REVIEW ARTICLE

Pedictirics

VOLUME 16 DECEMBER 1955 NUMBER 6

REVIEW ARTICLE

CONGENITAL

ADRENOCORTICAL

HYPERPLASIA

WITH

DISTURBED

ELECTROLYTE

REGULATION

,I

By Torben Iversen, M.D.*

P

RENATAL adrenocorticah hyperplasia

with increased secretion of androgenic steroids heads to progressive vinihization producing the picture of congenital

adneno-genital syndrome, which in females is

usu-ally characterized by pseudohermaphrodit-ism and in males manifests itself as macro-genitosomia praecox during the first years of life.

Sometimes tile abnormal androgenic

ac-tivity in the adreno-genital syndrome is as-sociated with a disturbance of the adreno-cortical electrolyte regulation similar to that

5eefl in adrenocortical insufficiency. As a

rule, the clinical manifestations begin dun-ing the first few weeks of life with vomiting,

loss of weight, dehydration and episodes of

circulatory collapse. The condition is often seen in siblings and will, in untreated cases,

usually lead to death within the first few

months of life. Administration of desoxy-corticosterone, cortisone and sodium cillor-ide may correct the defective electrolyte

regulation and, in addition, cortisone is

From the Department of Pediatrics,

Rigshos-pitalet, University of Copenhagen, the Queen Louise Children’s Hospital, Copenhagen, and the Department of Medicine, Amtssygehuset, Univer-sity of Aarhus, Denmark.

* ADDRESS: Amtssygehuset, Aarhus, Denmark.

capable of suppressing tile androgenic

effects.

On the basis of the cases described ill

the literature and of personal eases, it is the

purpose of this paper to give a survey of

the characteristic picture of electrolyte

dis-tunbance and virilization due to congenital

adrenocortical hyperplasia, for which the

term “dysadrenocorticism” has been coined.

HISTORICAL

In 1886 Phillips’ described a ease of female pseudohenmaphroditism in an

in-fant. Three of seven siblings had presented

similar genital abnormalities and had

gradually become emaciated and died at

the age of 3 to 6 weeks. “This child took the breast and kept well for a week as the others did; it then began to waste and died

aged nineteen days.” Neeropsy revealed

hy-pentrophy of the clitoris and persistent urogenital sinus, while the internal genital organs were female. The adrenals were “very large.” but were not described in

de-tail in the report. “Fortunately for the eom-munity, the survival of these creatures is

In 1905 Fibiger,2 from the Queen Louise

Children’s Hospital in Copenhagen, de-scnibed a case of bilateral adrenal hyper-plasia in an infant with female pseudo-henmaphroditism. “The patient had suffered from gastnoentenitis which had commenced

shortly after birth. The infant was admitted in an atrophic condition, weighing 2,800

gm., was very weak and died during the

first 24 hours in hospital.” Fibiger was among the first investigators to emphasize the possibility of a pathogenetic relation be-tween the genital abnormalities and the

adrenal changes, but he did not describe the clinical picture in detail. In the light of

our present knowledge, the perusal of the original case record seems to show that the case was one of dysadrenocorticism, for

which reason a brief abstract of the record

is given below, supplemented by studies of

Lehmann.3

There was no known predisposition to con-genital malformations in the family, and the parents were in good health. At birth the infant weighed 4,250 gm. and had been considered to be a boy. Since birth, vomiting, loss of weight and progressive deterioration of tile general health had occurred. The patient had at first been fed on a proprietary infant food, but was later given barley water and diluted cow’s milk. Stools had been normal until the last few days before addmission when diarrhea developed.

On admission at the age of 63 weeks the infant was dehydrated and emaciated. The skin was cold, hands and feet cyanotic. Broncho-pneumonia was diagnosed. The penis was about 13 cm. long with a well-developed glans par-tially covered by prepuce. The urethral orifice was seen very near the apex of the glans form-ing an oblong slit. Apart from the absence of the raphe the scrotum was of normal appear-ance. Testes were not palpable.

The patient was given sterile water to drink and saline infusions, and the condition irn-proved, but sudden death occurred about 12 hours after admission.

The internal genital organs were female, but about the base of the bladder the urethra was surrounded by a well-developed prostrate, and the vagina, measuring about 13 cm., entered into the urethra. The testes could not be

dem-onstrated. Both adrenals were greatly enlarged, the right measuring 4.5 by 3.5 by 3 cm. and the left 4.5 by 3.5 by 2 cm. The surface was markedly folded with numerous convolutions and furrows. Histologic examination revealed distinct differentiation of the adrenocortical zones.

The infant was the third of 6 siblings. The first child, who had also been a pseudo-hermaphrodite, had fed poorly from birth,

lost weight, became apathetic and died at the age of 17 days. The second child, a male with normal external genitalia had

pre-sented a similar clinical picture and died at 39 days. The fifth child of the family, likewise a pseudohermaphrodite, had also lost weight since birth; projectile vomiting supervened and death occurred at 3 weeks.

In 1918, Pritchard4 demonstrated the

specimens of very enlarged adrenals from an infant (male?) aged 5 weeks, who died suddenly. Histologic examination showed simple hypentrophy of the adnenals.

Lehmann,3 in 1919, described the clinical picture in 2 siblings with

pseudohenmaph-roditism. One of the infants, who died

at the age of 5 weeks, had lost weight since birth. The other infant likewise lost weight

after birth, and vomiting and diarrhea de-veloped. At the time of admission at age 6 weeks the infant was dehydnated and emaciated. Progressive cachexia developed and death ensued at the age of 3 months.

Necropsy revealed adrenocortical

hyper-plasia.

In 1924 Scabell5 described congenital adnenocontical hyperphasia in 2 siblings, a

male infant with normal genitals, who died at 3 months, and a female pseudoherma-phrodite, who died at 4 months of age. Both

of the infants had had persistent vomiting

and loss of weight.

Debn#{233}and Semehaigne,6 in 1925, reported the case of a male infant who was

ad-mitted at 10 months of age because of poor appetite and no weight gain after birth.

multiple nanrowings of the colon and

cx-treme ilypentrophy of the adnenals. The

authors assumed a connection between the

infant’s wasting and the congenital

mal-formations.

In 1928 von Gienke7 reported adrenal

hyperplasia in a 4-week-old male infant

who had failed to thrive and had suffered from persistent vomiting, diarrhea, and “in-toxication.” The author assumed that the

symptoms in this and other cases of

adrenoeortieal hyperplasia were due to toxic substances from the hyperplastic

adrenal cortex, for which reason the conch-tion was described as “Interrenale

Intoxi-kation.”

