CONGENITAL HYPOPLASTIC ANEMIA

(1)

By Howard A. Pearson, Lt., (MC) USN, and Thomas E. Cone, Jr., Capt., (MC) USN Pediatrics Service, U. S. Naval Hospital, Bethesda, Maryland

(Submitted April 5, accepted July 17, 1956.)

The opinions or assertions contained in this article are the private ones of the writers and are not to

be construed as official or reflecting the Navy Department or the Naval Service at large.

ADDRESS: (H.A.P.) U. S. Naval Hospital, Bethesda 14, Maryland.

CONGENITAL

HYPOPLASTIC

ANEMIA

192

C

ONGENITAL hypoplastic anemia is a rare

form of refractory, chronic anemia of

infancy and childhood. A few cases of this

disease treated successfully with

adreno-corticotropin (ACTH) and cortisone have

been described recently. Even more

inter-esting has been the discovery of an

aberra-tion of tryptophan metabolism associated

with the disease.

It is the purpose of this paper to review briefly the clinical features and the

litera-ture of this condition. We shall report

another case of congenital hypoplastic

anemia in which a dramatic appearance of

reticubocytes and erythrocyte precursors,

together with a rise in the erythrocyte

count and concentration of hemoglobin

fol-lowed the use of ACTH and cortisone.

Fur-ther, the effectiveness of an interrupted

schedule of cortisone administration is

de-scribed which maintained the remission

while avoiding the clinical features of

hy-percorticism produced by continuous use

of cortisone.

REVIEW OF THE LITERATURE AND

CLINICAL FEATURES

In 1936 during an exhaustive review of

anemia in childhood, Josephs’ made

refer-ence to two children with refractory aplas-tic anemia confined to a failure of

erythro-poesis. These children were treated with

repeated blood transfusions over a period

of years.

In 1938 Diamond and Blackfan described

the syndrome, to which their names have

been applied as an eponym, as: A slowly

progressive anemia, beginning early in

in-fancy, without any hemorrhagic tendency,

with only moderate leukopenia, with the

production of a small and inadequate

num-ber of reticulocytes from a bone marrow

which shows moderate hypoplasia.’

This disease has been termed chronic

congenital aregenerative anemia by Vogel,

Erf, and Rosenthal;’ essential

erythroblasto-penia by Hansen;4 and, more recently,

ery-throgenesis imperfecta by Cathie.’ The

dis-ease is a pure erythrocyte deficiency. As

emphasized by Smith,6 it has been

separ-ated as a clinical entity from the group of

hypoplastic and aplastic anemias of

child-hood because the failure of hematopoesis is restricted entirely to the erythrocytes

without simultaneous impairment of

leuko-cyte or platelet production. The bone

mar-row is characterized by marked decrease of

erythrocyte progenitors, and this is reflected

by low or absent reticulocyte response

de-spite the severity of the anemia. In some

instances there may be a relatively normal

number of early erythroid precursors with

a distinct failure of maturation beyond the

stage of the basophilic normoblast.’ The

granubocytic and megakaryocytic elements

are normal. The disease is rarely found at

birth, but typically develops as a

progres-sive anemia appearing in the first few

months of infancy. After 3 months of age

it is differentiated from the more common

hypoplastic type of anemia which follows

erythroblastosis by a persistently low

re-ticubocyte count. In contrast, the

convales-cent phase of this hemolytic disease of the

newborn is characterized by reticulocytosis

reaching a maximum at 6 to 8 weeks of

age.7 The onset of this condition early in

infancy separates congenital hypoplastic

anemia as a syndrome from other types of

acquired pure erythroctyic anemia.

(2)

Although Cathie5 has described a typical facies including snub nose, wide-set eyes, and thick upper lip, it must be admitted

that these are common in normal children.

Despite the profound anemia which these

children may develop, they maintain

nor-ma! weight, stature, and general health so

long as erythrocytes are supplied through

transfusion.

In this disease no predisposing toxic

agent has been demonstrated. There is no

consistent blood group incompatibility

be-tween mother and infant, although Smith(

reported two cases in which

isoimmuniza-tion seemed to be important. Early in the

disease, before the modifying effects of

multiple transfusions appear, there is no

evidence of a hemolytic component.

Coombs’ test is invariably negative, there

is no hyperbilirubinemia, and in a typical

case Gleiss and Greiner8 demonstrated

nor-mal survival of transfused erythrocytes.

