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Evaluation of Deficiency of 21 -Hydroxylation in Patients with Congenital Adrenal Hyperplasia 0

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Evaluation of Deficiency of 21 -Hydroxylation in Patients with Congenital Adrenal Hyperplasia 0 Arch Dis Child: first published as 10.1136/adc.43.230.410 on 1 August 1968. Downloaded from Arch. Dis. Childh., 1968, 43, 410. Evaluation of Deficiency of 21 -hydroxylation in Patients with Congenital Adrenal Hyperplasia 0. M. GALAL, B. T. RUDD, and N. M. DRAYER From the Institute of Child Health, University of Birmingham Congenital adrenal hyperplasia can manifest therapy in these 13 children started within the first 3 itself in a variety of clinical and biochemical weeks of life. abnormalities (Bongiovanni and Root, 1963). The In addition to the 18 patients with congenital adrenal salt-losing tendency in some of these patients can hyperplasia, 3 children with shortness of stature and 3 with early signs of puberty were given ACTH to be due to the absence of specific enzymes: dehydro- investigate their adrenal function. None of these genases or hydroxylases (Bongiovanni and Root, patients had received steroids and all had normal free 1963; Ulick et al., 1964; Visser and Cost, 1964). cortisol and 17-hydroxycorticosteroid urinary excretion In addition to the impaired production of certain rates. The age and sex of the patients in the 3 groups steroids, antagonism by steroids or other compounds and details of the steroid therapy are listed in Table I. could, theoretically, account for the salt-losing tendency (Neher, Meystre, and Wettstein, 1959; ACTH test. Twenty-four hour urine collections Jacobs et al., 1961). were obtained before and during ACTH stimulation. The purpose ofthis study was to discover whether, ACTH gel (Organon) was given intramuscularly at a copyright. despite the continuation of steroid therapy, stimula- dose of 20 I.U. twice daily for 3 consecutive days. tion of the adrenal cortex with ACTH would measure the capacity of the 21-hydroxylase enzyme Methods system to convert steroid precursors to cortisol. One-twentieth volume of a 24-hour urine collection This procedure would then support the diagnosis was hydrolysed with a ,-glucuronidase preparation of this type of congenital adrenal hyperplasia, if from Patella vulgata. The liberated steroids were withdrawal of therapy was considered to be extracted with ethyl acetate-ether (1 : 2), washed with undesirable. alkali and water, and chromatographed in the system http://adc.bmj.com/ This study was also intended to investigate light petroleum-toluene-85% acetic acid (1: 1: 2). whether the degree of 21-hydroxylase deficiency Three widely separated fractions were obtained (Bush, in the pathway leading to cortisol production could 1961). The fraction of medium polarity, containing pregnanetriol, was oxidized with sodium bismuthate. be related to the two clinical variants of 21-hydroxy- The oxidized product was chromatographed in the lase deficiency-salt-losers and non-salt-losers. system light petroleum-dekalin-85% methanol (1: 1: 2) (Bush, 1961). The Zimmermann chromogen, with a Children Studied mobility similar to authentic aetiocholanolone, was on September 27, 2021 by guest. Protected Eighteen normotensive patients were diagnosed as eluted with methyl sulphoxide and measured spectro- having congenital adrenal hyperplasia. 13 of these photometrically (Epstein and Zak, 1963). patients were girls, all of whom had signs of virilism. The most polar fraction containing the 17-hydroxy- The abnormal quantities of total 17-oxogenic steroids, corticosteroids was eluted. The Porter-Silber reaction and pregnanetriol excreted in the urine by the 18 patients (Silber and Porter, 1954) was used for quantitative deter- indicated a 21-hydroxylase deficiency. In 10 girls and mination and the Allen formula (Allen, 1950) was applied. 3 boys the salt-losing condition was shown in the first weeks of life by the occurrence ofvomiting accompanied Recoveries of added tetrahydrocortisol to urine. by a low serum sodium and a high serum potassium. When 5-10 ,ug. of tetrahydrocortisol (MRC reference All 18 patients received glucocorticoid therapy, either steroid) were added to different urine samples, and the as dexamethasone or as prednisolone (1 patient). In urines were taken through the described method, the addition, the 13 salt-losers received salt, 8 also received recoveries ranged from 60 to 112%, with a mean of 9- a-fluorohydrocortisone, and 1 received DOCA. Steroid 84-5%. The levels of tetrahydrocortisol standard added to the urines corresponded to 0l 1 mg. to 2 mg. of Received December 28, 1967. Porter-Silber chromogens excreted per 24 hours. 