She was given intravenous infusions of glucose
and feedings every 2 hours and did well. The
bilateral flank masses proved on laparotorny to
be enlarged, non-cystic kidneys and the infant
was recognized as a case of a newly- described
sy-ndrome of hy’poglcemia, hyperplastic fetal
visceromegaly, and macroglossia. The case is
re-ported in detail elsewhere.
Diazoxide was started at 5 weeks of age
be-cause of persistent hypoglycemia. Twenty-five
milligrams were given orally twice daily. A white
cell count, differential count, smear, and platelet count were normal just prior to the onset of ther-apy. Figure 1 shows the moderate neutropenia,
(lowest count 1,056 when the total count was
8,800) and the marked eosinophilia that occurred a few days after diazoxide was started. At no time was thrombocytopenia or purpura Pres’Iit. A bone
marrow examination was compatible with a
drug-induced neutropenia. The absolute neutrophil and
eosinophil counts returned to normal within 2
months after diazoxide sas discontinued.
K.T., a 15-year-old, white male, was admitted
to this hospital with a 5-month history of well
documented hy-poglycemic episodes that at times progressed to loss of consciousness. Two months prior to admission here lie had undergone an
ex-ploratory laparotomy and resection of the tail and a portion of the body’ of the pancreas. No
ade-noma was found and the hpogl’cemia persisted
unchanged. On admission he was a muscular, 78
kg adolescent with no abnormalities on physical
examination. He was found to have severe andl
persistent hypoglycemia audi markedly elevated serum insulin levels; the details of an evaluation of carbohydrate and lipiti metabolism will be the subject of another report.
The patient was placed on diazoxide to
facili-“1 tate control of hypoglycemia. Initially a dose of
SCPT(MER ‘ OCTOBER . ‘. ‘ .
100 ing of diazoxide three times a day’ had little
effect. The dose was doubled and there was
nausea and vomiting, which disappeared when
9000
8000
7000
0
6000
is000
; 4000
! 3000
C-,
COO
DIAZOX IDE
0mg/kg/d
BONE MARROW
I
--.---4
TOTAL NEUTROPHILS
_.,VEOSINOPHILS
AUGUST
PEDIATRICS, Vol. 40, No. 1, July 1967
Experience
and Reason
Briefly
Recorded
“In Medicine one must pay attention not to plausible theorizing but to experience and reason together. . . . I agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions from what is observed. . . . But conclusions drawn from unaided reason can hardly’ be serviceable; only those drawn from observed fact.” hippocrates: Precepts.
. . .
(Short communication.s of factual material are
as Letters to the Editor.)
published here. Comments and critici.srns appear
Hematologic Reactions to Diazoxide
Diazoxide, a non-diuretic drug of the
benza-thiadiazide series, has been found to be a
use-ful adjunct in the management of hypoglycemia
of various etiologies.3 Iii addition to a brief
reference to one of the present cases,4 only one
other report’ of adverse effects of the diazoxide
on the formed elements of the blood has
ap-peared in the literature. The purpose of this
pa-per is to call attention to hematologic
abnormali-ties that developed in bvo of the three patients whom we have treated with this drug.
CASE REPORTS
L.P., a Caucasian female, was born at the
Yale-New Haven Hospital after a normal
preg-nancy and delivery. At birth she weighed 4,365
gm. A markedly enlarged and protruding tongue
and bilateral flank masses were noted. On the third day of life lethargy, poor feeding, and
sei-zures became apparent and were associated with
blood sugar levels less than 20 mg per 100 ml.
Fic. 1. L.P.: Neutropenia and eosinophilia ascribed
300 B B 250 200 2 ISO o 00 50 A a. 20 DIAZOX IDE 7mg/kg
. BONE MARROW
TI, PLATELETS
-- - -
_j,,/j
,0SINOPHILEa 700 600 ‘-500 #{176} 400 z 300 200 0 00 A
JANUAR( FEBRUARY MARCH
FIG. 2. K.T.: Thrombocytopenia and eosinophiia ascribed to diazoxide.
