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Congenital adrenal hyperplasia with defect in electrolyte metabolism
T h e J o u r n a l of P E D I A T R I C S
69
Congenital adrenal byperplasia with defect in electrolyte metabolism Observations before the onset of symptoms
Five infants with "'salt losing" congenital adrenal hyperplasia were treated prior to the onset of symptoms of electrolyte imbalance. All were females with genital defects and all had elevated excretion of both 17-ketosteroids and pregnanetrlol. There were observed from birth and the other two were first seen at 4 and 9 days of age, respectively. Hyperkalemia was found in all patients before the onset of symptoms and was the first evidence that an abnormality of electrolyte homeostasis existed. Maximum serum potassium values ranged from 6.8 to 12.5 mEq. per liter prior to therapy. Serum sodium determinations and urinary sodium-potassium ratios were not helpful in establishing an early diagnosis. The signs and symptoms of adrenal insufficiency were prevented by early therapy. Serum potassium concentration fell from the very high initial values; however, mild to moderate hyperkalemia persisted for 2 to 3 months despite therapy zoith cortisone, desoxycortieosterone, and added salt.
L. Leighton Hill, M.D.,* Curtis M. Johnson, M.D., William T. Dobbins, M.D., and George W. Clayton, M.D. HOUSTON~
TEXAS
C o N G-E N I T A g adrenal hyperplasia with disturbance in electrolyte metabolism has been recognized for some time and its manifestations and treatment, well documented. Although the etiology of the defect in electrolyte metabolism remains obscure, it is From the Department of Pediatrics, Baylor University College of Medicine, and the Junior League Clinic, Texas Children's Hospital, Houston, Texas. Supported in part by United States Public Health Grant A-3536. "• Department o] Pediatrics, Baylor Universit~ College o[" Medidne, Texas Medical Center, Houston, Texas.
thought to represent a more complete defect in C~1 hydroxylation of 17-hydroxycorticosterone and aldosterone than in the patient with simple virilism. 1 Past reports for the most part have dealt with the clinical and laboratory findings at the onset of symptoms of electrolyte imbalance?, 3 To our knowledge, studies on infants with this condition prior to the onset of clinical manifestations have not been reported. We have been interested in determining if biochemical changes could be detected and diagnosis of electrolyte defect could be made before the onset of clinical symptomatotogy.
70
January 1963
Hill et al
SERUM
POTASSIUM
mEq./L.
the onset of overt symptoms. This study deals with observations made on these five patients, the criteria for making the diagnosis of electrolyte defect, and the results of therapy.
M.I.
M E T H O D S AND M A T E R I A L S
SERUM SOD,UM ;~Eq/L 160 140
9 , 9 ,
"
.'B . , .
" ".'
"
,,
9 .. 9
9
~\~'\\%'~~~\\\\\\\%'\\\\\\\~ 9
' ~~I
120~-
9
9
9
SODIUM
CHLORIDE
CORTISONE o
9 ,
4
12
~
G R A M S PER DAY
25 Mg.
16
28 3E OF LIFE
DAY
0
48
52
60
Fig. 1 In this clinic, 45 patients with congenital adrenal hyperplasia have been observed over the past 6 years. Twenty-three of these patients were of the "salt-losing" type. We have had the opportunity to observe 5 of this group of 23 and to institute therapy prior to 14
SERUM POTASSIUM
rr, E q / L .
P.O.
12
All of the patients were females and exhibited genital defects. Three were observed from birth and two were admitted at 4 and 9 days of age, respectively. One of the patients (G. H.) had an older sibling with congenital adrenal hyperplasia who had exhibited severe electrolyte disturbance. Another (L. C.) had an older sibling who died at 3 weeks of age and had dehydration and vomiting. Three of the infants had no prior history of the condition and two (P. B. and 1V[. I.) had other siblings who were normal. Buccal smears were obtained on all. Twenty-four hour urine collections for sodium and potassium determinations were obtained by the use of a metabolic bed. Serum sodium and potassium determinations were carried out at least once daily. Urinary 17-ketosteroids were determined by the method of Callow, Callow, and Emmens. 4 The normal values for newborn infants in this laboratory is less than 0.5 mg. when the samples are read in the Beckman D U spectrophotometer and the Allen correction factor applied? Determination of urinary pregnanetriol was carried out by the method of Bongiovanni and Clayton. G RESULTS
leO/r 160
lEO
SERUM
b
SODIUM
SODIUM
DOCA 'zf
mEq./L.