In 1939 Butler, Ross and Talbot8

re-ported a case of adrenocortieal insufficiency associated with macrogenitosomia praecox in a boy aged 20 months. Dehydration and diffuse pigmentation of the skin were

ob-served at the age of 2 weeks, and at 2

months penile enlargement was noted. The concentration of sodium in the serum was low and potassium high, and the excretion of androgen in the urine was excessive.

Clinical improvement occurred after treat-ment with sodium chloride and

adreno-cortical extract, and the patient is still alive (1954).

Wilkins, Fleischmann, and Howard,9 in

1940, published a case of adrenocortical

in-sufficiency in a boy aged 3% years with macrogenitosomia praecox and adrenocor-tieal hyperplasia. From early age he had had poor appetite, had vomited, and was

always craving for salt. The penis and scro-turn were unusually large at birth, and pubic hair appeared at the age of 15 months. Death occurred suddenly. The authors as-sumed that the hyperplastic androgenic

adrenocortical tissue had replaced the dcc-trolyte-regulating elements of the cortex.

In 1940 Dijkhuisen and Behn’#{176}reported 4 eases of adrenocontical hyperplasia in in-fants (3 boys and 1 girl) who had all suffered from severe vomiting suggestive of

intestinal stenosis from the first weeks of life, and who exhibited marked

dehydra-tion. One of the boys had penineal hypo-spadias, while the girl had normal external genital organs. The disorder was described as “a new clinical entity of the neonatal period,” and it was supposed that the

hon-mone secretion of the adrenal cortex was increased.

In 1950 Wilkins et a!.” reported that

cortisone was capable of suppressing the production of androgens in patients with

adrenocortical hyperplasia, and in 195212 reports of a favorable effect of cortisone

and corticosterone in infants suffering from

dysadrenocorticism were published.

NOMENCLATURE

Among Anglo-American terms may be

mentioned “dysfunction of the adrenal

gland,”3 “mixed adrenal cortical disease,”4

“hypo-mineralo-corticoidism,”5 and “con-genital adrenal hyperplasia combined with defective electrolyte regulation.”6

In French literature, the condition is

re-ferred to as “syndrome de Debr#{233}-Fibiger”

by

Marie et al.’ In German and Swiss literature von Gierke’sT term “Internenale

Intoxikation” is often seen. Schaehenmann and Zollinger18 used the name “Pseudo-pylorusstenose.” Fanconi and Landolt’9

in-troduced the term “Dyscorticismus,” which comprised disorders with enlargement of

the adrenals and abnormalities of 1 or more of their pant-functions. The authors

re-ferred to the clinical picture produced by

disturbance of the electrolyte regulation as “Pixie’s syndrome.” However, in the case

described by Pine’0 in 1919 “definite thickening of the muscle at the pyloric orifice” was present, and only 1 of the adnenals were enlarged. Thomas” named

the disorder “Paradoxe Nebennierenin-suffizienz.”

ETIOLOGY

The cause of dysadrenocorticism is

pan-tially unknown. The frequent occurrence of dysadrenocorticism in siblings, affecting

reces-sive 1)ut not sex-linked transmission. Wolff” described dysadnenocorticism in identical

tWills. Harris and Scowen” reported

maenogenitosomia I)r1eeX in a boy whose

father’s parents had a child of undetermined

sex, who collapsed and died when a few

weeks old. Consanguinity has been de-senibed only in 1 ease, in which the parents were first cousins.’4 Werthemann2l found

a common ancestor in the fourth parental

generation of 2 families with dysadneno-conticism, but this finding was later proved to be wrong.’ On the basis of its familial

occurrence Knudson27 estimated that a

re-cessive transmission is probable, and similar studies on the present series point in the

same direction. Bauen’8 expressed the view

that pseudohermaphroditism and

adreno-cortical hyperplasia are parallel phenomena due to insufficient prevalence of one genetic sex determiner over the other.

In addition to genetic factors, external

hormonal factors during fetal life may be

of decisive importance in sexual differen-tiation. Witschy’9 showed that administra-tion of estrogenic hormones could induce

adrenal hyperplasia and reversion of the

gonads in larval frogs. Small doses given to genetic males led to henmaphroditism or

complete feminization with transformation of the testes to ovotestes or ovaries, while

large doses illduced maseulinization both in genetic females and males. Witschy’9 states that an abnormal maternal estrogenie

influ-enee OIl the fetus may be a probable cause

of the congenital adrenogenital syndrome

in man. Studies of the hormone patterns

during pregnancy in women who have given

birth to cilildnen with dysadnenocorticism will be of great interest.

PATHOGENESIS

It is generally assumed that the genital changes are due to an excessive production of androgenie hormones by the hyperplastic adrenal cortex during pre- and postnatal life. The elevated concentration of 17-ketostenoids in the plasma’#{176} and the greatly increased output of androgens and neutral 17-ketosteroids in the urine are in favor

of this assumption. Studies by

chroma-tography have silown that the

17-ketoster-oids also deviate qualitatively from those

normally present.” “ The audnogenic effect

usually manifests itself in females after the third and before the fifth fetal months, i.e., after the occurrence of the sexual differen-tiation of gonads and genital duets, and

before the formation of separate urethral and vagillal tubes.” The earlier the

andro-genie activity begins in fetal life the more pronounced will be the external virihization. In a case of dysadrenocorticism described by Matheson and Ward’ the virihization probably began before the tenth fetal week. Prader” divides tile genital changes in female pseudohermaphroditism into 5

differ-ent types according to the time of onset of vinilization.

The increased androgenie activity may be explained by a primary defect in the

production of glucogenetic hormones (glu-cocorticoids) and sodium-retaining

hor-mones (mineralocorticoids) by the adrenal

cortex, which is compensated by an

in-creased production of adrenocorticotnophie hormone (ACTH) resulting in

adrenocorti-cal hyperplasia and overproduction of androgenic adrenocortical hormones.’#{176} This

theory is supported by the demonstration that ACTH is present in the blood of

pa-tients with adrenoeortieal hyperplasia,

while detectable quantities of this

hor-mone are not found in controls.” Further, it has been shown that these patients have

exceptionally low concentrations of

17-hdroxyeortieosteroids in the plasma and

illability to respond to administration of

exogenous ACTH by an elevation of the

17-hydnoxycorticosteroid level of the

plasma.’8 It is proposed that the defective

synthesis of glucogenetic hormones is due

to a block in the conversion of 17-hydroxy-progesterone into

879 androgenic steroids has not been

de-termined. The defective steroid synthesis

ill tile adrenal cortex is presumably due to

a genetically determined lack of an

enzy-matie system.”