The exact pathophysiobogy of the

syn-drome is not known. Diamond and

Black-fan2 hypothesized an inborn error of

meta-bolism of some unknown, but essential

blood building substance. This assumption

seems to have been substantiated by the

work of Altman and Miller.9 These investi-gators noted a blue-fluorescing substance in the urine of a patient with congenital

hypoplastic anemia, and this substance was

identified as anthranilic acid, a metabolite

formed in the breakdown of the essential

amino acid, trypthophan. Urine specimens

from eight additional cases also showed

an-thranilic acid; whereas the urine of normal children did not.

When riboflavin deficient rats are fed

tryptophan, anthranilic acid is excreted in

large amounts; however, it disappears from

the urine when a complete diet is

re-stored.1#{176} Altman and Miller9 treated a pa-tient with massive doses of riboflavin

with-out changing the erythrocyte count or

con-centration of hemoglobin, but some

de-crease in the anthranilic aciduria was

noted.

DalglieshU demonstrated xanthurenic

acid, as well as other unusual metabolites

of tryptophan in the urine of pyridoxine

de-ficient rats which were fed tryptophan.

Re-cently Harris Ct al.12 reported response of

an anemia in an adult to pyridoxine;

ab-normalities of tryptophan metabolism were

also noted and these were corrected by

large parenteral doses of pyridoxine.

Tryp-tophan itself is the direct precursor of

nicotinic acid in mammals.1’

The known refractoriness of congenial

hypoplastic anemia to therapy with

B-vita-mins, at least in the usual therapeutic

dos-age, would seem to exclude simple

vita-mm deficiency as being responsible for the

disease. These children, except for the

anemia, are healthy and show none of the

stigmata of avitaminoses.

It has been shown that the porphyrin

molecule may be synthesized from glycine

and succinic acid. The source of the suc-cinic acid is believed to be the tricarboxy-lic acid cycle.’4 B-vitamins are cofactors of the enzymatic transformations in the tricar-hoxybic acid cycle. The exact nature of the

abnormality of tryptophan metabolism and

the role it plays in congenital hypoplastic anemia remains to be elucidated.

Almost every hematinic has been used

in this disease. Iron, cobalt, copper, liver,

all of the known vitamins and maternal

plasma have been administered without

success. Splenectomy has been occasionally effective, but definite criteria for

recom-mending this procedure have yet to be

es-tablished.2’6

In the past the only treatment of proved value has been repeated transfusions, given

frequently enough to maintain the

hemo-globin at a concentration compatible with

health. Transfusions are generally required

at 4- to 8-week intervals and can be tech-nically difficult in children. In addition transfusion in a very anemic child may

over-load an already taxed heart. A bong-term

complication of multiple transfusions is an

increased concentration of iron in the

serum’5 and hemosiderosis. Other

limita-tion and hazards of blood transfusions have

been outlined by Smith.’6

(3)

12 patients cited by Diamond.” Cases have

been reported with spontaneous recovery

at subnormal concentrations of hemoglobin

which were, however, compatible with

health.”

Since their advent into clinical medicine,

ACTH and cortisone have been used in

many hematologic syndromes. In a normal

person, a transient neutrophilic

leukocy-tosis and evidence of increased prolifera-tion of erythrocytes follows administration

of corticosteroids or increased adrenal

ac-tivity.’8 ACTH and cortisone may have a

modifying influence upon processes which

selectively depress the growth and

differen-tiation of the various blood cells.The most impressive results have been seen in

im-munohematobogic disorders such as

ac-quired hemolytic anemia’9 and idiopathic

thrombocytopenic purpura.2#{176} A beneficial effect has not been consistently seen in the various types of hypopbastic cytopenias and anemias.”

Gasser” reported a case of pure erythro-cytic anemia with marked erythroid

depres-sion in the marrow which followed measles

and was successfully treated with cortisone.

Loeb, Moore, and Dubach” described two

brothers who at the age of 17 successively

developed severe anemia in which the

mar-row showed selective erythroid hypoplasia.

The anemia responded to ACTH and

corti-sone, and complete cure followed

splenec-tomy.

In 1953 Fisher and Allen24 reported a case of erythrogenesis imperfecta in which

ACTH and cortisone produced and

main-tained a hematologic remission.