CHLORIDE
M g J DAY
G R A M S PER DAY
;- OOCA
~
o -
PELLETS
CORTISONE
O
4
0
MQ.
12
40 DAY
Fig. 2
25
OF
LIFE
44
Corticosteroid studies. All of the patients had elevated 24 hour excretion of both 17ketocorticosteroids and pregnanetriol. The initial 17-ketocorticosteroid excretions ranged from 0.7 mg. per 24 hours to 4.3 mg. per 24 hours. One patient's (J. H.) excretion of 17ketocorticosteroids rose from 0,9 mg. per 24 hours to 4.0 mg. per 24 hours over a 4 day period prior to cortisone therapy. The values decreased to normal after cortisone therapy was begun. Determinations of pregnanetriol were made for diagnostic purposes and changes in urinary excretion
Volume 62 Number 1
following the institution of therapy were not followed. Metabolic studies. Serum sodium and potassium concentrations and the therapy employed for each patient are shown in Figs. 1 through 5. Hyperkalemia was present in all patients prior to the onset of clinical symptoms and constituted the first evidence that an abnormality of electrolyte homeostasis existed. T h e m a x i m u m serum potassium values prior to therapy ranged from 6.8 to 12.5 mEq. per liter. The patient (P. B.) with the lowest value (6.8 mEq. per liter) subsequently had 5 serum potassium values in excess of 7.0 mEq. per liter. Initial response to therapy was usually characterized by a fall from very high serum potassium levels to lower but still abnormal values. Subsequent response was not dramatic; in fact, none of the infants had consistently normal potassium levels after as long as 1 to 2 months of therapy. Despite the persistence of hyperkalemia, the only symptomatic infant in this group was M. I., and her course was complicated by aspiration pneumonia, gastroenteritis, and hypernatremia. In general hyponatremia was not as consistent or severe as hyperkalemia and was of little use as an early diagnostic aid. Two of the patients had serum sodium levels of less than 130 mEq. per liter at some time during the period of observation, but even in these patients the majority of values were above this level. Two of the infants developed hypernatremia while on therapy, one who received added salt and one who did not. Patient M. I. who developed severe hypernatremia (up to 178 mEq. per liter) received large doses of desoxycorticosterone (subcutaneous pellets and intramuscularly) in an attempt to lower the serum potassium concentration. There was no perceptible edema in either of these patients. Urinary sodium-potassium ratios ranged from 0.9 to 3.1 prior to treatment and rose markedly in 4 of the 5 patients with therapy. T h e 4 patients who experienced a rise were given salt in addition to that in their diet. One patient (J. H.) who did-not receive additional salt experienced a drop in the
Adrenal hyperplasia
O.E.
SERUM POTASSIUM mEq./L.
180l160
tzo
71
SERUM SODIUM mEq./L.
k
"
*
*
SODIUM CHLORIDE GRAMS PER DAY
oF
CORTISONE 25 Mg. ,
,
o
, 8
4
, I,I
IZ
I(3
I,I
I,I
I,I
I,I
I,I
I,I
I,I
I,I
I,
20 24 28 32 36 40 44 46 52 56 60 DAY OFLiFE
Fig. 3 L.A.C. 11II21
SERUM,...o P O T A S S I U M
mEq./L.
0
1 8 o |r
SERUM
SODIUM
mEq./L.
[6o
SODIUM
DOCA
CHLORIDE
Ma.
GRAMS PER DAY
/ DAY
~OCA PELLETS
CORTISONE .
