Treatment Of 21-hydroxylase Deficiency Research Articles

New advances in diagnosis and treatment of 21-hydroxylase deficiency

21-hydroxylase deficiency (21-OHD) is an autosomal recessive hereditary disease, which results in reduced synthesis of aldosterone and cortisol and increased adrenal androgens due to lack or reduced activity of 21-hydroxylase during the synthesis of adrenal steroids.In recent years, the backdoor metabolic pathway of adrenal androgen synthesis and the role of adrenal specific 11-oxygenated C19 steroid in 21-OHD have been recognized, and some adrenal specific androgen sources are gradually becoming diagnostic and therapeutic indicators for 21-OHD.On basis of original glucocorticoid and salt corticosteroid replacement therapy, new drugs and treatments are gradually developed and applied in clinical practice.Nov, the latest progress in diagnosis, treatment and monitoring of 21-OHD is reviewed. Key words: 21-hydroxylase deficiency; Diagnosis; Treatment; Monitoring

Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision).

Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The “Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)” published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.

Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency

Congenital adrenal hyperplasia is a general term applied to a group of several inherited enzymatic defects of cortisol biosynthesis. The most frequent cause of this disease is by far 21-hydroxylase deficiency which is considered one of the commonest metabolic disorders. The degree to which the activity of this enzyme is diminished correlates with the severity of congenital adrenal hyperplasia and therefore the clinical presentation of 21-hydroxylase deficiency has a wide spectrum of clinical and laboratory abnomalities. The recent developments have improved prenatal diagnosis and treatment of affected females to minimise genital virilisation. Despite progress made in its recognition and treatment, diagnosis and management of 21-hydroxylase deficiency is still the subject of many debates and controversies. In this paper, aetiology, symptoms, diagnosis and treatment of 21-hydroxylase deficiency in various groups are reviewed with putting special emphasis on the results of recently published studies.

Congenital adrenal hyperplasia

The congenital adrenal hyperplasias are a group of autosomal recessive disorders associated with impaired steroidogenesis. Several types of the congenital adrenal hyperplasias are associated with decreased cortisol production and excessive adrenal sex steroid secretion. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common and prototypic example of this group of disorders. Herein, we review the clinical features, pathophysiology, molecular genetics, and treatment of 21-hydroxylase deficiency. There is also a brief discussion of other steroidogenic enzyme defects that are associated with clinical features due to excessive androgen secretion.

Prevention of ambiguous genitalia by prenatal treatment with dexamethasone in pregnancies at risk for congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by a deficiency of the 21-hydroxylase enzyme. In the classic forms of CAH (simple virilizing and salt-wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully utilized for over a decade. This article reports on 595 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2002 at the New York Presbyterian Hospital-Weill Medical College of Cornell University. No significant or enduring side effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is effective in significantly reducing or eliminating virilization in the newborn female. Prevention of genital virilization in female newborns with classic CAH avoids the risk of sex misassignment and diminishes the need for corrective surgery and the resulting psychological impact that may extend into adulthood.

PRENATAL TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA: The United States Experience

Based on the author's experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is safe and effective in significantly reducing or eliminating virilization in the affected female, and the same outcome seems to be true in the treatment of 11 beta-hydroxylase deficiency. Prenatal treatment spares the newborn female the consequences of genital ambiguity, genital surgery, sex misassignment, and gender confusion. Of the monogenic disorders, steroid 21- and 11 beta-hydroxylase deficiency are two of the few in which prenatal treatment is effective and influences postnatal life.