Arrow-smith25 in 1953 cited a most interesting case

of this disease. Cortisone administration

was followed by reticulocytosis, but not by

an increase in the concentration of

hemo-globin. However, during the course of the

cortisone treatment there was a change in

the appearance of the bone marrow from

normoblastic to megaloblastic. Simultaneous

administration of cortisone and vitamin B1,

produced and maintained a remission,

al-though neither was effective alone. Smith6

reported two cases which were refractory

to cortisone therapy. Burgert, Kennedy, and

Pease’#{176}cited a therapeutic failure with

cortisone, but a reticubocytosis was noted

following cortisone administration.

Diamond successfully treated five

pa-tients with daily cortisone administration.

The amount of cortisone required to effect

remission varied from patient to patient.

In some cases the anemia responded to

small doses.’7

History

CASE REPORT

The patient, a white male infant, was born on December 27, 1954, at the U.S. Naval

Hos-pita!, Bethesda, Maryland. He was the first

child of 21-year-old Caucasian parents. A

half-brother by the mother’s previous marriage was normal. There was no family history of anemia

or blood dyscrasia. The mother was in good

health and had no exposure to hematotoxins during pregnancy. The hemoglobin at term was

12.5 gm/100 ml. Labor and delivery were

un-eventful. The child’s birth weight was 3,200

gm. The cord was stripped at delivery. The

child was considered normal during the neo-natal period, and had no jaundice or pallor.

The weight gain was normal with an evapor-ated-milk formula.

At 7 weeks of age, the child became quite

irritable and pallor was noted. These

svrnp-toms were progressive, and at 8 weeks of age

he was admitted for study. There was no

ex-posure to myebotoxins or drugs during these 2 months.

Physical Findings

On examination he was markedly pale. The

weight was 4,560 gm. There was no icterus;

the spleen and liver were not enlarged. The

heart rate was 170/mm, and an apical systolic murmur was heard. A left indirect inguinal hernia was present.

Laboratory Findings

The erythrocyte count was 720,000/mm3;

hemoglobin, 2.25 gm/100 ml; leukocyte,

dif-ferential and platelet counts, normal;

reticubo-cyte count, 1.2%; erythrocytes appeared

normo-cytic, normochromic on direct smear.

The mother’s blood typed 0, CDe/CDe, with

a saline anti-A titer of 1:256 and a saline

(4)

ARTICLES

TABLE I

September 21, 1955

Iliac Marrow March 8, 1955 After 14 Days

Tibia! Marrow of ACT!!, Differential 40 mg/day,

(500 Cells) Intramuscularly,

Differential (500 Cells)

(%) (%)

IIyeIollasts: 0.6 0.2

Progranulocytes: 1 .2 2.2

Myelocytes: 7.2 5.4

Metamyelocytes: 16.4 9.8

Bands: 16.8 17.4

Segmented: 10.0 14.0

Lymphocytes: 37.2 19.2

Monocytes: 0.0 0.0

Basophils: 0.2 0.2

Eosinophuls: 6.2 5.2

Megakaryocytes: l’resent in all Present in all

smears. smears. Total nucleated

erythroeytes 4.2 26.2

Rubriblasts 0.3 0.6

Prorubricyte 0.8 1 .6

Rubricyte 2.0 5.2

Metarubricyte 1 .1 18.2

Myeloid: Nucleated

erythrocyte ratio 1l:1 2:1

CDe/cDE, and Coombs’ test was negative.

The patient was given 220 ml of matched blood in divided doses. After transfusion the blood values were: hemoglobin, 9.0 gm/100 ml;

erythrocytes, 2,600,000/mm’; reticulocytes, 0.0%.

Bone marrow aspirated from the left tibia

showed marked erythroid depression. The

myeloid series were normal and normal

mega-karyocytes were seen on the fixed section (Table

I).

Course

The patient was given cortisone orally, 50

mg/day for 14 days. There was no change in

the morphology of erythrocytes and the

con-centration of hemoglobin steadily decreased.

After the 1.2% reticulocytes noted on admis-sion, none were seen on 20 subsequent exami-nations.

After 3 weeks of hospitalization, the con-centration of hemoglobin had decreased to 6.5

gm/100 ml. The child was given another 110

ml of blood. After transfusion the hemoglobin

was 9.5 gm/100 ml. He was discharged

re-ceiving iron medication and a multiple-vitamin preparation including: Thiamine hydrochloride

2.0 mg, riboflavin 1.5 mg, nicotinamide 1.0

mg, pyridoxine 1.0 mg, vitamin B12 1 sg and ascotjic acid 50 mg.

