in Metabolic Basis
of Inherited Disease. New York, McGraw
Hill, 1960.
2. Lasker, M. : Essential Fructosuria. Hum. Biol.,
13:51, 1941.
3. Roe, J. H. : A colorimetric method for the de-termination of fructose in blood and urine. J. Biol. Chem., 107:15, 1934.
4. Karvonen, M. J.: Absence of fructose from
human cord blood. Acta Paeciiat. (Stockh.), 37:68, 1949.
5. Hagerman, 1). 1)., and Villee, C. A. : The
trails-port of fructose by the human placenta. J.
Clin. Invest., 31:911, 1952.
6. Huggett, A. St. C. : Carbohydrate metabolism
in the placenta and foetus. Brit. Med. Bull.,
17, 122, 1961.
7. Bickel, H. : Modern Problems in Pediatrics, quoted in Advances in Clinical Chemistry,