EXPERIENCE AND REASON-BRIEFLY RECORDED 91
the dose was decreased to 150 mg three times a
day. No other medication was administered
con-current with diazoxide. A white cell count,
differ-ential count, and smear were normal prior to
treat-ment and 2 days after diazoxide was started. Fig-ure 2 shows the dramatic fall in the platelet count which was noted 8 days after the onset of ther-apy. The thrombocytopenia was accompanied by a mild eosinophilia. At no time was there neu-tropenia or purpura. A bone marrow examination
2 days after diazoxide was discontinued showed
only erythroid hyperplasia.
After full recovery from the hematologic reac-lion an islet cell adenoma of the pancreas was resected. Subsequently, he has been free of hypo-glycemia.
COMMENT
Drash, et aL recently described their
experi-ence with diazoxide in a dosage from 5 to 20
mg per kg per day in the treatment of
hypo-glycemia in seven children. Various side effects
(including ketonuria, fluid retention and
hy-ponatremia, hirsutism, and mild
hypemrice-mia) were reported by these authors, but they
observed no hematological reactions.
Figure 3 demonstrates the similarity in
structure betwen diazoxide and
chlorothia-zide. Since hematological abnormalities have
been reported with therapy of other members
of the benzathiadiazide family,7 it is not
sur-prising that diazoxide should have this capabi-lily. Black5 knows of one case of neutropenia
and one case of thrombocytopenic purpura in
a total of 741 patients treated for hypertension
with a combination of diazoxide and
trichlor-methiazide. Wales and Wolff’ recently
report-ed a 41-year-old woman who developed
neu-tropenia and thrombocytopenia while receiving
/ N CL 7
CL 0NH H2N- Q/NH
DIAZOXIDE CHLOROTHIAZIDE
Fic. 3. Chemical structures of diazoxide and
chlor-othiazide.
diazoxide and hvdrochlorothiazide; subsequent
challenge with diazoxide alone resulted in a
recurrence of both manifestations. In both of
our patients the hematologic reaction occurred
while they were on diazoxide alone.
The incidence of hematologic side effects of
diazoxide therapy in children with
hypogly-cemia awaits more experience, but the
occur-rence of two such manifestations at this early
stage in the evaluation of the drug urges
thoughtful consideration whenever it is used.
SUMMARY
One case of neutropenia and one case of
thrombocytopenia were seen in patients
receiv-ing diazoxide for hypoglycemia.
J
EROME T. COMBS, M.D.J
EROME A. GRUNT, M.D.IRA K. BRANDT, M.D.
Department of Pediatrics
Yale University School of Medicine
333 Cedar Street
New Haven, Connecticut 06510
This work was supported in part by grant No.
Ti AM 5351 from the Public Health Service.
The patients reported were studied in the Yale Children’s Clinical Research Center supported by U.S. Public Health Grant No. FR 00125-02.
We wish to thank Dr. J. Black of the Schering Corporation for supplies of diazoxide.
REFERENCES
1. Drash, A., and Wolff, F. : Drug therapy in leucine-sensitive hypoglycemia. Metabolism, 13:487, 1964.
2. Craber, A. L., Porte, D., Jr., and Williams,
R. H. : Clinical use of diazoxide and
mech-anism for its hyperglycemic effects. Diabetes,
15:143, 1966.
3. Drash, A. L., Wolff, F., Langs, H. M.,
Nit-owski, H. M., and Blizzard, R. M. : The use
of diazoxide in the treatment of
hypogly-cemia. J. Pediat., 69:970, 1966.
92 DOWN’S SYNDROME
Hypoglycemia, hyperplastic fetal viscero-megaly, macroglossia and umbilical
abnor-malities: a syndrome. New Eng. J. Med.,
275:236, 1966.