O
Fig. 4
.
.
4
.
8
25
I,II, 12 16 ZO 24 DAY OF L I F E
Mg.
I ,I 2:O 3 :>
, 36
, 40
72
January 1963
Hill et al
14
rag. initially, to as much as 4.0 rag. per day; however, the average daily dose was 2.0 rag. Eventually desoxycorticosterone pellets were implanted. Four to 8 Gin. of salt were added to the daily formula of each child with the exception of J. H. who was treated with desoxycorticosterone and cortisone only. After the implantation of pellets, the added salt was gradually withdrawn from the diet.
J.H.
IZ I
SERUM POTASSIUM mEq./L.
IO L
sL
Oo,
18o r 160
SERUM SODIUM
t
DISCUSSION
mEq./L.
~
DOrA
Mn / D&Y OCA PELLETS
CORTISONE ,
,
0
4
II 8
12
16
E5Mg.
l,
I,
20
24
I,I 28
I
,
,
32
36
40
DAY OF LIFE
Fig. 5
ratio to below pretreatment levels. Measurements of fluid intake, urinary output, and total 24 hour sodium excretion and twice daily body weights revealed no evidence of sodium diuresis in these patients prior to therapy. Electrocardiographic studies. Electrocardiograms were done on each patient prior to therapy. Although the serum potassium was markedly elevated in each instance, there was no evidence of a hyperkalemic effect on the electrocardiogram. TREATMENT T h e r a p y was essentially the same as outlined by WilkinsY Each patient received 25 rag. of cortisone acetate intramuscularly daily for 7 days, the dose was then reduced gradually to 25 rag. every third day. All of the patients received desoxycorticosterone, intramuscularly, in doses ranging from 0.5
The studies on these patients revealed that hyperkalemia appeared within the first few days of life and preceded the onset of clinical symptoms and sodium diuresis. Reports concerning electrolyte levels in the early newborn period in normal infants have been numerous and conflicting. Overman, and his colleagues 8 reported a mean plasma potassium of 4.4 mEq. per liter with a range of 3.5 to 5.6 mEq. per liter in normal newborn infants during the first 4 days of life. During the first month of life these authors found a mean value of 5.0 mEq. per liter with a range of 4.1 to 5.3 mEq. per liter. Elkington and Danowski ~ recorded a mean level of 5.9 mEq. per liter with a standard deviation of _+1.4 mEq. per liter in infants from birth to 6 weeks of age. Pincus and his associates 1~ found a mean value of 5.4 mEq. per liter with a standard deviation of _+0.7 mEq. per liter in term infants on the first day of life. In our patients the serum potassium concentrations were invariably higher than those listed for normal infants. It is suggested that in infants with adrenal hyperplasia, this finding is diagnostic of a defect in electrolyte metabolism; however, patients have been observed in this clinic, as well as others, in whom the onset of clinical and chemical evidence of an electrolyte disturbance was delayed. It Therefore, the finding of normal levels of potassium cannot definitely exclude an abnormality in electrolyte metabolism. Of considerable interest was the lack of electrocardiographic evidence of hyperkalemia in these patients. Inconsistent electrocardiographic evidence of hyperkalemia has
Volume 62 Nuraber 1
Adrenal hyperplasia
been n o t e d previously in o l d e r infants, and it is t h o u g h t t h a t a n o r m a l e l e c t r o c a r d i o g r a m does n o t rule out the possibility of h y p e r kalemia. T h e r a p y consisted of cortisone acetate, desoxycorticosterone; a n d in 4 of the 5 p a tients, a d d e d sodium chloride. T r e a t m e n t resulted in lowering of the s e r u m potassium, b u t in no instance was there an i m m e d i a t e r e t u r n to n o r m a l a n d usually there was a persistent elevation until 2 to 3 months of age. T h e persistent m i l d to m o d e r a t e h y p e r k a l e m i a d i d not seem to be influenced by the a d d i t i o n of salt or the a d m i n i s t r a t i o n of desoxycorticosterone. T h e failure of the latter to reduce the serum potassium to n o r m a l in these y o u n g infants c a n n o t be explained a l t h o u g h renal unresponsiveness to salt-ret a i n i n g hormones m a y h a v e been a f a c t o r ? 