Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension.

A unique syndrome in a three-year-old American Indian girl was characterized by signs and symptoms of mineralocorticoid excess in the absence of excessive secretion of any known sodium-retaining steroids. Hypertension and hypokalemic alkalosis were corrected by spironolactone or a low sodium diet. Plasma renin activity was suppressed but the secretion of aldosterone was undetectable and was not stimulated by salt depletion. There was no evidence of abnormal accumulation of aldosterone precursors and metabolism of a tracer dose of the hormone was normal. Secretion rates of cortisol, corticosterone, deoxycorticosterone, deoxycortisol and aldosterone were very low and did not increase normally with ACTH administration. However ACTH administration aggravated hypertension and hypokalemia. Dexamethasone did not improve hypertension. Despite low secretion of glucocorticoids and mineralocorticoids, the patient showed no addisonian features and survived severe illness. Secretion of a factor of adrenocortical origin was suggested by the exacerbation of the syndrome of ACTH. The unidentified factor appears to be both a potent glucocorticoid and mineralocorticoid.

Adrenocortical function, electrolyte metabolism, and blood pressure during prolonged adrenocorticotropin infusion in juvenile hypertension.

The effect of a continuous 5-day ACTH infusion (40 U/24 h) on adrenocorticoid function, electrolyte metabolism, and blood pressure was investigated in eight normotensive children and eight patients with hypertension of unknown origin. There was a continuous rise of plasma cortisol and deoxycorticosterone in all patients. Plasma aldosterone rose transiently in the normotensive and the hypertensive group. A transient kaliuresis and a continuous fall in serum K+ were observed in all patients. ACTH induced sodium retention and weight gain. The observed increase in systolic blood pressure correlated significantly with the cumulative sodium retention in the normotensive and the hypertensive groups. No correlation between sodium retention and diastolic pressure was found. ACTH on a low salt diet (10 meq/24 h) produced a blood pressure rise which was smaller than that on regular salt. The blood pressure rise did not correlate with any of the hormones measured. This study provides evidence for an unidentified ACTH-stimulable adrenal factor capable of raising blood pressure in normotensive children and patients with juvenile hypertension. The ACTH-induced blood pressure rise is only partly salt dependent and the mechanism of the rise remains unclear.

Prevalence of nonclassical steroid 21-hydroxylase deficiency based on a morning salivary 17-hydroxyprogesterone screening test: a small sample study.

Early morning salivary 17 alpha-hydroxyprogesterone (17-OHP) determination differentiates patients with non-classical 21-hydroxylase deficiency (NC21OHD) from those who are not affected. Using this test, we have conducted a trial screening study for NC21OHD and have compared the study results with previously reported figures for the frequency of this disorder. Testing was performed on 258 subjects recruited from among the medical students and employees of the New York Hospital-Cornell Medical Center. In 2 of the 249 admissible subjects, the 0700-0900 h salivary 17-OHP level was within the range for NC21OHD patients (0.72-6.7 nmol/L; n = 8). These 2 individuals were subsequently confirmed to be affected by ACTH testing. Of the subjects with morning salivary 17-OHP levels below the cut-off point of 0.72 nmol/L, 29 were recalled for ACTH testing and were confirmed to be unaffected. Prevalence of NC21OHD in the test population was determined according to ethnic group. Our study gives a prevalence by screening of 1.14% among caucasians, which agrees with values of 0.81% and 1.06% obtained by different analytical methods. Further, both affected subjects were Ashkenazi Jews, and the prevalence of 3.23% among study members from this group concurs with increased rates of 3.64% and 4.97% already reported. On the basis of a small population sample, screening so far confirms the claim that NC21OHD is the most common autosomal recessive human disorder. Using values from ACTH-proven unaffected subjects (n = 47) and NC21OHD patients (n = 10), we establish preliminary normative data for morning salivary 17-OHP levels of 0.172 nmol/L for unaffected subjects (95% confidence interval, 0.05-0.54 nmol/L) and 1.76 nmol/L for NC21OHD-affected subjects (95% confidence interval, 0.42-7.32 nmol/L).

First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency).

Prenatal treatment of pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was carried out in conjunction with chorionic villus sampling (CVS) in the first trimester for analysis of restriction fragment length polymorphisms. Fourteen families of a total of 49 families at risk for this disease elected to undergo both prenatal treatment and diagnosis via CVS. Dexamethasone administration to the pregnant woman was initiated at a mean gestational age of 7 weeks (range, 4-10 weeks) before testing to determine whether the fetus was affected with 21-hydroxylase deficiency, and CVS was performed at a gestational age of 8-10 weeks. Two affected female fetuses were identified by molecular genetic techniques among this group; neonatal physical examination demonstrated amelioration of the degree of genital ambiguity compared with both nonprenatally treated older sisters with 21-hydroxylase deficiency. The duration of unnecessary prenatal dexamethasone treatment for unaffected or male fetuses was substantially reduced in the CVS group compared with that in a cohort of 8 prenatally treated pregnancies in which amniocentesis was performed in the early second trimester. There were no major morbidities observed in the treated pregnancies. Postnatal confirmation of CVS diagnosis was obtained in all cases in which DNA from an affected sibling was available for comparative analysis with the DNA from chorionic villus tissue. We conclude based on these data that the benefit/risk ratio is favorable for prenatal administration of dexamethasone in pregnancies at risk for 21-hydroxylase deficiency. Treatment should be initiated during the first trimester in conjunction with diagnosis by CVS/molecular genetic techniques. Long term postnatal surveillance is recommended for all offspring of dexamethasone-treated pregnancies.

