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Prophylactic Adrenalectomy of a Three-Year-Old Girl with Congenital Adrenal Hyperplasia: Pre- and Postoperative Studies¹

Division of Pediatric Endocrinology (D.F.G., J.J.V.W.) and the Section of Pediatric Urology (T.P.B.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599; and the Institutes for Women and Child Health and Molecular Medicine, Karolinska Institute (E.M.R., A.W.), Stockholm, Sweden

Address all correspondence and requests for reprints to: Judson J. Van Wyk, M.D., Division of Pediatric Endocrinology, CB #7220, 509 Burnett-Womack, University of North Carolina, Chapel Hill, North Carolina 27599-7220.

	Abstract

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Long term follow-up studies of children with congenital adrenal hyperplasia have documented less than desirable outcomes, including reduction in final adult height, obesity, virilism, and decreased fertility. We have proposed that children with the most severe forms of congenital adrenal hyperplasia would be better off if their adrenals were removed at an early age. We report here on our experience with prophylactic bilateral adrenalectomy in a 3-yr-old girl with a double null mutation of the CYP21 gene. The results of sodium balance studies, performed preoperatively on our patient and her unaffected fraternal twin sister, and hormonal data are presented as well. In contrast to her twin, who markedly increased her sodium retention in response to ACTH, our patient showed increased natriuresis, suggesting a deleterious effect of her adrenals on sodium homeostasis. Adrenalectomy was carried out at the time of necessary genital repair. No surgical or postsurgical complications were encountered.

	Introduction

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THE MEDICAL treatment of congenital adrenal hyperplasia (CAH) has not been substantially altered since the introduction of cortisol in the early 1950s despite reports of less than optimal outcomes. Treatment is complicated by the difficulty inherent in suppressing adrenal androgens with dosages of gluco- and mineralocorticoids that are in the physiological range. Alternating cycles of androgen and glucocorticoid excess often lead to attenuation in growth, obesity, virilization, and precocious or delayed puberty (1, 2, 3). Adult women frequently have menstrual abnormalities, hirsutism, reduced bone mineralization, and decreased fertility (4, 5). We have proposed that girls with severe forms of CAH could be more easily managed and would enjoy a better quality of life if their adrenals were removed at an early age and they were then managed like other patients with primary adrenal insufficiency (6). This should permit these children to attain their full growth potential without the struggle against obesity and virilization that is inherent in our current medical approach. The rationale as well as the pros and cons of such a surgical alternative have recently been debated in this journal (6).

We report here our experience with the first such prophylactic adrenalectomy in a 3-yr-old girl with a double null mutation of the 21-hydroxylase gene (CYP21), carried out concurrently with reconstruction of her genital anomalies. This marks the beginning of a study to compare the long term outcome of patients treated with bilateral adrenalectomy to that of conventionally treated controls. Before surgery, we compared our patient’s steroid and natriuretic responses to ACTH stimulation to those of her normal fraternal twin sister. The normal twin responded to ACTH with marked sodium retention, whereas our patient responded to ACTH with increased sodium loss. These findings again demonstrate that adrenals of patients with CAH may actually increase the risk of salt-losing crises in times of stress.

	Case Report

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LZ is a 3.1-yr-old white female with 21-hydroxylase deficiency diagnosed prenatally by amniocentesis. Prenatal evaluation was prompted by the clinical diagnosis of CAH in an older brother, who had presented at 2 weeks of age with severe salt-wasting. This first child became ill and died suddenly at 18 months of age. The cause of death was never determined. In the subsequent clomiphene-induced pregnancy, the mother was found to be carrying twins, and amniocentesis was carried out at 15 weeks gestation under ultrasound guidance. Elevated 17-hydroxyprogesterone (17-OHP) and androstenedione levels in LZ’s amniotic fluid (2245 and 391 ng/dL, respectively) were diagnostic for CAH (7). Her twin AZ’s levels were not considered diagnostic. In the hopes of limiting clitoromegaly, treatment of the mother with dexamethasone (20 µg/kg·day) was initiated during the 17th week of gestation and continued until term.