2 T w o of the infants developed h y p e r n a t r e m i a while receiving the drug; however, none of t h e m h a d detectable edema. I n view of the occasional occurrence of h y p e r n a t r e m i a a n d the failure of large a m o u n t s of desoxycorticosterone to lower serum p o t a s s i u m levels to n o r m a l , it is assumed t h a t doses of desoxycorticosterone in excess of 2 rag. p e r d a y should n o t be employed. SUMMARY
AND
CONCLUSIONS
F i v e infants w i t h a d r e n a l h y p e r p l a s i a of the "salt-losing" t y p e have been studied p r i o r to the onset of a d r e n a l insufficiency. I n these infants h y p e r k a l e m i a was detected w i t h i n the first few days of life a n d p r e c e d e d t h e a p p e a r a n c e of clinical s y m p t o m s a n d sodium diuresis. I t is suggested t h a t persistent elevation of serum p o t a s s i u m concent r a t i o n in an infant w i t h congenital a d r e n a l h y p e r p l a s i a is diagnostic of a defect in electrolyte m e t a b o l i s m a n d t h a t a p p r o p r i a t e t h e r a p y , if b e g u n early, should p r e v e n t the
73
occurrence of signs of a d r e n a l insufficiency in m o s t instances. REFERENCES
1. Bongiovanni, A. M., and Eberlein, W. R.: Defective steroidal biogenesis in congenital adrenal hyperplasia, Pediatrics 21: 661, 1958. 2. Inverson, T.: Congenital adrenogenital hyperplasia with disturbed electrolyte regulation; dysadrenocorticism, Pediatrics 16: 875, 1955. 3. Scherz, R. G., and Geppert, L. J.: Recognition and treatment of adrenal crises in the newborn infant, J. PEDIAT. 53: 64-5, 1958. 4. Callow, N. H., Callow, R. K., and Emmens, C. W.: Colorimetric determination of substances containing grouping-CH2CO- in urine extracts as an indication of androgen content, Biochem. J. 32: 1312, 1938. 5. Allen, W. M.: A simple method for analyzing complicated absorption curves, of use in the colorimetric determination of urinary steroids, J. Clin. Endocrinol. 10: 71, 1950. 6. Bongiovanni, A. M., Clayton, G. W., Jr.: A simplified method for the routine determination of pregnandiol and pregnantriol in urine, Bull. Johns Hopkins Hosp. 94: 180, 1954. 7. Wilkins, L.: The diagnosis and treatment of endocrine disorders in childhood and adolescence, ed. 2, Springfield, Ill., 1957, Charles C Thomas, Publisher. 8. Overman, R. R., Etteldorf, J. N., Bass, A. C., and Horn, G. B.: Plasma and erythrocyte chemistry of the normal infant from birth to two years of age, Pediatrics 7: '565, 1951. 9. Elkington, J. B., and Danowski, T. S.: The body fluids, Baltimore, Md., 1955, The Williams & Wilkins Company. 10. Pincus, J. B., Gittleman, I, F., Saito, M., and Sobel, A. E.: A study of plasma values of sodium, potassium, chloride, carbon dioxide~ carbon dioxide tension, sugar, urea, and the protein base-binding power, pH and hematocrit in prematures on the first day of life, Pediatrics 18: 39, 1956. 11. Cara, J., and Gardner, L. I.: Two new subvariants of virilizing adrenal hyperplasia, J. PEDIAT. 57: 461, 1960. 12. Leboef, G., Steiker, D. D., Bongiovanni, A. M., and Eberlein, W. R.: Renal unresponsiveness to salt retaining hormones in infancy, Abstract No. 33, Progr. Forty-third meeting of the Endocrine Society, June 1961, New York, N. Y., Endocrine Society (abst. 33).