Effect of glucocorticoids and ACTH on antipyrine clearance in children.

Administration of dexamethasone and infusion of adrenocorticotropic hormone (ACTH) to children for periods up to 4 days did not alter the half-life, apparent volume of distribution, or metabolic clearance rate of antipyrine, a drug principally metabolized by the mixed-function oxidase system of the liver. We conclude that the short-term administration of glucocorticoids and ACTH with ensuing stimulation of endogenous glucocorticoid production is unlikely to produce clinically significant changes in the rate of drug metabolism.

Effects of growth hormone on antipyrine kinetics in children.

The kinetics of antipyrine, a drug used as a clinical indicator of hepatic drug-metabolizing enzyme activity, were examined in children after short- (5 days to 1 wk) or long-term (6 wk to 1 yr) treatment with human growth hormone (hGH). After short-term treatment the mean volume of distribution of antipyrine (aVd) (also a measure of total body water) increased from 0.49 to 0.58 l/kg (p less than 0.005). The mean aVd after long-term treatment did not differ from the mean pretreatment value, but it rose in three of the eight subjects examined. Neither the mean serum half-life (t 1/2) nor the metabolic clearance rate of antipyrine for the group as a whole was altered after short- or long-term treatment with hGH. However, t 1/2 rose to 135% to 151% of control value in three of nine children and decreased to 63% of control value in one after short-term treatment, while after long-term treatment it rose to 128% to 176% of control value in four of eight children. The results indicate that hGH can increase total body water and should be used cautiously in children with impaired cardiac, renal, or hepatic function. The data further suggest that hGH may alter antipyrine t 1/2 in some children. The variable nature of the changes precludes any uniform prediction about growth hormone effects on drug metabolism, but it may be necessary in some children to modify the dosage of other drugs administered with hGH.

The effects of long-term normalization of sodium balance on linear growth in disorders with aldosterone deficiency.

The effect of normalization of sodium balance was evaluated in children with aldosterone deficiency of several etiologies. In salt-losing congenital adrenal hyperplasia (CAH), treatment with a mineralocorticoid in doses that normalized plasma renin activity (PRA) induced a marked increase in linear growth. Serum 17-hydroxyprogesterone (17-OHP) and androgens fell further when adequate sodium balance was achieved, allowing in some cases a reduction in glucocorticoid replacement dose. Together with PRA measurement they were the most sensitive indicators of adequate mineralocorticoid and glucocorticoid replacement therapy. In 2 teenage children with aldosterone deficiency due to Addison's and autoimmune polyglandular disease similar improvement in growth as well as onset of puberty occurred when sodium balance was normalized by increased mineralocorticoid therapy. These studies show that adequate sodium balance is essential for normal growth and pubertal development.

Somatomedin and growth hormone in psychosocial dwarfism.

The diagnosis of psychosocial dwarfism (PSD) was made in a 7 year old boy upon admission to the hospital. In the period following admission, he grew at a slightly accelerated rate of 0.6 cm in 24 days (extrapolated growth rate--9.1 cm/yr); his caloric intake was 1663 calories/day (147 cal/kg/day), stimulable growth hormone was 5.9 ng/ml and somatomedin activity was in the hypopituitary range (0.24, 0.05 U/ml). In the following period of marked catch-up growth of 8.6 cm in 102 days (extrapolated growth rate 30.8 cm/yr), his caloric intake decreased significantly to 1514 cal/day (106 cal/kg/day, 0.005 less than p less than 0.01), stimulable growth hormone in this period was 13.6 ng/ml and somatomedin activity normalized (0.98 U/ml). While under continued observation, with separation from his favorite nurse, his growth velocity dropped significantly to the rate immediately following admission, but there was no change in his stimulable growth hormone or in somatomedin activity. With the return of his favorite nurse, he resumed his previous rapid catch-up growth with no change in caloric intake (p equals not significant), growth hormone level, or somatomedin activity. Upon transient return to his depriving home, his growth rate decreased to 1.4 cm in 70 days (extrapolated growth rate 7.2 cm/yr); growth hormone remained in the normal range. Somatomedin activity was in the low normal range (0.57 U/ml) and rose to high normal activity (1.31 U/ml) as rapid catch-up growth resumed after he had been readmitted. We conclude from these data that: 1. Serum somatomedin in longstanding untreated PSD may be in the hypopituitary range. 2. Markedly fluctuating growth rates during recovery in this patient with PSD were not due to changes in caloric nutrition, growth hormone release or somatomedin activity, but to an as yet unidentified factor affecting growth during emotional stress.