At birth, LZ was significantly virilized (Prader stage 4). Her fraternal twin, AZ, was anatomically normal. Using allele-specific PCR (8), it was determined that LZ had inherited a complete deletion of the CYP21 gene from her father and an R356W mutation from her mother. This latter point mutation is consistently associated with the most severe, salt-wasting form of CAH and has been shown to totally inactivate 21-hydroxylase activity in transfected COS cells (9). Consequently, LZ is hemizygous double null for CYP21. Her twin AZ, like their mother, is heterozygous for the R356W mutation.

The girls were born at 37 weeks gestation. At 3 days of age, LZ’s 17-OHP level was 19,805 ng/dL. After initial adrenal suppression, LZ was treated with cortisone acetate by injection ranging in dosages from 16–22 mg/m²·day. At 14 months of age she was switched to oral hydrocortisone. She also received fludrocortisone (0.1–0.15 mg/day). On four occasions between 7 weeks and 33 months, she required dose adjustment or short course dexamethasone for incomplete adrenal suppression, as evidenced by 17-OHP levels ranging from 1,470–10,925 ng/dL. Growth and development, however, remained normal. At the time of the study, when LZ was 3 yr, 1 month, her height was at the 50th percentile, weight was at the 25th percentile, and her skeletal age was the same as her chronological age.

Adrenalectomy was performed through bilateral subcostal incisions just before clitoral reduction/recession and exteriorization of the vagina. The two procedures, performed under a single exposure to general anesthesia, were accomplished without difficulty. No complications were encountered either at the time of surgery or postoperatively, and the hospital stay (3 days) was not lengthened by the addition of adrenalectomy. LZ is currently being maintained on 10 mg/m²·day hydrocortisone and 0.05 mg/day fludrocortisone.

	Materials and Methods

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In the week before LZ’s adrenalectomy, both girls were admitted to the University of North Carolina General Clinical Research Center (GCRC) to compare their steroid and natriuretic responses to ACTH stimulation. To more nearly approximate physiological replacement, 10 days before admission the dosage of hydrocortisone taken by LZ was reduced from 15 to 10 mg/m²·day in three divided doses. This, along with her usual dose of 0.1 mg fludrocortisone each morning, was continued throughout the study.

On admission to the GCRC, the girls were placed on identical diets that contained 72 mEq/day sodium. After 2 days of adjustment to this diet, sodium balances, based on dietary intake minus urinary excretion, were calculated daily for the next 5 days. On the morning of day 4, as a means of simulating stress, both girls received the ACTH analog cosyntropin (Cortrosyn, Organon, West Orange, NJ); 0.25 mg, iv, every 6 h for a total of four doses. The first dose was administered after drawing blood for basal electrolytes, complete blood count, cortisol, 17-OHP, and ACTH. These were repeated at 1 and 6 h. Five months after adrenalectomy, LZ returned to the GCRC for a repeat of the ACTH stimulation test. These blood samples were obtained under conditions of considerable stress due to difficulties in obtaining venous access. Basal ACTH and 17-OHP levels were also repeated 9 months after surgery. This sample was obtained while LZ was anesthetized for a urological procedure.

Approval of all pre- and postoperative studies in the subject and her normal control as well as adrenalectomy were approved by the committee on the protection of the rights of human subjects at the University of North Carolina, Chapel Hill. Informed consent was obtained from both parents.

	Results

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Both girls remained generally well, active, and playful throughout the study, and there were no substantial fluctuations in their weights or vital signs. There were also no significant differences between the girls in serum electrolytes and blood counts; both parameters remained within normal limits.

Figure 1 shows the 24 h sodium balance during the study. Both twins maintained similar positive sodium balance on the 3 control days before ACTH treatment. However, after ACTH stimulation, AZ’s sodium excretion decreased significantly, increasing her positive balance (+35.5 mEq/24 h), whereas LZ responded with increased sodium diuresis, resulting in a small negative balance by day 5 (-7.1 mEq/24 h).