69
Congenital adrenal byperplasia with defect in electrolyte metabolism Observations before the onset of symptoms
Five infants with "'salt losing" congenital adrenal hyperplasia were treated prior to the onset of symptoms of electrolyte imbalance. All were females with genital defects and all had elevated excretion of both 17-ketosteroids and pregnanetrlol. There were observed from birth and the other two were first seen at 4 and 9 days of age, respectively. Hyperkalemia was found in all patients before the onset of symptoms and was the first evidence that an abnormality of electrolyte homeostasis existed. Maximum serum potassium values ranged from 6.8 to 12.5 mEq. per liter prior to therapy. Serum sodium determinations and urinary sodium-potassium ratios were not helpful in establishing an early diagnosis. The signs and symptoms of adrenal insufficiency were prevented by early therapy. Serum potassium concentration fell from the very high initial values; however, mild to moderate hyperkalemia persisted for 2 to 3 months despite therapy zoith cortisone, desoxycortieosterone, and added salt.
L. Leighton Hill, M.D.,* Curtis M. Johnson, M.D., William T. Dobbins, M.D., and George W. Clayton, M.D. HOUSTON~
TEXAS
C o N G-E N I T A g adrenal hyperplasia with disturbance in electrolyte metabolism has been recognized for some time and its manifestations and treatment, well documented. Although the etiology of the defect in electrolyte metabolism remains obscure, it is From the Department of Pediatrics, Baylor University College of Medicine, and the Junior League Clinic, Texas Children's Hospital, Houston, Texas. Supported in part by United States Public Health Grant A-3536. "• Department o] Pediatrics, Baylor Universit~ College o[" Medidne, Texas Medical Center, Houston, Texas.
thought to represent a more complete defect in C~1 hydroxylation of 17-hydroxycorticosterone and aldosterone than in the patient with simple virilism. 1 Past reports for the most part have dealt with the clinical and laboratory findings at the onset of symptoms of electrolyte imbalance?, 3 To our knowledge, studies on infants with this condition prior to the onset of clinical manifestations have not been reported. We have been interested in determining if biochemical changes could be detected and diagnosis of electrolyte defect could be made before the onset of clinical symptomatotogy.
70
January 1963
Hill et al
SERUM
POTASSIUM
mEq./L.
the onset of overt symptoms. This study deals with observations made on these five patients, the criteria for making the diagnosis of electrolyte defect, and the results of therapy.
M.I.
M E T H O D S AND M A T E R I A L S
SERUM SOD,UM ;~Eq/L 160 140
9 , 9 ,
"
.'B . , .
" ".'
"
,,
9 .. 9
9
~\~'\\%'~~~\\\\\\\%'\\\\\\\~ 9
' ~~I
120~-
9
9
9
SODIUM
CHLORIDE
CORTISONE o
9 ,
4
12
~
G R A M S PER DAY
25 Mg.
16
28 3E OF LIFE
DAY
0
48
52
60
Fig. 1 In this clinic, 45 patients with congenital adrenal hyperplasia have been observed over the past 6 years. Twenty-three of these patients were of the "salt-losing" type. We have had the opportunity to observe 5 of this group of 23 and to institute therapy prior to 14
SERUM POTASSIUM
rr, E q / L .
P.O.
12
All of the patients were females and exhibited genital defects. Three were observed from birth and two were admitted at 4 and 9 days of age, respectively. One of the patients (G. H.) had an older sibling with congenital adrenal hyperplasia who had exhibited severe electrolyte disturbance. Another (L. C.) had an older sibling who died at 3 weeks of age and had dehydration and vomiting. Three of the infants had no prior history of the condition and two (P. B. and 1V[. I.) had other siblings who were normal. Buccal smears were obtained on all. Twenty-four hour urine collections for sodium and potassium determinations were obtained by the use of a metabolic bed. Serum sodium and potassium determinations were carried out at least once daily. Urinary 17-ketosteroids were determined by the method of Callow, Callow, and Emmens. 4 The normal values for newborn infants in this laboratory is less than 0.5 mg. when the samples are read in the Beckman D U spectrophotometer and the Allen correction factor applied? Determination of urinary pregnanetriol was carried out by the method of Bongiovanni and Clayton. G RESULTS
leO/r 160
lEO
SERUM
b
SODIUM
SODIUM
DOCA 'zf
mEq./L.