During the next 6 months, the patient was admitted to the hospital on eight occasions at 3- to 5-week intervals for transfusions. He was given fresh, matched blood, in doses of 20 ml/ kg of body-weight. The indication for trans-fusion was arbitrarily selected as a

concentra-tion of hemoglobin below 7.0 gm/100 ml. On

one occasion when the hemoglobin was 5.5 gm/

100 ml, 1.6% reticubocytes were noted; other-wise none were seen on many determinations. Despite fluctuations of hemoglobin values, the weight gain and motor development were satis-factory. He had frequent minor upper respira-tory infections. However, the serum proteins were normal by electrophoretic analysis. Re-peated leukocyte and platelet counts were nor-ma!.

When the child was 9 months of age, he was

admitted to the hospital for study. He was

again noted to be pale but not icteric. The liver

and spleen were not palpable.

The hemoglobin was 4.7 grn/100 ml;

ery-throcytes, 1,690,000/mm’; no reticubocytes were seen. The concentration of bilirubin in serum and of urobiliogen in urine was normal.

Coombs’ test was again negative. Osmotic

fragility of the erythrocytes was normal. The patient was treated with intramuscular

ACTH, 10 mg four times daily (Fig. 1). After 5 days of this, reticubocytes began to appear

in the peripheral blood, reaching a peak of

6.8% on the eighth day of therapy. A small

but definite rise in the erythrocyte count and hemoglobin value was also noted. The

erythro-cytes remained normochromic and normocytic. The ACTH was discontinued after 14 days.

There was a rise in reticulocytes to 11.0%, 3

days after discontinuing the ACTH, but this

fell to 0.0% within 10 days. A concomitant de-crease in the erythrocytes and hemoglobin was

also noted. Bone marrow aspirated from the

iliac crest, 2 days after the course of ACTH, yielded an essentially normal appearing mar-row; the erythrocytic series displayed normal proportions and maturation, the granulocytic

and megakaryocytic series were normal

(Table I).

(5)

corti--4 0

a

‘I

x- ETiCS

A - Hbg 0 - RBC

65 DAYS

Fic. 1.

196

sone was begun in a dose of 50 mg daily. A

reticulocytosis again occurred. During the next

6 weeks a rapid rise in the erythrocyte and

hemoglobin values occurred with a varying

high level of reticubocytes. After 4 weeks of

cortisone therapy, the child developed a

typi-cal moon-facies. His appetite while taking

cortisone was voracious.

When the hemoglobin reached 12.8 gm/100

ml, an attempt was made to decrease the

dose of cortisone to 37.5 mg/day. On this

regi-men, reticubocytes disappeared from the peri-pheral blood and in 2 weeks the hemoglobin decreased to 10.3 gm/100 ml.

The patient was then treated with an

inter-rupted dosage schedule of cortisone, 125 mg

for 3 days consecutively each week and none for the remaining days of the week.

Prophy-lactic tetracycline and supplemental orange

juice were also given. The hemoglobin was

maintained between 9.0 and 10.0 gm/100 ml

by this program.

While on this regimen, the child was again admitted to the hospital. Daily reticulocyte

counts showed a phasic increase coinciding with the days on which cortisone was administered,

with a rapid decline during the rest of the

week (Fig. 2).

After 4 months on the interrupted program

of therapy with cortisone an elective

herni-orraphy was performed. The patient tolerated the surgery well and the healing process was entirely satisfactory. Postoperatively he de-veloped a temperature of 39.5#{176}Cand the physi-cal and roentgenographic signs of moderate

pneumonitis were found. This responded satis-factorily to conventional doses of tetracycline.

Cortisone was discontinued for 7 consecu-tive days and a 24-hour urine specimen was

obtained. A qualitative testfor the presence of

anthranilic acid in the urine was performed

using the method of separation described by

Brown and Price’8 Fluorescence and a color

reaction with Ehrlich’s reagent, as described by Dalgliesh,” were used to identify the com-pound. The patient’s urine gave positive reac-tions for anthranilic acid. During the last 3

days of this interval, no reticubocytes were

ob-served.

