0021-972X/79/4904-0546$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1979 by The Endocrine Society
Vol. 49, No. 4 Printed in U.S.A.
Prenatal Diagnosis of ll/?-Hydroxyiase Deficiency Congenital Adrenal Hyperplasia* ARIEL ROSLER, ESTHER LEIBERMAN, ADA ROSENMANN, RUTH BEN-UZILIO, AND JOSEPH WEIDENFELD Departments of Endocrinology and Metabolism and Human Genetics, Hadassah Hebrew University Medical Center, Jerusalem, and the Department of Pediatrics, Soraka Medical Center, Ben Gurion University of the Negev, Beersheva, Israel
ABSTRACT. To predict 11/3-hydroxylase deficiency congenital
adrenal hyperplasia antenatally, studies were performed in urines and amniotic fluids from 2 pregnant women who had previously given birth to affected infants and whose present pregnancies also resulted in infants with the disease. Urinary tetrahydro-11-deoxycortisol [pregnane-3a, 17a, 21-triol-20-one (THS)] was abnormally elevated in the first, second, and third trimesters (maximal values, 3.5 and 0.9 mg/24 h, respectively) but was undetectable after delivery in these mothers, in 15 normal pregnancies (10-40 weeks of gestation), and in 6 heterozygote parents. Amniotic fluid levels of THS, tetrahydrocortisol [pregnane-3a, 11/3, 17a, 21-tetra-ol-20-one (THF)], tetrahydro-
cortisone [pregnane-3a, 17a, 21-triol-ll, 20-dione (THE)] measured by RIA at 18 weeks of gestation in the first mother and at 40 weeks in the second revealed 12.5- and 8.4-fold increases in THS, respectively, but normal THF and THE levels compared to mean levels in normal pregnancies. The THS to THF plus THE ratio, which was constant throughout pregnancy in 125 normal women (mean ± SD, 0.63 ± 0.34) despite the variable levels of these metabolites, was significantly elevated in both patients (4.4 and 3.8, respectively). These studies indicate that prenatal diagnosis of ll/?-hydroxylase deficiency congenital adrenal hyperplasia based on hormonal measurements is feasible. (J Clin Endocrinol Metab 49: 546, 1979)
Subjects and Methods
P
RENATAL diagnosis of congenital adrenal hyperplasia (CAH) has been attempted by numerous investigators (1), yet all studies have been done in 21hydroxylase deficiency exclusively because of the relative rarity of the other forms of CAH (2,3). We have observed that in Israel, among Jews of North African origin, there is a higher incidence of 11/Mvydroxylase deficiency (4). This fact has provided us with a population in whom to investigate the possibility of antenatal diagnosis in this rare form of CAH. In this paper, we report on studies in two pregnant women who had previously given birth to affected children with ll/?-hydroxylase deficiency CAH. Prenatal hormonal measurements suggested that these mothers were again carrying affected fetuses. The diagnosis, which was based on the elevated concentrations of tetrahydro-11-deoxycortisol (THS)1 in maternal urine and amniotic fluid, was confirmed postnatally.
Patient histories
Received March 23, 1979. Address requests for reprints to: Ariel Rosier, M.D., Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel. * This work was supported in part by a grant (to A.R.) from the Misrad Haklita, State of Israel. 1 The following abbreviations will be used for standard nomenclature of the steroids discussed: tetrahydro-11-deoxycortisol (THS), pregnane3a, 17a, 21-triol-20-one; tetrahydrocortisol (THF), pregnane-3a, 11)8, 17a, 21-tetra-ol-20-one; tetrahydrocortisone (THE), pregnane-3a, 17a, 21-triol-ll, 20-dione; 11-deoxycortisol, A4-pregnene-17a, 21-diol-3, 20dione.