CHLORIDE
M g J DAY
G R A M S PER DAY
;- OOCA
~
o -
PELLETS
CORTISONE
O
4
0
MQ.
12
40 DAY
Fig. 2
25
OF
LIFE
44
Corticosteroid studies. All of the patients had elevated 24 hour excretion of both 17ketocorticosteroids and pregnanetriol. The initial 17-ketocorticosteroid excretions ranged from 0.7 mg. per 24 hours to 4.3 mg. per 24 hours. One patient's (J. H.) excretion of 17ketocorticosteroids rose from 0,9 mg. per 24 hours to 4.0 mg. per 24 hours over a 4 day period prior to cortisone therapy. The values decreased to normal after cortisone therapy was begun. Determinations of pregnanetriol were made for diagnostic purposes and changes in urinary excretion
Volume 62 Number 1
following the institution of therapy were not followed. Metabolic studies. Serum sodium and potassium concentrations and the therapy employed for each patient are shown in Figs. 1 through 5. Hyperkalemia was present in all patients prior to the onset of clinical symptoms and constituted the first evidence that an abnormality of electrolyte homeostasis existed. T h e m a x i m u m serum potassium values prior to therapy ranged from 6.8 to 12.5 mEq. per liter. The patient (P. B.) with the lowest value (6.8 mEq. per liter) subsequently had 5 serum potassium values in excess of 7.0 mEq. per liter. Initial response to therapy was usually characterized by a fall from very high serum potassium levels to lower but still abnormal values. Subsequent response was not dramatic; in fact, none of the infants had consistently normal potassium levels after as long as 1 to 2 months of therapy. Despite the persistence of hyperkalemia, the only symptomatic infant in this group was M. I., and her course was complicated by aspiration pneumonia, gastroenteritis, and hypernatremia. In general hyponatremia was not as consistent or severe as hyperkalemia and was of little use as an early diagnostic aid. Two of the patients had serum sodium levels of less than 130 mEq. per liter at some time during the period of observation, but even in these patients the majority of values were above this level. Two of the infants developed hypernatremia while on therapy, one who received added salt and one who did not. Patient M. I. who developed severe hypernatremia (up to 178 mEq. per liter) received large doses of desoxycorticosterone (subcutaneous pellets and intramuscularly) in an attempt to lower the serum potassium concentration. There was no perceptible edema in either of these patients. Urinary sodium-potassium ratios ranged from 0.9 to 3.1 prior to treatment and rose markedly in 4 of the 5 patients with therapy. T h e 4 patients who experienced a rise were given salt in addition to that in their diet. One patient (J. H.) who did-not receive additional salt experienced a drop in the
Adrenal hyperplasia
O.E.
SERUM POTASSIUM mEq./L.
180l160
tzo
71
SERUM SODIUM mEq./L.
k
"
*
*
SODIUM CHLORIDE GRAMS PER DAY
oF
CORTISONE 25 Mg. ,
,
o
, 8
4
, I,I
IZ
I(3
I,I
I,I
I,I
I,I
I,I
I,I
I,I
I,I
I,
20 24 28 32 36 40 44 46 52 56 60 DAY OFLiFE
Fig. 3 L.A.C. 11II21
SERUM,...o P O T A S S I U M
mEq./L.
0
1 8 o |r
SERUM
SODIUM
mEq./L.
[6o
SODIUM
DOCA
CHLORIDE
Ma.
GRAMS PER DAY
/ DAY
~OCA PELLETS
CORTISONE .
O
Fig. 4
.
.
4
.