Then the child was given cortisone orally,

125 mg daily for 5 days. A reticulocvtosis

av-eraging 2% was noted. On the fifth day another

24-hour urine collection was made, and the

qualitative test for anthranilic acid was again

positive. Unfortunately, we were unable to

perform a precise quantitative determination,

but there appeared to be no change in the

(6)

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two determinations. Tests done simultaneously

on the urine of three normal children showed no

anthranilic acid. Dr. Albert Sjoerdsma of the

National Heart Institute, Bethesda, Maryland,

kindly analyzed the patient’s plasma for

cir-culating tryptophan. The same concentration was found before and during cortisone

treat-ment, 1.3 mg/100 ml of plasma, which is

within the range for normal adults. It also is

comparable with the value for a normal child

obtained at the same time. Analysis of the

urine for 5-hydroxyindole acetic acid was performed after 7 days without cortisone. The

value obtained was 1.9 mg/24 hr, which is

within the limits for normal adults.

5-hydroxy-indole acetic acid is the urinary endproduct of

serotonin, and serotonin is synthesized in an-other pathway of tryptophan metabolism.’9

At the time of writing, the child had received

the interrupted treatment with cortisone for

over 8 months. The moon-facies had regressed,

and growth and development were normal.

Without cortisone the child went into rapid

relapse. During uncomplicated rubella, corti-sone was not given for 2 weeks, and the

con-centration of hemoglobin decreased to 2.3 gm/

100 ml. Reticubocytosis and a rise in the hemo-globin value promptly occurred when cortisone was restarted. During the last 5 months of observation the hemoglobin value averaged

12.0 gm/100 ml.

DISCUSSION

The syndrome of congenital hypoplastic

anemia has been shown to be due to a

fail-ure of formation or maturation of

erythro-cytes. Its congenital nature seems rather

certain, despite the fact that these children are not usually noted to be anemic during

the neonatal period.

The finding of anthranilic acid, an

un-usual byproduct of tryptophan metabolism, in the urine of several of these children has raised interesting possibilities concerning the pathogenesis of the disease. It is hoped that more cases may be tested in order to

determine if anthranilic aciduria is an

(7)

pure erythrocytic anemia in adults may be associated with a similar abnormality.1’

Experimental work in animals has shown

that anthranilic aciduria is seen in states of riboflavin deficiency. Children with this

syndrome show no evidence of deficiency

of B-vitamins and do not respond to

con-ventional oral doses of vitamins. Further

studies to determine whether the anemia

will respond to larger doses of specific

B-vitamins, and whether parenteral

admin-istration might be necessary (thus indicating

defective absorption) will determine

wheth-er vitamin deficiency is important in the

pathogenesis of this disease.

Why cortisone administration should

oc-casionally be effective in this disease is

un-known. There is no consistent evidence of

endocrine abnormality or signs of

hypo-adrenalism in these children. Whether

corti-sone itselfexerts a direct stimulating effect on the marrow, or whether it counteracts some inhibitor of erythrocytic maturation,

is not known. Therefore the use of

corti-sone in treatment remains empiric.

Our studies indicate that the aberrant

metabolite of tryptophan, anthranilic acid, persists in the urine despite the beneficial effect of cortisone on production of

retic-ubocytes and hemoglobin. No abnormality

of concentration of tryptophan in the blood

or of 5-hydroxyindole acetic acid in the

urine was noted. This would seem to

indi-cate that if a block is present in tryptophan

metabolism, it is not sufficient to be

re-flected in an elevated concentration of

tryp-tophan in the blood. Further, the

inter-conversion of tryptophan, serotonin, and

5-hydroxyindole acetic acid would appear to

be intact.

A threshold for the effective dose of

corti-sone was seen in the case reported. When

the cortisone dosage was decreased by only

12.5 mg daily, relapse occurred.

The effectiveness of an interrupted sched-ule of treatment with cortisone was demon-strated in this case; when 50 mg were given daily, the patient developed moon-facies

but if the total weekly dosage was given

during only 3 days of a week, a steady

satis-factory concentration of hemoglobin was

maintained without signs of hypercorticism.

After 4 months on the interrupted regimen,

the patient tolerated a surgical procedure

and a complicating postoperative

pneu-monitis was not masked by the steroid

therapy.

In the future management of this patient,

studies with administration of pyridoxine and riboflavin are planned. However, unless

a more specific treatment is discovered, we

feel that the present regimen of interrupted

administration of cortisone is satisfactory

for this patient.

SUMMARY

A case of congenital hypoplastic anemia

is reported in which a course of ACTH was

followed by evidence of remission in the

peripheral blood and marrow. The

remis-sion had been maintained for 10 months

by administration of cortisone.