View larger version (30K): [in this window] [in a new window]   Figure 1. Sodium balance over 5 days of study. Sodium intake was calculated based on the amount of food offered less that returned to the metabolic kitchen (white bars). Sodium output was measured in 24-h urine samples (amount subtracted from the top of the white intake bars). The resultant balance is represented by solid bars (LZ) and cross-hatched (AZ). ACTH caused marked sodium retention in AZ, increasing positive balance. LZ experienced increased natriuresis, resulting in negative balance after ACTH.

	Discussion

Top Abstract Introduction Case Report Materials and Methods Results Discussion References

LZ’s increased natriuresis after ACTH treatment, in contrast to the salt retention of her sister, supports the hypothesis that individuals with complete forms of CAH have a paradoxical salt-losing response to stress. This is in agreement with previous studies in patients with CAH and in studies of healthy adults demonstrating salt-wasting after the administration of such adrenal steroids as 17-OHP, 16-hydroxyprogesterone, or progesterone (10). Sodium diuresis is thought to result when resistance to exogenous gluco- and mineralocorticoids is caused by competitive inhibition of steroid receptors from hyperstimulated adrenal steroid intermediates and metabolites. Although LZ’s baseline 17-OHP level indicates less than perfect control at the time of the study, the levels after ACTH stimulation were well short of those reported in untreated patients with CAH (11). Had LZ suffered a crisis during a period of noncompliance or complete escape from control, it is likely that natriuresis would have been more significant and perhaps life-threatening.

Five months after adrenalectomy, LZ demonstrated significantly elevated ACTH and measurable 17-OHP levels. The elevated ACTH level may in part be due to the severe stress experienced by LZ after several failures to gain iv access. Four months later, in a sample obtained while LZ was asleep, 17-OHP was undetectable, and ACTH had fallen to a more modest level. Nevertheless, these findings reinforce concerns that activation of abnormal adrenal steroidogenesis might recur if adrenal rests are present in the ovaries or elsewhere. Ectopic adrenal tissue has been demonstrated in testes in adult males with CAH (12) and has been found in normal children in multiple locations from the diaphragm to the pelvis (13). It has also been suggested as the cause of renewed virilization in two girls with CAH who were adrenalectomized in late childhood after failure of medical therapy (14, 15). It is not clear how common and how clinically significant ectopic adrenal tissue is likely to be in postadrenalectomy patients. We will follow our study subjects with twice yearly ACTH and 17-OHP measurements and, if elevated, with yearly pelvic ultrasound.

Until we gain further postoperative and long term experience in these patients, especially with regard to morbidity in times of crises and the frequency and significance of adrenal rests, we believe that adrenalectomy should be offered as experimental therapy only. As girls generally suffer the most severe sequelae, and those with double null mutations of the CYP21 gene particularly so, it is logical that they should be targeted initially. In addition, girls with severe biosynthetic defects will be significantly virilized at birth, presenting an opportunity to perform adrenalectomy at a young age concurrent with necessary genital surgery, as was done in this case.

Although other forms of experimental therapy are currently being investigated (16), many benefits of bilateral adrenalectomy, performed at an early age in patients with severe 21-hydroxylase deficiency, can be confidently predicted. With an end for the need to suppress adrenal androgens, the common cycle of escape from control, followed by repeated courses of high dose steroids, should be a thing of the past. The need for frequent clinic visits and laboratory evaluation should also be reduced. As long as physiological replacement of necessary adrenal steroids is maintained, and as long as significant activation of adrenal rests does not occur, one would expect normal growth and development in children and normal ovulation and fertility in women.

	Acknowledgments

 
We thank Don K. Nakayama for his assistance with the surgery, and Ali S. Calikoglu for help in preparation of the manuscript.

	Footnotes

 
¹ This work was supported in part by a grant (RR-00046) from the General Clinical Research Centers program of the Division of Research Resources, NIH.

Received March 28, 1997.

Revised June 2, 1997.

Accepted June 16, 1997.

	References

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