8
25
I,II, 12 16 ZO 24 DAY OF L I F E
Mg.
I ,I 2:O 3 :>
, 36
, 40
72
January 1963
Hill et al
14
rag. initially, to as much as 4.0 rag. per day; however, the average daily dose was 2.0 rag. Eventually desoxycorticosterone pellets were implanted. Four to 8 Gin. of salt were added to the daily formula of each child with the exception of J. H. who was treated with desoxycorticosterone and cortisone only. After the implantation of pellets, the added salt was gradually withdrawn from the diet.
J.H.
IZ I
SERUM POTASSIUM mEq./L.
IO L
sL
Oo,
18o r 160
SERUM SODIUM
t
DISCUSSION
mEq./L.
~
DOrA
Mn / D&Y OCA PELLETS
CORTISONE ,
,
0
4
II 8
12
16
E5Mg.
l,
I,
20
24
I,I 28
I
,
,
32
36
40
DAY OF LIFE
Fig. 5
ratio to below pretreatment levels. Measurements of fluid intake, urinary output, and total 24 hour sodium excretion and twice daily body weights revealed no evidence of sodium diuresis in these patients prior to therapy. Electrocardiographic studies. Electrocardiograms were done on each patient prior to therapy. Although the serum potassium was markedly elevated in each instance, there was no evidence of a hyperkalemic effect on the electrocardiogram. TREATMENT T h e r a p y was essentially the same as outlined by WilkinsY Each patient received 25 rag. of cortisone acetate intramuscularly daily for 7 days, the dose was then reduced gradually to 25 rag. every third day. All of the patients received desoxycorticosterone, intramuscularly, in doses ranging from 0.5
The studies on these patients revealed that hyperkalemia appeared within the first few days of life and preceded the onset of clinical symptoms and sodium diuresis. Reports concerning electrolyte levels in the early newborn period in normal infants have been numerous and conflicting. Overman, and his colleagues 8 reported a mean plasma potassium of 4.4 mEq. per liter with a range of 3.5 to 5.6 mEq. per liter in normal newborn infants during the first 4 days of life. During the first month of life these authors found a mean value of 5.0 mEq. per liter with a range of 4.1 to 5.3 mEq. per liter. Elkington and Danowski ~ recorded a mean level of 5.9 mEq. per liter with a standard deviation of _+1.4 mEq. per liter in infants from birth to 6 weeks of age. Pincus and his associates 1~ found a mean value of 5.4 mEq. per liter with a standard deviation of _+0.7 mEq. per liter in term infants on the first day of life. In our patients the serum potassium concentrations were invariably higher than those listed for normal infants. It is suggested that in infants with adrenal hyperplasia, this finding is diagnostic of a defect in electrolyte metabolism; however, patients have been observed in this clinic, as well as others, in whom the onset of clinical and chemical evidence of an electrolyte disturbance was delayed. It Therefore, the finding of normal levels of potassium cannot definitely exclude an abnormality in electrolyte metabolism. Of considerable interest was the lack of electrocardiographic evidence of hyperkalemia in these patients. Inconsistent electrocardiographic evidence of hyperkalemia has
Volume 62 Nuraber 1
Adrenal hyperplasia
been n o t e d previously in o l d e r infants, and it is t h o u g h t t h a t a n o r m a l e l e c t r o c a r d i o g r a m does n o t rule out the possibility of h y p e r kalemia. T h e r a p y consisted of cortisone acetate, desoxycorticosterone; a n d in 4 of the 5 p a tients, a d d e d sodium chloride. T r e a t m e n t resulted in lowering of the s e r u m potassium, b u t in no instance was there an i m m e d i a t e r e t u r n to n o r m a l a n d usually there was a persistent elevation until 2 to 3 months of age. T h e persistent m i l d to m o d e r a t e h y p e r k a l e m i a d i d not seem to be influenced by the a d d i t i o n of salt or the a d m i n i s t r a t i o n of desoxycorticosterone. T h e failure of the latter to reduce the serum potassium to n o r m a l in these y o u n g infants c a n n o t be explained a l t h o u g h renal unresponsiveness to salt-ret a i n i n g hormones m a y h a v e been a f a c t o r ? 