The effectiveness of an interrupted regi-men of administration of cortisone in main-taining remission and yet avoiding clinical

signs of hypercorticism is described.

An abnormality of tryptophan

metabo-lism, as evidenced by the finding of

an-thranilic acid in the urine was noted. The

anthranilic aciduria persisted during

corti-sone therapy despite a beneficial effect on

production of reticubocytes and

hemo-globin.

Concentration of tryptophan in the blood

and urinary excretion of 5-hydroxyindole acetic acid were normal.

ACKNOWLEDGM ENTS

The authors wish to express their

ap-preciation to Lt. G. I. Plitman, (MC)

USNR, and Lt. Cdr. S. A. Kaplan, (MC)

USNR, for their valuable suggestions. Also

to Cdr. M. R. Schmoyer, (MC) USN, for

his assistance in interpreting the bone mar-row preparations.

REFERENCES

1. Josephs, H. W.: Anaemia of infancy and

early childhood. Medicine, 15:307, 1936.

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Hypoplastic anemia. Am.

J.

Dis. Child.,

56:464, 1938.

3. Vogel, P., Erf, L. A., and Rosenthal, N.:

Hematobogic observations on bone

mar-row obtained by sternal puncture. Am.

J.

Clin. Path., 7:436, 1937.

4. Hansen, H. C. : Uber die essentielle

Ery-throblastopenie. Acta. haemat., 6:335, 1951.

5. Cathie, I. A. B. : Erythrogenesis imperfecta.

Arch. Dis. Childhood, 25:313, 1950. 6. Smith, C. H. : Hypoplastic and aplastic

anemias of infancy and childhood; with a consideration of the syndrome of

non-hemolytic anemia of the newborn.

J.

Pediat., 43:457, 1953.

7. Hyman, C. B., and Sturgeon, P.:

Observa-tions on the convalescent phase of

erythroblastosis fetalis. PEDIA’rnlcs, 16:

15, 1955.

8. Gleiss,

J.,

and Greiner, H.: Beitrag zur Frage der Lebensdauer transfundierter und kurzfristig konservierter Erythrocy-ten bei einem Fall von isoliert aplastis-cher Anaemie vom Typ Diamond-Black-fan. Monatsschr. Kinderh., 99:382, 1951. 9. Altman, K. I., and Miller, G.: A

disturb-ance of tryptophan metabolism in

con-genital hypoplastic anemia. Nature, 172:

868, 1953.

10. Porter, C. C., Clark, I., and Silber, R. H.: Effect of B vitamin deficiencies on

tryp-tophan metabolism in rat. Arch.

Bio-chem., 18:339, 1948.

11. Dalgliesh, C. E.: The relationship between

pyridoxine and tryptophan metabolism

studied in the rat. Biochem.

J.,

52:3,

1952.

12. Harris,

J.

W., Price,

J.

M., Whittington, R. M., Weisman, R. Jr., and Horrigan, D. L.: Pyridoxine responsive anemia in

the adult human. Reported at the 48th

Annual Meeting of the American

So-ciety for Clinical Investigation, Atlantic City, N.J., April 30, 1956.

13. Harper, H. A.: Review of Physiologic

Chemistry, 4th Ed. Los Altos, Califor-nia, Lange Medical Publications, 1953, p. 102.

14. Shemin, D.: The succinate-glycine cycle;

the role of delta-amino-levulinic acid in

porphyrin synthesis. Ciba Foundation

Symposium on Porphyrin Biosynthesis

and Metabolism. Boston, Little, 1955,

p.4.

15. Palmen, K. and Vahlquist, B.: Stationary hypoplastic anemia. Acta haemat., 4: 273, 1950.

16. Smith, Carl H.: Transfusions in pediatric

practice: Indications and limitations. PEDimIcs, 17:596, 1956.

17. Diamond, L. K. : Editorial comments, in

Year Book of Pediatrics. Chicago, Yr.

Bk. Pub., 1955, p. 308.

18. Bethell, F. H., Neligh, R. B., and Conn,

J.

W. : Changes in blood corpuscular

values following the administration of

pituitary corticotropin to normal persons.

Proceedings of the Second Congress of

International Society of Hematology,

Buffalo, 1948, p. 31.

19. Dameshek, W., Rosenthal, M. C., and

Schwartz, L. I.: Treatment of acquired

hemolytic anemia with ACTH. New

England

J.