DEXAMETHASONE TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA IN UTERO: AN EXPERIMENTAL THERAPY OF UNPROVEN SAFETY

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common cause of genital virilization in female infants resulting from inappropriate fetal adrenal androgen secretion. Some investigators have advocated treating pregnant women who are at risk for carrying a CAH fetus with dexamethasone to suppress fetal adrenal androgen synthesis. Experience to date shows that this treatment can be effective in ameliorating the genital virilization in female fetuses. However, the doses used are supraphysiological, the mechanism of dexamethasone action in the fetus is unclear and no long-term followup studies have been done. To be effective the treatment would need to be started by week 6 of gestation but the genetic diagnosis cannot be made until week 12. If the mother has had a previous CAH child, only 1 in 4 pregnancies will be affected and only the female fetuses stand to benefit from treatment, thus, 7 of 8 fetuses will be treated needlessly. In view of these and other concerns, the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees at centers that see enough of these patients to collect meaningful data.

Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia)

Congenital adrenal hyperplasia, caused by any one of a number of inborn errors of steroidogenesis in which cortisol is not sufficiently produced by the adrenal cortex, is in most cases due to a deficiency of the enzyme steroid 21-hydroxylase. Classic 21-hydroxylase deficiency occurs in about 1 in 14,000 live births. In classic 21-hydroxylase deficiency, the most common cause of genital ambiguity in females, prenatal exposure to excess androgens results in virilization of the female fetus. Newborn males have normal genitalia. Postnatally, untreated females as well as males present with signs of androgen excess. Three fourths of classic 21-hydroxylase deficiency cases do not effectively synthesize aldosterone and are salt-wasting, a condition that is potentially fatal. An allelic variant of classic 21-hydroxylase deficiency, termed nonclassic 21-hydroxylase deficiency, is associated with a milder enzymatic defect and no genital ambiguity at birth, but postnatal virilization may be seen. The 21-hydroxylase enzyme, a cytochrome P450 hemeprotein (cytochrome P450c21), is encoded by the gene CYP21, which has a closely neighboring homologous pseudogene, CYP21P. Mutations in the CYP21 gene, causing 21-hydroxylase deficiency, are common and occur owing to two mechanisms: gene deletion and apparent gene conversion. Prenatal diagnosis is important to identify a fetus affected with 21-hydroxylase deficiency. Genital ambiguity in affected females can be prevented by proper administration of dexamethasone to the pregnant mother. Postnatally, the treatment of 21-hydroxylase deficiency is lifelong hormonal replacement. With carefully supervised medical treatment, congenital adrenal hyperplasia patients have the capacity for normal puberty and fertility.

Prenatal diagnosis and treatment of 21-hydroxylase deficiency

Prenatal diagnosis of 21-hydroxylase deficiency, the most common use of congenital adrenal hyperplasia (CAH), has benefited from the advances in endocrinologic and molecular genetic studies. In 1976, prenatal diagnosis of the disease was first attempted by measuring 17-hydroxyprogesterone in the amniotic fluid in the second trimester of pregnancy. Discovery of a close linkage between HLA and the disease gave a second approach for prenatal diagnosis, the latter being made by linkage study of the haplotypes of the index case in a given family. Diagnosis was later made directly by molecular biology. Currently, the studies of the C4-CYP21B gene locus by Southern blotting and the CYP21B gene mutations by PCR ethods simplify the diagnositic procedure of an early and accurate prenatal diagnosis in the first trimester. In these conditions all families are now informative. Moreover, using a direct genetic analysis associated with the possibility of detecting the heterozygotes in a non-related CAH population, a prenatal diagnosis can be done in a family without a previously CAH affected child. From our results in a series of 274 pregnancies at risk for CAH in whom prenatal diagnosis has been made by these different approaches, it can be cncluded that steroid analysis in the amniotic fluid is an accurate method but provides only a late (second trimester) diagnosis, while an early and accurate diagnosis now relies on adequate molecular enetic studies on chorion villus biopsies. In the aim to prevent the virilization of the external genitalia in CAH female fetuses, prenatal treatment was instituted in our group in 1979 by giving dexamethasone to the mother. This prenatal treatment appears safe for the fetus and the child and is effective in preventing virilization of CAH affected females. Although the degree of prevention is not always complete in all cases, the advantages of prenatal treatment are prevailing over the complications observed in a few mothers.