5. Wales, J. K., and Wolff, F. : Hematological side-effects of diazoxide. Lancet, 1 :53, 1967.
6. Beckwith, J. B., Wang, C.-!., Donnell, C. N.,
and Gwinn, J. L. : Hyperplastic fetal
vLsceromegaly with macroglossia,
omphalo-cele, cytomegaly of the adrenal fetal cortex,
post natal somatic gigantism, and other ab-normalities : a newly recognized syndrome.
Proceedings of the American Pediatric
So-ciety, p. 56, 1964.
7. Schotland, M. C., and Grumbach, M. M.:
Neutropenia in an infant secondary to
hydro-chlorothiazide therapy: with a review of
hematologic reactions to “thiazide” drugs.
PEDIATRICS, 31:754, 1963.
8. Black, J.: Personal communication.
Studies of Granulopoiesis and Granulocyte Kinetics in Down’s
Syndrome
Patients with Down’s syndrome associated
with trisomy of a No. 21 chromosome have
been investigated from many points of view to
discover possible effects of an excess of genetic
material. Interesting morphologic differences of
the leukocytes from these patients have been
described,1,2 as well as a high incidence of
leukemia and leukemia-like disorders.3’4
Bio-chemical differences of the leukocytes in
Down’s syndrome have also been observed.
Significant elevations of a number of leukocyte
enzymes have been documented in the
non-dysjunction but not the translocation variety of
Down’s syndrome.’
Alternate hypotheses have been suggested
to explain these enzyme increases. First, that
they reflect an extra dosage effect due to
tripli-cation of genetic loci on the No. 21
chromo-some. Second, it has been suggested that the
increases may merely indicate a lowered mean
age of the granulocyte population due to a
shortened survival time since immature cells
possess higher activities of many enzymes.6 A
third possibility might be that genetic
imbal-ance exerts some general, relatively nonspecific
effect on leukocyte enzyme activity.
Two studies measuring the survival time of
leukocytes in Down’s syndrome have been
re-ported. Galbraith and Valberg presented
nor-mal leukocyte survival curves in four adults
with Down’s syndrome. In addition, a normal
mean blood granulocyte mass and turnover
rate were On the other hand, Raab
and associates presented leukokinetic studies
indicating a shortened mean circulating
half-life in seven individuals with Down’s syndrome
and a significant increase in granulocyte
turn-over rate in four of these.8
In the present investigation a number of
non-isotopic studies were performed in an
at-tempt to further elucidate granulopoiesis and
granulocyte kinetics in these patients. Detailed
hematologic studies describing cellularity and
morphology of the marrow in Down’s
syn-drome have not been published to our
knowl-edge. Therefore, the mitotic and maturation
granulocyte compartments were investigated
by examining the cellularity and
myeloid-eryth-roid ratio of bone marrow aspirate. The size
of the marrow granulocyte reserve was
esti-mated by the peripheral leukocyte response
following injection of a purified bacterial
endo-toxin extract. Finall’, granulocyte turnover
was studied by measuring the level of
murami-dase (lysozyme) activity in the serum, since
increases of this enzyme have been suggested
as indicating an increased granulocyte
turn-over.9”0 No differences were seen betweeen
children with trisomy No. 21 Down’s
syn-drome and controls in any of these studies.
It has been demonstrated that even enzymes
such as G6PD, whose synthesis is governed by
genes located on the X-chromosomes, are
in-creased in Down’s syndrome. Since sex
chro-mosomes are not involved in Down’s
syn-drome, it is unlikely that simple gene
triplica-tion is responsible for the observed enzyme
in-creases. The studies described here do not
support the concept that there is a significant
abnormality of granulopoiesis or granulocyte
kinetics. Thus, the increases of leukocyte
en-zymes demonstrated in Down’s syndrome may
merely reflect some relatively non-specific
gen-eral effect of genetic imbalance on leukocyte
enzyme levels or be due to some as yet
unde-scribed mechanism.
MATERIALS AND METHODS
Five children between the ages of 2 and 14
years with proven trisomy No. 21 Down’s
svn-drome constituted the study group. The
con-trols were five children from the same