The hyperplastie adrenais also seem to

secrete abnormally large amounts of estro-gens, the effect of which is usually inhibited 1)y tile increased amounts of

Cases of congenital adnenocortical

hyper-plasia with electrolyte imbalance have been described in girls who had normal external

1, 10 and in boys whose external

genitals were transformed in a female di-rection ill the form of hypospadias4548 or

were of normal female 26 The excretion

of steroids is unknown in these forms.

Finally, it may be stated that a few cases

of female pseudohermaphroditism have been recorded in which the adrenals were Ilormal, and in which there were no signs of increased androgenic activity or

electro-lyte imbalance.9

As already mentioned, Wilkins et al.9

originally assumed that the electrolyte dis-order in dysadnenocorticism was due to re-placement of tile electrolyte-regulating dc-ments of the adrenal cortex by the

hyperplastic androgenic tissue. However,

various observations suggest that the

dcc-trolyte disorder is not exclusively due to

lack of sodium-retaining hormones. Thus,

desoxyconticosterone is often only slightly active in amounts which relatively exceed therapeutic doses in true adrenocortical

in-sufficiency. In addition, ACTH may induce marked urinary excretion of sodium and

551 It is now generally

as-sumed that the electrolyte imbalance is

also, on even exclusively, due to the pro-duetion by the hyperplastic adrenal cortex of substances which promote loss of sodium

accompanied by chloride and water, and thus exert an antagonistic effect on the salt-regulating hormones of the adrenal

cor-tex.”””

In dysadrenocorticism administration of cortisone causes a diminished activity of the adrenal cortex evidenced

by

a diminished excretion of 17-ketosteroids. Moreover,

sodium retention is observed. These effects

are presumably due to suppression of the

1)noduetion of ACTH by the pituitary and

ilence a diminished adrenocortical produc-tion of androgens and substances causing loss of sodium. In addition, cortisone exerts a direct salt-retaining effect.’2

ADRENALS

At birth the adrenals normally weigh

6 to 7 gin. together. In a large series,

T#{228}hk#{228}’4found an average weight of 6.5 gm. in full-term infants, aged 0 to 7 days. At 2 to 3 months the average weight was

3.5 gm and at 12 to 24 months 5.2 gm.

At birth the so-called fetal or transient cortex (“andnogenie zone” or “fetal reticular zone”) represents on an average 85 per cent of the volume” and 73 per cent of the

thick-ness54 of the total adrenal cortex. The cells of the fetal cortex are large with coarsely granular eosinophihic cytoplasm and vesic-ular nuclei and are arranged in a pattern similar to that of the permanent reticular zone. At birth the permanent on adult eon-tex is composed of cells arranged in whirls which represent the zona glomerulosa, and

in the second week of life a cellular

struc-tune similar to that of the zona fasciculata develops. During the third postnatal month the zona reticulanis makes its initial

ap-pearance.” Simultaneously with the

de-velopment of the adult cortex involution

of the fetal cortex occurs. At the age of 1

month the latter is made up of scattered degenerated cells and irregular stroma. At that time the adult cortex has become 2 to 3 times as thick as it was at birth.’6 The cells of the zona neticulanis are presumably

developed from persistent cells in the fetal cortex.” At the end of the first year of life the fetal cortex has disappeared.

The function of the fetal cortex is un-known. Brosten and Vines’8 postulated that

staining with Vines’ ponceau-fuchsin

re-vealed evidence of secretion of androgen and found fuchsinophihic granules in the

investigators, e.g., Blackman,ST consider this staining nonspecific, and no other evidence

suggesting an androgenie function in fetal

life is available.

Which zone of the cortex undergoes hyperplasia in dysadrenocorticism has not

yet been determined. In this connection, the fetal zone, the zona reticularis, and the zona fascicuhata, have been suggested.

Animal experiments seemed to support the assumption that the

ehectrolyte-reguhat-ing hormones of the adrenal cortex were

produced in the zona and

in conformity with this, absence on poor

development of this zone has often been described in dysadrenocorticism. However, more recent studies have proved that the

regulation of electrolyte metabolism can-not be attributed to the zona glomerulosa.6’

SURVEY OF CASES

As previously pointed out, the

character-istic electrolyte disorder in dysadrenocorti-cism was demonstrated in 1939,8 and the clinical picture was emphasized as a noso-logic entity in 1940.’#{176}The literature prior to 1939 includes several reports on

adreno-cortical hyperplasia in children who died

in infancy, but in most of these cases the clinical description is incomplete and patho-logic changes are emphasized. However, 19 infants (6 boys and 13 girls), some of whom have been mentioned before,

pre-sented the clinical picture of

dysadneno-corticism and are included in the series.

The cases described by Tilp,44 Pine,20 Brutschy,’ and Dietnich and Siegmund62 were excluded, because they were either atypical or hacked sufficient clinical data.

From 1939 to and including 1954 there appeared reports of at least 106 cases of dysadrenocorticism (44 boys and 62 girls). Some of the patients described by Mdl-gren6’ and by Zahn2G presumably also suffered from dysadrenocorticism, but the clinical data are so scant that the reports

had to be excluded. The present series also includes 5 cases from a personal

communi-cation by Baar64 in 1954 and 2 cases from

a personal communication by Prader6’ in 1954, and finally 3 cases of my own. Thus this series comprises a total of 135 patients,

viz., 57 boys and 78 girls. A summary of

the individual eases is given in Table I.

Occurrence in Siblings

Dysadrenocorticism was observed in 2

or more infants of the same sibship in 28

families. Among these the disease occurred in 2 siblings in 24 families, in 3 siblings in

3 families, and in 5 siblings in 1 family. Two patients (Cases 132 and 133) were identical twins. In 38 families

dysadreno-corticism was not present in the siblings of the patient, and in 20 cases the patient was

an only child. Information as to the oc-currenee in siblings is lacking in 31 cases.

Both or all affected siblings are included

ill the series provided that sufficient clinical and pathologic data is available. Two

sib-lings are included in 12 instances, and 3

siblings (Cases 4, 5, and 64; Cases 33, 34, and 97; Cases 45, 46, and 47) in 3 instances. Thus, the 135 children of the present series

were the offspring of 117 marriages. As mentioned previously, consanguinity was only reported in 1 case.24 In many re-ports it is stated that the parents were

healthy and that the pregnancy had been

uneventful. In at least 9 instances the mother had delivered a normal infant after

having given birth to a 82 86 on

fe-23 12, 46, 77, 92 infant with

dysadreno-corticism. Table II shows the occurrence of dysadrenocorticism in siblings relative to

the size of the sibships. It appears from the table that 66 patients had a total of 141

siblings, of whom 34 had

dysadrenocon-ticism, i.e., the incidence in siblings was 24 pen cent, which suggests a recessive

trans-mission.