410 Arch Dis Child: first published as 10.1136/adc.43.230.410 on 1 August 1968. Downloaded from Evaluation of Deficiency of 21-hydroxylation in Congenital Adrenal Hyperplasia 411 TABLE I Results of ACTH Stimulation Test in 24 Children Treatment Test Age - 21- 9 a-fluoro- at Time 17-OHCS Pregnanetriol hydroxylation Case Sex Dexamethasone hydrocortisone (g/Sa4lhr.) of Test (mg./24 hr.) (mg./124 hr.) Deficiency No. Sex (mg./24 hr.) ~(mg./24 hr.) (g/4hr)(M BL* ACTH* BL* ACTH* Salt-losing patients with congenital adrenal hyperplasia 1 F 0 *5 0*1 4 5 wk. ND 0*1 ND 0*4 80 2 F 0 *5 0*1 5 6 ,, ND 0*1 ND 1*6 94 3 F 0 *28 0*1 3 3 mth. ND ND ND 1*3 100 4 M 0 375 0*1 3 3 ,, 0*1 0*1 ND 0 5 100 5 M 0 *375 0*1 5 3 ,, 03 0*3 ND 2*4 100 6 F 0 3 0 1 2 3 ,, 01 0 3 ND 0 4 67 7 F 0 375 0-1 4 2.j yr. 0-2 0 4 0 9 2 2 87 8 F 0 5 'Ad lib' 3 ,, 0-2 03 1.1 40 96 9 F 0 25 6 4,, 01 0*2 ND 0 *5 83 10 M 016 0.1 4 5k ,, 0 4 0 5 5-5 8-5 97 11 F 0 *5 'Ad lib' 6 , 02 0 7 0*4 9 9 95 12 F 0*5 'Ad lib' 8k ,, 0*1 0 3 ND 17 8 98 Prednisolone DOCA Salt (mg./24 hr.) Implant (mg.) (g./24 hr.) 13 F 3 200 2 3 mth. 0 2 0 *3 ND 5 *4 98 Dexamethasone Age when Steroid Therapy (mg./24 hr.) Started Non salt-losing patients with congenital adrenal hyperplasia 14 F 0*12-5 4 wk. 5 wk. 0.1 2 *3 ND 0 3 12 15 F 0 6 3 mth. 3 yr. 0 5 2-1 0 7 2-6 54 copyright. 16 M 0 5 21 yr. 3 ,, 0-1 0-6 0-2 0 3 17 17 M 0 75 2 , 3i ,, 0-1 1-2 0-2 1-1 45 18 F 0 5 3 , 12 , 0.1 0-2 0-1 0 5 80 Patients without congenital adrenal hyperplasia 19 F 2kyr. 0 9 6-5 0-1 0 3 3 20 F 2k ,, 0-6 16-0 0-2 0-5 2 21 F 5 ,, 1-2 12-5 0-1 0-3 2 22 M 6 ,, 11 15-0 0-1 0 3 1 23 F 6,, 0 7 7 *5 0*1 0*4 4 24 M 6k, 11 11-2 0-2 0 4 2 http://adc.bmj.com/ * 24-hour urine collections before (BL) and on the 3rd day of ACTH stimulation. ND = Not detected. Recovery and oxidation efficiency of pregnanet- a Porter-Silber chromogen concentration range of 0 to riol. To normal urines after hydrolysis was completed, 2 - 6 mg./24 hours. The standard deviation was ±0 * 12 5, 10, and 20 tsg. 11-oxy aetiocholanolone were added. mg./24 hours. Thus, for a single analysis the expected The recovery of this steroid after extraction and paper variation from the true value would be +00-24 mg./24 chromatography was 79%o (range 69-89%). The hours (95% confidence limits). The precision of the on September 27, 2021 by guest. Protected fraction which contains 11-oxy aetiocholanolone also method for the steroids present in the fraction ofmedium contains pregnanetriol, and it is assumed that the recovety polarity, containing pregnanetriol, was similar (Rudd and of pregnanetriol after extraction and chromatography is Galal, 1967). similar to that of 1 1-oxy aetiocholanolone. Pregnanetriol, 20 ,ug., was used as a standard, under- Results going the same subsequent oxidation and second paper chromatographic step as the biological sample. By Preliminary studies in 7 of the children with this procedure, losses of pregnanetriol from the biological congenital adrenal hyperplasia have shown that, on sample, occurring during the oxidation and second average, the maximum Porter-Silber chromogen stage chromatography, are compensated for by similar excretion was obtained on the third day of ACTH losses from the standard (the recovery of pregnanetriol stimulation (Fig. 1). The increase in the urinary after this procedure was 76-80%). excretion of the Porter-Silber chromogens and Precision. The precision of the method for the pregnanetriol on the third day of ACTH is shown 17-hydrocorticosteroids was established by the analysis in Table I. of paired data. Seven pairs of urines were studied with The percentage of 21-hydroxylase deficiency Arch Dis Child: first published as 10.1136/adc.43.230.410 on 1 August 1968. Downloaded from 412 Galal, Rudd, and Drayer 22 100l SI. 2-0 * = Salt-losers 90- Ax Non-solt-losers - 1-8 80- A 0 u 1-b - c 70- 4) - 1.4. -0 6O- A E 2- 0 50- A ~0 40- 0-8- -c 30- 0 06 - 20- A 0-4- 10- A 0-2 - 0 Salt-losers Non-salt-losers Without CAH 0- 2 3 CAH Day of ACTH FIG. 2.-Calculated degree of 21-hydroxylation deficiency in 24 children. FIG. 1.-Porter-Silber chromogen excretion before and copyright. during 3 days of ACTH stimulation in 7 children with jects excrete more tetrahydrocortisone than preg- congenital adrenal hyperplasia.
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