2 T w o of the infants developed h y p e r n a t r e m i a while receiving the drug; however, none of t h e m h a d detectable edema. I n view of the occasional occurrence of h y p e r n a t r e m i a a n d the failure of large a m o u n t s of desoxycorticosterone to lower serum p o t a s s i u m levels to n o r m a l , it is assumed t h a t doses of desoxycorticosterone in excess of 2 rag. p e r d a y should n o t be employed. SUMMARY
AND
CONCLUSIONS
F i v e infants w i t h a d r e n a l h y p e r p l a s i a of the "salt-losing" t y p e have been studied p r i o r to the onset of a d r e n a l insufficiency. I n these infants h y p e r k a l e m i a was detected w i t h i n the first few days of life a n d p r e c e d e d t h e a p p e a r a n c e of clinical s y m p t o m s a n d sodium diuresis. I t is suggested t h a t persistent elevation of serum p o t a s s i u m concent r a t i o n in an infant w i t h congenital a d r e n a l h y p e r p l a s i a is diagnostic of a defect in electrolyte m e t a b o l i s m a n d t h a t a p p r o p r i a t e t h e r a p y , if b e g u n early, should p r e v e n t the
73
occurrence of signs of a d r e n a l insufficiency in m o s t instances. REFERENCES
1. Bongiovanni, A. M., and Eberlein, W. R.: Defective steroidal biogenesis in congenital adrenal hyperplasia, Pediatrics 21: 661, 1958. 2. Inverson, T.: Congenital adrenogenital hyperplasia with disturbed electrolyte regulation; dysadrenocorticism, Pediatrics 16: 875, 1955. 3. Scherz, R. G., and Geppert, L. J.: Recognition and treatment of adrenal crises in the newborn infant, J. PEDIAT. 53: 64-5, 1958. 4. Callow, N. H., Callow, R. K., and Emmens, C. W.: Colorimetric determination of substances containing grouping-CH2CO- in urine extracts as an indication of androgen content, Biochem. J. 32: 1312, 1938. 5. Allen, W. M.: A simple method for analyzing complicated absorption curves, of use in the colorimetric determination of urinary steroids, J. Clin. Endocrinol. 10: 71, 1950. 6. Bongiovanni, A. M., Clayton, G. W., Jr.: A simplified method for the routine determination of pregnandiol and pregnantriol in urine, Bull. Johns Hopkins Hosp. 94: 180, 1954. 7. Wilkins, L.: The diagnosis and treatment of endocrine disorders in childhood and adolescence, ed. 2, Springfield, Ill., 1957, Charles C Thomas, Publisher. 8. Overman, R. R., Etteldorf, J. N., Bass, A. C., and Horn, G. B.: Plasma and erythrocyte chemistry of the normal infant from birth to two years of age, Pediatrics 7: '565, 1951. 9. Elkington, J. B., and Danowski, T. S.: The body fluids, Baltimore, Md., 1955, The Williams & Wilkins Company. 10. Pincus, J. B., Gittleman, I, F., Saito, M., and Sobel, A. E.: A study of plasma values of sodium, potassium, chloride, carbon dioxide~ carbon dioxide tension, sugar, urea, and the protein base-binding power, pH and hematocrit in prematures on the first day of life, Pediatrics 18: 39, 1956. 11. Cara, J., and Gardner, L. I.: Two new subvariants of virilizing adrenal hyperplasia, J. PEDIAT. 57: 461, 1960. 12. Leboef, G., Steiker, D. D., Bongiovanni, A. M., and Eberlein, W. R.: Renal unresponsiveness to salt retaining hormones in infancy, Abstract No. 33, Progr. Forty-third meeting of the Endocrine Society, June 1961, New York, N. Y., Endocrine Society (abst. 33).