The disorder seems to manifest itself without any relation to birth order. The

distribution of 111 cases of dysadrenocorti-cism according to birth order is compared

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F-C

z

13

‘I)

C z

13

CI)

C

‘I)

z

C

F-‘I) 13 1.

z

.3

z

-3

3’.

F-CI)

C,

‘f.

. IC

9

.‘IC

:;‘!‘-!!-1j!!!

;

-EE2E

PICICICIC

. 2

2 IC

IC

.

-2 IC

t’

C--C_.

E

No. of

(‘hsldren

. .

in Family

, . 0?

iamslzes

Total

Siblings

No. of Families with 2 to 5

Affected Children

S 4 )

Total

Affected

,.

Sibling.s’

l

3

4

.5

6 7

9

8 #{149} 7 -

- -

7

18 36 7 1 - - 9

11 33 4 1 - - 6

5 20 3 1 - - 5

‘ 10 1 - - I 5

1 6 I - - - I

1 8 I - --- - I

66 141 I (5 1 34

Total

TABLE III TABLE II

OccuuItExcE OF 1)YSADRENOCORTICISM IN SIBLINGS RELATIVE TO THE SIZE OF TIlE SIBs1IIs

Incidence and Sex Distribution

According to the literature congenital adnenocortical hyperplasia occurs more

fre-quently in females than in males. Thus,

Bratrud and ThompsonoO in 1943 were able

to collect 55 cases in females, but only 14 cases in males, and Bentinck et al.’#{176}9in 1952 disclosed among the siblings of 43 females with pseudohenmaphnoditism 40 cases of female pseudohenmaphroditism and 17 cases of virihism in males. On the other hand, judging from the reports, congenital adrenocortical hyperplasia is more

fre-quently associated with electrolyte dis-tunbance in male than in female infants. Thus, in Bratrud and Thompson’s series, electrolyte imbalance was present in 11 of 14 males, but only in 6 of 55 females, and

Bentinck et al. observed electrolyte im-balance in 9 of 17 males and in 20 of 83 females. Russell,110 in 1954, found

electro-lyte disorder in 26 of 38 males and in 45

of 115 females with congenital

adneno-genital syndrome. The higher incidence of adnenocortical hyperplasia among females

is, perhaps, only apparent, because the

greater tendency to electrolyte imbalance in males may result in a higher lethality in these during infancy where signs of viniliza-tion have not yet become manifest, so that the adrenocortical hyperplasia may escape

recognition as long as its clinical manifesta-tions are not commonly known.

For the reasons just mentioned the possi-bihities of recognition and description of

cases of dysadrenocorticism are greater in

females than in males, and therefore it cannot be expected that the sex distribution in the present series is in conformity with

the actual facts. Furthermore, it must be considered that the patients of the series were selected on the basis of the sufficiency of the recorded clinical data regardless of

sex. A more probable expression of the

actual sex distribution may be obtained by

determining the sex distribution of affected

I)IsTIuBu’rIoN OF DYSADIIENOCORTICISM ACCORDING TO BrnTII ORoEL! COMPARED WIT!! THAT OF UNAFFEcTED SIBLINGS

Birth Number 1 2 3 4 5 6 7 8 9 Total

17 17 6 6 3 (P (1 0 (1 49

19 ‘20 11 6 3 1 1 (1 1 (2

frtd boys Affected girls

Total

Non-affected siblings

36 37 17 1 6 1 1 0 1

45 24 16 7 3 3 1 1 0

111

50

45

40

35

30

25

20

15

10

5

::

GIRLS

-

BOYS

2 3 4 5 6 7

AGE IN WEEKS

FIG. 1. Age at onset of symptoms in 109 infants, 46 boys and 63 girls, with dysadrenocorticism. siblings of the patients. In 27 families, the

ratio of males to females among the next

younger child with the disease was 11:16,

and the distribution among 33 affected sib-lings of 25 older patients was 15 males and

18 females. These figures suggest that the

occurrence of dysadrenocorticism is slightly more frequent in females than in males.

In 11 families, the affected siblings were

of different sex. In 6 families, both, on all,

siblings were males, and in 10 families,

females.

Clinical Manifestations of Electrolyte

Disturbance

Initial symptoims. The first symptoms

were often refusal of feedings, failure to

thrive, apathy and hypotonicity. In 79 pa-tients (31 boys and 48 girls) the disease was

6/)

I-z

Li I-.

0

Li

m

z

60

55

885 ushered in by regurgitation or vomiting. The time of onset of initial symptoms was stated in 109 cases (46 boys and 63 girls). In 60 cases (44 per cent), symptoms began during the first week of life and in all cases before the age of 7 weeks. A more detailed survey is given in Figure 1.

Vomiting. Vomiting constituted a cardi-nal symptom and was present in 126 cases

(54 boys and 72 girls), i.e., 93 per cent. It often began as regurgitation after feedings, but in the course of a few weeks copious and frequent vomiting occurred both in

and without relation to the feedings. In 37 patients (18 boys and 19 girls), the

vomit-ing was projectile. Eight infants (Cases 8, 14, 15, 32, 40, 46, 111, and 114) were subjected to laparotomy because of

ob-StTUetiOIl. “The abdominal sear of the infant

Wilo continues to vomit after a pyloroplasty

may be a ‘badge of adrenal

insuffi-ciency.’ “7 Gastric peristalsis was observed

in 5OIT1 instances (Cases 17, 30, 31, 32, 36,

45, 47, and 74). Tile vomitus usually

con-sisted only of food, but was occasionally bilious (Cases 6, 10, 16, and 111), dankish brown (Case 45) or fecal (Cases 8 and 9).

The time of onset of vomiting was stated in

40

35

30

6/)

F-z 25

Li

F-Q. 20

0

15

Li

: 10

z

5

(Cases 41, 65, 72, 76, 81, 98, and 110) neither

vomiting nor diarrhea was mentioned. On

the other hand, some of the patients had

occasional constipation.

Crises. Eighty-eight patients (34 boys and

54 girls), i.e., 65 per cent, had episodes of circulatory collapse with cyanosis or pallor,

rapid irregular pulse, sweating, loss of

eon-sciousness and, sometimes, convulsions.

These crises might occur without any

ap-E GIRLS

-

BOYS

I 2 3 4 5

AGE IN WEEKS

6 7 11 12

FIG. 2. Age at onset of vomiting in 109 infants, 48 boys and 61 girls, with dysadrenocorticism.