Med., 244:117, 1951.

20. Meyers, M. C., Miller, S., Linman,

J.

W.,

and Bethel!, F. H. : The use of ACTH

and cortisone in idiopathic thrombocyto-penic purpura and idiopathic acquired

hemolytic anemia. Ann. mt. Med., 37: 352, 1952.

21. Hill,

J.

M., and Hunter, R. B. : ACTH

treatment in refractory anemias.

Pro-ceedings of the Second Clinical ACTH

Conference, Vol. 2. New York,

Blaki-ston, 1951. p. 181.

22. Gasser, C.: Aplastische Anaemie

(chron-ische Erythroblastophtise) und Cortison.

Schweiz. med. Wchnschr., 81:1241,

1951.

23. Loeb, V., Moore, C. V., and Dubach, R.:

The physiologic evaluation and manage-ment of chronic bone marrow failure.

Am.

J.

Med., 15:499, 1953.

24. Fisher, 0. D., and Allen, F. M. B.:

Eryth-rogenesis imperfecta or congenital

hy-poplastic anemia (Diamond-Blackfan

type). Arch. Dis. Childhood, 28:363,

1953.

25. Arrowsmith, W. R., Burns, M. B., and Segaloff, A.: Production of a megalo-blastic marrow by administration of cor-tisone in aplastic anemia, with subse-quent response to Vitamin B,2; a rela-tionship not previously described.

J.

Lab.

& Clin. Med., 42:778, 1953.

26. Burgert, E. 0., Kennedy, R. L.

J.,

and

Pease, G. L.: Congenital hypoplastic

anemia. PEDIATRICS, 13:218, 1954.

27. Diamond, L. K.: Personal communication. 28. Brown, R. R., and Price,

J.

M.:

Quantita-tive studies on metabolites of tryptophan in the urine of the dog, cat, rat, and man.

J.

Biol. Chem., 219:985, 1956. 29. Sjoerdsma, A., Weissbach, H., and

Uden-friend, S.: A clinical, physiologic, and biochemical study of patients with ma-lignant carcinoid. (argentaffinoma). Am.

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200

SUMMARIO IN INTERLINGUA

Congemte

Anemia

Hypoplastic

Congenite anemia hypoplastic es un forma

rar de chronic anemia refractori in infantes e

juveniles. In iste condition le medulla ossee es

characterisate per un marcate reduction del

progenitores del erythrocytos, sed le elementos granulocytic e megacaryocytic es normal. Ben que be exacte pathophysiobogia del morbo non es cognoscite, be recente discoperta de acido anthranilic in le urina de iste patientes es un

facto interessante. Acido anthranilic es un

inusual metabolito del amino-acido

trypto-phano. In animales experimental on bo vide in

statos de carentia de pyridoxina o de ribo-flavina.

In be passato le so! tractamento esseva

repetite transfusiones, con omne le pertinente

difficultates e riscos. Le usual hematinicos e

vitaminas non stimula le erythropoiese in iste condition.

Le presente reporto describe un puero blanc qui esseva observate durante quasi duo annos a causa de su congenite anemia hypoplastic.

Al etate de 8 septimanas, profunde anemia

esseva constatate con valores de hemoglobina de 2,25 g per 100 ml. Nulle reticulocytos esseva

notate. Ii habeva etiam nulle signos serologic

de isoimmunisation. Le medulla ossee exhibiva

un specific hypoplasia erythroide con un

pro-portion myeloido-erythroide de 12:1. Le

pa-tiente requireva 11 transfusiones de sanguine

durante le prime 9 menses de su vita. Al etate de 9 menses, un curso de 14 dies de

adreno-corticotropina (ACTH) esseva sequite per

reticulocytosis e un augmento del valores de hemoglobina. A iste tempore le medulla ossee

esseva normal con un proportion

myeboido-erythroide de 2:1. Al tempore del redaction del presente reporto, be remission ha essite

mante-mte durante plus que 10 menses per medio de

un therapia oral de cortisona. Es describite

un interrumpite programma de dosage de

cortisona, in que be droga esseva administrate omne septimana in tres dies consecutive. Iste

regime manteneva le remission sed evitava be

aspectos clinic de hypercorticismo que esseva notate post administrationes diurne del mesme total dose septimanal.

Acido anthranilic esseva demonstrate in be

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1957;19;192

Pediatrics

Howard A. Pearson and Thomas E. Cone, Jr.