Patient 1. A 32-yr-old healthy Moroccan woman had two uncomplicated pregnancies. Her third pregnancy resulted in the birth of a male who, at the age of 2 yr, presented with excessive growth, signs of precocious puberty with macrogenitosomia, and hypertension (150/110). The diagnosis of 11/?hydroxylase deficiency was confirmed biochemically; urinary THS was 1.6 mg/24 h. During her fourth pregnancy, the mother was followed closely and urinary collections were obtained at 12, 20, and 36 weeks of gestation (Table 1). An amniocentesis was performed during the 18th week of gestation. An apparently normal 4100-g male infant was delivered at term. The infant was followed in the clinic and was suspected of having CAH by the age of 3 weeks because of moderately high levels of THS in the urine (Table 2). By the age of 2 months, he weighed 5450 g and had a length of 60.5 cm (both above the 75th percentile). By 8 months of age, physical examination revealed a large and normotensive baby with hyperpigmented nipples but no signs of virilization. Bone age was 2 yr. The diagnosis of ll/?-hydroxylase deficiency was confirmed by several hormonal determinations (Table 2). Patient 2. A 33-yr-old healthy Moroccan woman had six pregnancies, four of them uncomplicated. The others resulted in two males who, at the age of 2.5 and 1 yr, respectively, presented with excessive growth, signs of precocious puberty with macrogenitosomia, and hypertension (150/115 and 145/100). The
546
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PRENATAL DIAGNOSIS OF 110-HYDROXYLASE DEFICIENCY TABLE 1. Urinary steroid values in pregnant mothers who gave birth to affected infants with 1 l/?-hydroxylase deficiency CAH, other parents of affected children, and normal pregnant women Steroid (mg/24 h) Patient no.
Condition
1 1 1 1 2 2 2 2
12 weeks gestation 20 weeks gestation 36 weeks gestation 8 months after delivery 10 weeks gestation 28 weeks gestation 32 weeks gestation 1 month after delivery
17-KS
17-OHCS
8.0
6.8
5.2
12.2 14.9 12.0
Parents of affected children" Males (n = 3) Females, nonpregnant (n = 3) Normal women, 10-40 weeks gestation (n - 15)
4-15
THS
Pregnanetriol
2.2 3.5 3.4
0.4 0.6 0.8
3.2 5.1 4.7
Vol. 49, No. 4 Printed in U.S.A.
Prenatal Diagnosis of ll/?-Hydroxyiase Deficiency Congenital Adrenal Hyperplasia* ARIEL ROSLER, ESTHER LEIBERMAN, ADA ROSENMANN, RUTH BEN-UZILIO, AND JOSEPH WEIDENFELD Departments of Endocrinology and Metabolism and Human Genetics, Hadassah Hebrew University Medical Center, Jerusalem, and the Department of Pediatrics, Soraka Medical Center, Ben Gurion University of the Negev, Beersheva, Israel
ABSTRACT. To predict 11/3-hydroxylase deficiency congenital
adrenal hyperplasia antenatally, studies were performed in urines and amniotic fluids from 2 pregnant women who had previously given birth to affected infants and whose present pregnancies also resulted in infants with the disease. Urinary tetrahydro-11-deoxycortisol [pregnane-3a, 17a, 21-triol-20-one (THS)] was abnormally elevated in the first, second, and third trimesters (maximal values, 3.5 and 0.9 mg/24 h, respectively) but was undetectable after delivery in these mothers, in 15 normal pregnancies (10-40 weeks of gestation), and in 6 heterozygote parents. Amniotic fluid levels of THS, tetrahydrocortisol [pregnane-3a, 11/3, 17a, 21-tetra-ol-20-one (THF)], tetrahydro-
cortisone [pregnane-3a, 17a, 21-triol-ll, 20-dione (THE)] measured by RIA at 18 weeks of gestation in the first mother and at 40 weeks in the second revealed 12.5- and 8.4-fold increases in THS, respectively, but normal THF and THE levels compared to mean levels in normal pregnancies. The THS to THF plus THE ratio, which was constant throughout pregnancy in 125 normal women (mean ± SD, 0.63 ± 0.34) despite the variable levels of these metabolites, was significantly elevated in both patients (4.4 and 3.8, respectively). These studies indicate that prenatal diagnosis of ll/?-hydroxylase deficiency congenital adrenal hyperplasia based on hormonal measurements is feasible. (J Clin Endocrinol Metab 49: 546, 1979)
Subjects and Methods
P
RENATAL diagnosis of congenital adrenal hyperplasia (CAH) has been attempted by numerous investigators (1), yet all studies have been done in 21hydroxylase deficiency exclusively because of the relative rarity of the other forms of CAH (2,3). We have observed that in Israel, among Jews of North African origin, there is a higher incidence of 11/Mvydroxylase deficiency (4). This fact has provided us with a population in whom to investigate the possibility of antenatal diagnosis in this rare form of CAH. In this paper, we report on studies in two pregnant women who had previously given birth to affected children with ll/?-hydroxylase deficiency CAH. Prenatal hormonal measurements suggested that these mothers were again carrying affected fetuses. The diagnosis, which was based on the elevated concentrations of tetrahydro-11-deoxycortisol (THS)1 in maternal urine and amniotic fluid, was confirmed postnatally.