109 instances (48 boys and 61 girls). In 36 (27 per cent) of these cases, the vomiting

began during the first week of life and in

tile remaining patients before the age of

7 weeks, save 1 (Case 52), who did not

vomit until the age of 11 weeks. More than

one-half of the infants began to vomit

be-fore tile age of 2 weeks, and in only 18

instances did vomiting start after the fourth week of life. A closer analysis is given in

Figure 2.

Diarrhea. Tills symptom was less

fre-(1ue11t tilan vomiting and was usually as-soeiated Witil a deterioration of the general coildition. A total of 45 Patients (22 boys and 23 girls), i.e., 33 per cent, had had

pen-ods of loose stools. Two of these (Cases 2

and 22) had not vomited. In 7 patients

parellt cause or ill association with infee-tions and lasted from a few minutes to half an hour. Sometimes they occurred daily,

and not infrequently led to death.

Failure to thrive and loss of weight. The

salt and water loss in association with de-creased food intake and vomiting resulted in failure to thrive and loss of weight. At

least 109 patients (49 boys and 60 girls), i.e., 81 per cent, lost weight during the first

few months after birth. The birth weight,

which was stated ill 81 instances, was

usually normal. In 77 instances tile weight at l)irth ranged froni 2,500 to 4,500 gIll.;

1 infant (Case 69) weighed 2,000 gm., and

3 (Cases 26, 68, and 95) weighed more

VOMI TING

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I-z

Lii

I-WEIGHT LOSS

DEHYDRATION EMACIATION

CRISES 130

I20

110

i#{244}o

90

80

70

60

50

40

30

20

10

E:J

GIRLS

-

BOYS

DIARRHEA

PIGMENTATION

887

FIG. 3. Incidence of clinical manifestations of dysadrenocorticism in 135 infants, 57 boys and 78 girls. the period from the third to eighth week

of life was stated. The weight loss within

that period was more than 500 gm. in 22

eases. Tile 2 greatest losses in weight were 1,600 gm. in 4 weeks (Case 8), and 1,450

gm. in 63 weeks (Case 58).

Dehydration and Emaciation. At the time

of admission to the hospital 123 infants (53 boys and 70 girls), i.e., 91 per cent, were emaciated and/or showed signs of dehydna-tion. In some of the reports a distinction is not made between these signs, but dehy-dration, often very pronounced, was stated in 93 patients (42 boys and 51 girls), and

emaciation in 90 patients (40 boys and

50 girls).

Pigmentation. A generalized bronzed

pignlentation of the skin was observed in

13 patients, or 10 per cent, 5 boys (Cases

5,

7, 11, 14, and 25) and 8 girls (Cases 67, 75, 94, 98, 110, 118, 122, and 127). In about

half of the eases the pigmentation was

accentuated on tile areolae and in a few

eases around the genitalia. In 1 patient

(Case 11) the pigmentations were situated

on tile gums. Pigmentation was observed

Li

0

‘Si

I

140 TOTAL SERIES.

within the first 2 months of life in 6

pa-tients; in 1 of them (Case 110) as early as the first day of life and in 2 (Cases 7 and 127) at the age of 1 to 2 weeks.

The frequency of the clinical mamfesta-tions in tile entire series is given in Figure 3.

Genital Changes

Boys. Enlargement of the penis

(macro-genitosomia praeeox) was present in 16 cases. It was noticed at birth in 1 (Case 11), at 1 to 2 months in 6 (Cases 7, 25, 28, 30, 37, and 41), at 6 months in 2 (Cases 12 and 16), and at 1 to 2 years in 4 (Cases 38, 44,

48, and 55). For 3 boys (Cases 27, 35, and

42), the time at which penile enlargement was first observed was not stated. That genital enlargement is melltiolled in only one-fourth of the boys is due to the fact that most of them died before the age at which these changes usually occur. In all

boys over 2 years of age the penis was

un-usually large.

Hypospadias (male

pseudohermaphrodit-ism) was observed in 6 boys (Cases 4, 5, 8,

Urea or non-protein nitrogen content of children was confirmed by the

demonstra-tion of testes only in 3 of these patients; the

testes were situated in the inguinal canal (Case 4), in the scrotum (Case 5) and in the abdomen (Case 49). In 2 patients (Cases 19 and 56), the orifice of the urethra was on the underside of the glans (juxtaglandulan hypospadias), while the remaining cases presented penineoscrotal hypospadias. All

these boys died during the first year of life.

In 2 patients, rapid growth of testes was observed. In 1 of them (Case 11) the heft testis began to grow rapidly in the second

year of life; when the patient died at the age of years, it weighed 30 gm. In the

second boy (Case 7) both testes began to grow rapidly at the age of 7 years. In both cases the testes contained tissue with a histologic composition which corresponded to that of the hyperplastic adrenal tissue. Similar histologic changes were also re-vealed in a third patient (Case 12), but his testes were not markedly enlarged. In the

remaining cases the testes were of normal size for the age.

In some of the boys pubic hair appeared

before the age of 2 years; in 2 (Cases 28 and 35) even as early as 4 to 5 months of age, in 1 (Case 12) at 9 months, and in 3

(Cases 11, 38, and 48) at 1 to 2 years.

GirLi. One girl (Case 73) had normal

external female genitalia at birth. In 1 girl74

prenatal vinihization was evidenced by en-largement of the clitoris, but separate unethral and vaginal orifices were present. In another girl (Case 125) a separate vagi-nal orifice was covered by synechia of the labia majora. At birth all the remaining girls presented signs of pseudohermaphroditism

with hypentrophy of the clitoris and a corn-mon urethral and vaginal orifice. In the most vinihized girls the clitoris was penis-like with

a well-developed glans, and the labia ma-jona were fused in the midline (enyptonchid

scrotum). In a few of these patients (Cases 58, 60, 124, 129, and 1 reported by Allibone

et al.7) the urethral orifice was situated on

or near the apex of the glans, so that the

children during life had been considered to

be boys with cryptonchism. However,

cropsy revealed female internal genitalia. Most frequently the urogenital orifice was situated at the base of the penis-like clitoris, and many of the children had at birth been

considered to be boys with hypospadias and cryptorchism. In the less masculinized cases the wrinkled, hypentrophic labia ma-jora formed a groove in the midline (bifid scrotum), and the orifice of the urogenital

sinus was often funnel-shaped and vagina-like, situated between the labia at a greater distance from the enlarged clitoris. The labia minona were poorly developed, most frequently marked only by fibrous urethral margins which extended from the under-side of the clitoris to the urogenital orifice. Pubic hair was noted in 1 patient (Case

116) at S to 4 months, in another (Case 95) at 9 months, and in a third (Case 101) at

15 months.

In both boys and girls who lived beyond

infancy and who had not received

corti-sone, progressive virilization, advanced growth and epiphyseal ossification were

observed. However, due to epiphyseal fu-sion, height growth ceased at the age of

7 to 10 years.

Laboratory Examinations

Electrolytes of blood. Prior to the

initia-tion of specific treatment, serum concen-tnations of sodium (or total base) and/or

potassium were studied in 44 patients (18 boys and 26 girls). In almost all these cases hyponatremia and hyperpotassemia were

observed. The concentration of serum so-dium ranged from 91 to 139 mEq./l. and was below 135 mEq./l. in 34 of 37 cases. In 3 cases reduced concentration of total base (hess than 145 mEq./l.) was disclosed. The serum potassium level ranged from 5.2 to 12.2 mEq./l and was above 5.8 mEq./l. in 31 of 36 cases. Hypochioremia (serum level less than 95 niEq./1.) was present in

Case i\o. Serum Na mEq./l. ‘ Sernm K mEq./l. Serum Cl mEq./l. Serum HCO3 mEq./l. Blood Urea/NPN mg./1tTX ml. Blood Sugar mg./Kklml. Urinary 17-KS 11 I2 16 17 25 ‘27 28 30 34 35 37 38 41 42 44 55 56 92 93 95 96 98 99 100 101 102 104 109 110 I 12 I 13 116 I 18 119 120 121 122 123 125 126 127 128 130 131 134 high 100 57 51 56 54 132 62 37 59 30 89 43 36 87 34 61 88 54 48 40 58 40 50 120 111 120 120 101 125 118 126 128 131 139 127 108 115 119 119 127 110* 137* 130 137 124 125 134 130 144* 132 134 132 120 116 130 133 131 126 I 14 139 91 130 130 normal 78 74 75 36 76 90 normal 75 61 65 72 90 normal normal 94 75 93 92 99 102 159 96 9.0 7.9 9.3 6.0 10.0 7.5 6.3 8.7 7.7 5.6 6.0 6.6 7.6 8.9 6.4 5,4 7.6 6.3 6.4 7.7 5.8 5.9 6.9 7.4 7.4 12.2 9.0 6.4 5.2 7.2 5.6 11.9 10.2 7.4 11.0 7.4 low 86 69 93 98 77 92 94 80 86 97 84 75 92 86 94 97 86 100 91 87 106 96 94 82 89 100 97 112 105 80 87 88 71 93 74 91 88 19 14 12 8 15 18 15 14 17 10 13 13 5 22 18 16 high

27.0 (3 yr.)

2.5

high

14.0

5.7

5.9 (16 mo.)

4,5

7.4

11 .0

18.0 (21 mo)

2.7

4.2

10.0 (15 mo.)

6.5 (l2 mo.)

16.0 4.1 2.5 8.0 8.0 13.8 8.1 2.4/100 ml. 6.0 5.1 8.6 3.5 4.2 3.5

6.0 (18 mo.)

7.4 4.4 1.8 103 46 2.0 43 2.5

21 110 16.2(lSmo.)

* Total base.

TABLE IV

the blood was increased in 21 of 28 cases (Table IV).

Blood sugar coilcentratioll determined

(luring fasting or crisis was found to be ne-duced (below 60 mg. pen 100 ml.) in only

1 (Case 28) of 24 cases (Table IV).

Eosinophil count. In 10 patients (Cases

30, 34, 41, 45, 46, 57, 95, 98, 127, and 134) the

eosinophils comprised more than 4 per cent of the total leukocyte count, while low or normal values were observed in 11 patients (Cases 11, 27, 28, 43, 47, 55, 93, 94, 96, 124, and 135). The few cases which were illvesti-gated usually showed a poor response of

tile eosmophils to administration of ACTH. Electrocardiograms. Electrocardiographic

changes of tile type frequently seen in

hy-perpotassernia were observed in most of

the examined patients (Cases 12, 16, 28, 33, 34, 35, 41, 48, 56, 102, 104, and 128), usually in the form of tall, pointed T-waves. One pa-tient (Case 127) had a normal

electnocandio-gram in spite of high serum concentration of potassium. Kyle and Knop8#{176}described

heft bundle-branch-block and partial auricu-loventnieular block (Case 33) and aunicular fibrillation with periods of complete block

(

Case 34). France and NeilP#{176}’found alter-nate auniculan extrasystoles (Case 104). Bernheim et al.#{176} observed left bundle-branch-block (Case 128).

The rates of excretion of sodium and

chloride in tile urine were studied in only

a few patients, and in all cases the values

were either normal or increased (Table V). The excretion of neutral 17-ketosteroids

in tile urine was markedly increased in all

cases examined. In 30 children the

exere-tion in 24 hours ranged from 1.8 mg. (Case 127) to 16 mg. (Case 95) during the first year of life. One patient (Case 7) excreted 200 mg. per 24 hours at the age of 7 years

(Table IV).

The excretion of li-oxycorticoids was

studied only in a minority of cases. In 4 of these (Cases 7, 37, 44, and 98), the rate of excretion was stated to be normal; in 4 (Cases 16, 42, 48, and 120) it was increased,

and in 1 (Case 34) decreased.

The excretion of estrogens was examined

TABLE V

FIFE CoN’ENTII.tTIoN ANI) RATE OF EXCRETION OF

(‘IlLoltInE IN TIlE IIFtINE IN INTONATE!)

I’ATIENTS VITU I)YSAI)RENO(’ORTI(’ISM

, (Trinarj, (‘hloride

(a.e .

V0 Age II eight mEq./i. ntEq./2i

. hr.

7 2 weeks 2.6 kg. 60

17 6 weeks 3,0 kg. 62

27 2 months 3.6 kg. 11

38 21 months I 117

102 2 weeks 3.1 kg. I 6

104 4wecks 113

105 ‘24 months 169

109 1week 3.5 kg. 82

in some of Wilkins’ patients and showed increased output.4’

Treatment

Fifty-four patients (21 boys and 33 girls) received specific treatment, usually with desoxyconticosterone acetate (DCA) and sodium chloride; in some cases adrenoconti-cal extract was given. The dosage of the various adnenocontical preparations

obvi-ously depended on the actual condition

of the patient, the clinical effects of the preparation and on concurrent

administra-tion of sodium chloride. In addition,

pan-entenal administration of fluid was

frequent-ly

employed. A brief survey of the treatment during the first few months after the diag-nosis had been made, is given here.