Patient histories
Received March 23, 1979. Address requests for reprints to: Ariel Rosier, M.D., Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel. * This work was supported in part by a grant (to A.R.) from the Misrad Haklita, State of Israel. 1 The following abbreviations will be used for standard nomenclature of the steroids discussed: tetrahydro-11-deoxycortisol (THS), pregnane3a, 17a, 21-triol-20-one; tetrahydrocortisol (THF), pregnane-3a, 11)8, 17a, 21-tetra-ol-20-one; tetrahydrocortisone (THE), pregnane-3a, 17a, 21-triol-ll, 20-dione; 11-deoxycortisol, A4-pregnene-17a, 21-diol-3, 20dione.
Patient 1. A 32-yr-old healthy Moroccan woman had two uncomplicated pregnancies. Her third pregnancy resulted in the birth of a male who, at the age of 2 yr, presented with excessive growth, signs of precocious puberty with macrogenitosomia, and hypertension (150/110). The diagnosis of 11/?hydroxylase deficiency was confirmed biochemically; urinary THS was 1.6 mg/24 h. During her fourth pregnancy, the mother was followed closely and urinary collections were obtained at 12, 20, and 36 weeks of gestation (Table 1). An amniocentesis was performed during the 18th week of gestation. An apparently normal 4100-g male infant was delivered at term. The infant was followed in the clinic and was suspected of having CAH by the age of 3 weeks because of moderately high levels of THS in the urine (Table 2). By the age of 2 months, he weighed 5450 g and had a length of 60.5 cm (both above the 75th percentile). By 8 months of age, physical examination revealed a large and normotensive baby with hyperpigmented nipples but no signs of virilization. Bone age was 2 yr. The diagnosis of ll/?-hydroxylase deficiency was confirmed by several hormonal determinations (Table 2). Patient 2. A 33-yr-old healthy Moroccan woman had six pregnancies, four of them uncomplicated. The others resulted in two males who, at the age of 2.5 and 1 yr, respectively, presented with excessive growth, signs of precocious puberty with macrogenitosomia, and hypertension (150/115 and 145/100). The
546
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 09:37 For personal use only. No other uses without permission. . All rights reserved.
PRENATAL DIAGNOSIS OF 110-HYDROXYLASE DEFICIENCY TABLE 1. Urinary steroid values in pregnant mothers who gave birth to affected infants with 1 l/?-hydroxylase deficiency CAH, other parents of affected children, and normal pregnant women Steroid (mg/24 h) Patient no.
Condition
1 1 1 1 2 2 2 2
12 weeks gestation 20 weeks gestation 36 weeks gestation 8 months after delivery 10 weeks gestation 28 weeks gestation 32 weeks gestation 1 month after delivery
17-KS
17-OHCS
8.0
6.8
5.2
12.2 14.9 12.0
Parents of affected children" Males (n = 3) Females, nonpregnant (n = 3) Normal women, 10-40 weeks gestation (n - 15)
4-15
THS
Pregnanetriol
2.2 3.5 3.4
0.4 0.6 0.8
3.2 5.1 4.7