Treatment with DCA was instituted in 36 patients (14 boys and 22 girls). The ef-fective daily dose usually ranged from 2 to 5 mg. intramuscularly in combination with

2 to 5 gm. of sodium chloride given by

mouth. Adequate dosage resulted in cessa-tion of vomiting, weight gain and general

improvement, which often occurred quite dramatically in the course of a few days,

and the serum electrolytes shifted towards

normal values. When therapy was

with-drawn, the symptoms recurred.

DCA therapy was preceded by or sup-plemented with administration of

891 7, 16, 25, 28, 30, and 34; and 7 girls, Cases

98, 104, 109, 118, 119, 123, and 134). The

dosage varied within wide limits. In a few

cases lange doses were needed; thus, 1

patient (Case 30) had to be given as much

as 24 ml. of Eschatin#{174} and 2.5 to 6.0 mg. of DCA daily in order to obtain a weight

gain, and another (Case 16) received 16 ml. of Eschatin#{174} daily for 8 days, but a clinical effect was not obtained until a daily dose of 3 gIn. of sodium chloride was also

ad-ministered.

. Adnenocortical extract alone was used

in 4 patients (Cases 46, 92, 93, and 106) in small doses. Thus, 1 patient (Case 106) was given only 0.1 ml. of Eucorton#{174} and the remaining 3, 1 to 4 ml. intramuscularly daily.

One patient (Case 130) was treated with salt only.

Following stabilization of the condition 12 patients (6 boys, Cases 7, 25, 27, 30, 42, and 44; and 6 girls, Cases 95, 96, 102, 118,

120, and 122) had pellets of DCA, usually

in doses of 75 to 125 mg., implanted at

in-tervals of several months. After this pro-cedure, added salt given daily was

suffi-cient to maintain freedom from symptoms, and normal growth and development took place. If infections supervened, the salt

in-take and tile dosage of DCA usually had

to be increased.

Since 1950, several patients (Cases 28, 30, 35, 37, 38, 41, 42, 44, 48, 96, 102, 114, 117, 120, 121, 122, 122, 125, 127, 128, 132, 133, and 134) were also treated with cortisone in order to suppress the androgenic activity and to correct the electrolyte disturbance.

Course

The disease terminated fatally in all cases in which specific treatment was not given. Vomiting increased in severity, and

pro-gressive deterioration of the general

con-dition occurred, with asthenia, dehydration

and loss of weight. Crises with collapse

were occasionally encountered.

Sympto-matic treatment including parenteral

ad-ministration of fluid was only of temporary benefit. In most cases sudden and

unex-pected death occurred, sometimes in asso-ciation with crises and infections. Death

must be presumed to have been (liFe to

shock and hyperpotassemia coupled with dehydration and emaciation.

Of the 81 untreated infants (36 boys and

45

girls), one-fourth (21 patients) died with-in the first month of life, 4 of tilem (Cases

33, 54, 79, and 115) at the age of 6 to 10

days. Thirty-two patients died within the

second month, and 23 within the third to sixth months of life. In a few eases, the course was more prolonged and less severe. Thus, 4 patients (Cases 2, 49, 94, and 105) died at the age of 7 to 12 months. The pa-tient reported by Wilkins et al.#{176}(Case 11)

forms an exception; he survived for 3% years, presumably due to the high intake of salt. The ages at death of the children who did not receive specific treatment appear in Fig-ure 4.

Of the 54 patients (21 boys and 33 girls) who received specific treatment, 19 had died at the time when the reports were published. Of these, 13 patients (4 boys and 9 girls) died before the age of 6 montils,

but in some of these cases treatment had been given only for a short period or had been inadequate. DCA had been

with-drawn for 2 weeks in 1 patient (Case 57) and for 4 to 5 days in 2 patients (Cases 17 and 104). The doses of adrenocortical ex-tract administered in Cases 92, 93, and 106 were presumably inadequate. One patient (Case 34) died after a “mild sunburn.” In 1 of the patients (Case 128) the course was peracute, and histologic examination of the heart showed severe myocardial

changes. In the remaining 5 patients death occurred in association with pneumonia (Cases 14, 98, 119, and 129) or otitis media

(Case 126). One of the patients, a girl (Case 98), was subjected to 2-stage adnenalectomy at the age of 45 months. Following surgi-cal intervention the clinical condition was satisfactory, but death ensued 1 month after the last operation. In 6 children (3

boys and 3 girls) the ages at death ranged from 6 months to 3% years. The oldest

treat-ment smce 6 months of age. One patient

(

Case 1 10) received inadequate treatment after discharge, and another (Case 116) refused salt intake owing to eruption of

teeth. In 2 (Cases 46 and 75), death oc-cured in association with pneumonia and in 1 (Case 56) following otitis media.

Thus, 35 patients (14 boys and 21 girls)

were alive at the time when the reports

35

30

25

6/)

F-z

Li

F-

a-

U-0 15

Lii

I

z

5

and added salt at the age of 12 months (1950). Tile second patient was 2 years old at discharge in 1949. At that time the con-dition was excellent, being maintained by

added salt.

Six children, 5 boys (Cases 12, 16, 25, 27,

and 41) and 1 girl (Case 101) died during the follow-up period. Following asthenia and dehydration of sudden onset, the

pa-::

GIRLS

-

BOYS

I 2 3 4 5 6 7 8 9 10

AGE IN MONTHS

11 12 13 43 44

FIG. 4. Age at death in 81 patients, 36 boys and 45 girls, who did not receive specific treatment.

were published. Eight of these children

(1 boy and 7 girls), aged 4 months to 2

years, were reported in 1953 and 1954, and

at that time all still needed specific treat-ment of the electrolyte disorder.

Through the courtesy of the various

au-thors, I succeeded in 1954 in obtaining

in-formation as to the further course and

treat-ment of 25 of the 27 children who were reported before 1953. It was impossible to

trace Mazursky and Sawan’s98 patient (Case 99) and 1 of Panos’99 patients (Case 100). The first of these was still given DCA

tient described by Werner (Case 41) died at

the age of 18 months. He had received

DCA and cortisone, and the condition had l)een satisfactory until the time of death.

Signs of precocious sexual development

had disappeared. The patient described by

Carlgren (Case 27) died suddenly following an insulin tolerance test at the age of 2

years. Throughout the period of treatment he had received DCA and sodium chloride.

pa-REVIEW ARTICLE

tients reported by Panos (Case 101) died at

the age of about 3 years following acute diarrhea. The condition of the child had been excellent under treatment with added

salt. According to Canigren,” the patient reported by Darrow (Case 16) died at the age of about 5 years. The cause of death

was stated to be largely cardiac, and

nec-ropsy revealed enlargement of the heart

and adrenals. The boy described by Chenoweth (Case 25) was well for 2 years without treatment, but sudden death oc-curred in the course of a venipuncture at

the age of 5 years. Sexual precocity was

present, and the bone age was 8 years. The

adrenals were huge and showed hyper-plasia of all cortical elements. In 1946

Thelander68 reported that the patient (Case 12) she had reported previously had died at the age of 6 years following an attack of measles. He had been treated with DCA continuously. The combined weight of the adrenals was 74 gm.

Thus, a total of 19 patients (8 boys and 11 girls) were alive at the follow-up ex-amination in 1954. The ages of the

surviv-ing boys ranged from 3 to 16 years and of the surviving girls from 3 to 7 years. Five

boys and 5 girls were 5 years of age or

older.

In 12 patients (7 boys and 5 girls), of whom 5 were 5 years or olden, specific

treatment of the electrolyte disorder was

still required. The patient reported by Butler

et al. (Case 7), aged 16 years, was well. He was receiving 3 to 6 gm. of sodium chloride added to his diet daily, and 1 or 2 pellets of DCA (75 mg. each) were implanted at

inter-vals of about 8 to 10 months. The patient described by Tepper (Case 28), aged 5%

years, was given DCA and added salt until

the age of 3 years. At that time cortisone

therapy and a diet liberal in salt were initi-ated. The daily dose of cortisone, varying between 37.5 and 100 mg., was adequate

to control the electrolyte imbalance and to suppress the 17-ketosteroids, except at times of infection, when DCA in quite large

doses was needed in addition. At the age of

5 months, he exhibited signs of viilism for

the first time, and in the following year rapid increase in signs of vinihism was noted.

Since that time there has been no regres-sion. The 6%-year-old boy whose case was

reported by Jailer et al. (Case 44) was do-ing extremely well. He was receiving 10 mg. of hydrocortisone daily and had had pellets of DCA implanted. At 5 years all therapy was stopped, following which an adrenal crisis ensued. All patients described by Wilkins were doing exceedingly well. The 3 girls (Cases 120, 121, and 122) were given

8.3 to 12.5 mg. of cortisone intramuscularly and 3 to 5 gm. of sodium chloride daily,

and the boy (Case 42) received 75 mg. of cortisone orally and 5 gm. of sodium chlon-ide daily. It had not been necessary to

re-new the implantation of pellets. The pa-tients had had no more salt-losing crises in spite of having had the usual childhood

diseases. Their growth and osseous develop-ment had been approximately normal. No sexual hair had appeared, and there had

been no progress of vinihization or change in genitalia. Wilkins et al.16 recently published their experiences. The patients described

by

Knudson (Cases 35, 37, 38, 114, and 117) were also under treatment with cortisone

and had small amounts of salt added to their diets. On this regimen they had

pro-gressed well. Each was larger than the

mean for his age and each demonstrated distinct vinihism.

In the remaining 7 children, age 3 to 11

years (one boy, Case 30; and 6 girls, Cases 95, 96, 102, 109, 118, and 123), specific treatment with added salt and DCA was no longer required, and the condition was

satisfactory. In at least 2 of the patients (Cases 102, and 123), therapy was with-drawn as early as the age of 12 months. The parents of one of the patients de-scribed by Prader (Case 102) ceased to give extra salt without ensuing harmful effects, and refused continued administration of

cortisone because they considered the child a boy. However, 3 patients (Cases 30, 96, and 123) were given cortisone to suppress

Lii

I

z

15

10

5

FIG. 5. Distribution of the weight of the adrenals

in 64 patients who died before 12 months of age

because of dysadrenocorticism.

A diagnosis of dysadnenoeonticism should

-

_____

-

____

. be considered in the infant with a history

10 15 20 25 30 35 of apathy and hypotonicity, refusal of

G R AM S feedings and failure to thrive, dehydration

and persistent vomiting, possibly associated with periods of circulatory collapse,

sweat-ing, cyanosis, and disturbances in cardiac regulation has been corrected by this

treat-ment alone. In 2 of the girls (Cases 95 and 96), unethroplasty was performed about the age of 3 years, and they were raised

as boys. In 1 of the patients (Case 118),

the clitoris was amputated.

Pathology

Adrenals. In 100 of the 106 patients who died, the adrenals were described. In all

eases except 2, both adrenals showed diffuse

enlargement. The surface was markedly

convoluted so as to resemble the surface

of the brain. On the cut surface the greyish yellow or reddish brown adrenal cortex, which was increased in width, contrasted with the dank medulla. The adrenals

usu-ally measured 4 to 5 by 3 to 4 by 2 to 3 cm. and were occasionally larger than the

kid-neys. In 64 patients who died before the

age of 12 months the combined weight of

the two adrenals ranged from 11 gm. (Case

94) to 34 gIn. (Case 73). In 24 of these

pa-tients the total weight exceeded 20 gm. A

record of the distribution of the weight of

the adrenals appears in Figure 5. In 1 of

tile 2 patients (Cases 33 and 34) in whom

the adrenals were of normal size, histologic examination revealed cortical hyperplasia. In tile patient described by Werner (Case 41), who had been treated with cortisone

25

20

for about 1 year, the adrenals were only

moderately enlarged (total weight 9.9 gm.)

The histologic picture of the adrenal cortex was variable. Many

investiga-tons69’ 102 found hyperplasia of the fetal

cortex or of the zona reticularis, while

4, 17 observed hyperplasia of the

zona faseiculata. In many but not all eases the zona glomerulosa was narrow and

poorly developed. In the aforementioned patient treated with cortisone (Case 41),

the zona glomerulosa was increased in

width, while the faseiculata was distinct

and the reticulanis ill-defined.

Testes. As mentioned before, the testes in a few patients (Cases 7, 11, and 12) eon-tamed a tissue similar to that of the

hy-perplastie adrenals.

Pituitary. Nine of twelve patients (Cases

11, 75, 92, 93, 94, 104, 105, 135, and 1 of

the cases of Allibone et a!.) revealed a

definite on possible increase in basophihic cells or, in agreement with studies of Mell-gnen#{176}3 an increased number of hyaline basophilic cells and large cells with foamy cytoplasm and large nuclei.

Other organs. No consistent changes in

other organs were reported. In a few eases histologic changes in the myocardium were

revealed (Cases 34, 126, and 128). Atrophy of the thymus was reported in some eases. Calcium deposits in the tubules of the

kidneys were mentioned in 1 (Case 105).

Hypertrophie pylorie stenosis was never

encountered. The following congenital mal-formations were described : multiple

nan-rowings of the colon (Case 2); anomaly of

the mesentery (Case 74); interventricular

septal defect (Case 4i3); dextrocardia and

meningocele (Case 72), and horseshoe

kid-ney (Case 68).