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Antenatal Treatment for Classic 21-Hydroxylase Forms of Congenital Adrenal Hyperplasia and the Issues

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Antenatal Treatment for Classic 21-Hydroxylase Forms of Congenital Adrenal Hyperplasia and the Issues July/August 1999 ·Vol. 1 ·No. 5 invitedreview 1cmeartlcle Antenatal treatment for classic 21-hydroxylase forms of congenital adrenal hyperplasia and the issues Julie Trm•it::, MS 1 and DanielL. Metzger, MIY 3 8 This paper discusses perinatal issues specific to the classi­ tal folds, and a rugated scrotal sac. ·6- Fetal androgens can cal 21-hydroxylase deficiency forms of congenital adrenal also inhibit downgrowth of the vesicovaginal septum in hyperplasia including: prenatal testing, detection, risks, and females, 1 and thus severely virilized females may have a sin­ limitations of such procedures; and prenatal treatment, its gle perineal orifice consisting of a fused vagina and urethra potential benefits to the affected female fetus, and risks to both (urogenital sinus). 3 This urogenital sinus may appear as per­ the fetus and the mother. The information may be important ineoscrotal or phallic hypospadias or even as a "normal male" for a family to have before and during a pregnancy in order urethra. Such females may require clitoroplasty in infancy, and to make an informed decision about what course of action vaginoplasty and vaginal dilation in young adulthood. Inter­ they might want to pursue. nal female sexual organs develop normally because they are 6 8 INTRODUCTION not influenced by androgens. • Because the male fetus is normally exposed to high levels The 21-0H deficiency form of CAH (for this paper, the of testicular androgens, affected newborn males will not have abbreviation CAH will be used to describe congenital adrenal apparent genital deformities but may present with slight hyper­ hyperplasia due to 21-0H deficiency only) affects the devel­ pigmentation of the external genitalia due to excess ACTH opment of genetic females by virilization of the external gen­ and related peptides. 3 italia. The increase in secretion of androgens by the adrenals Cortisol deficiency occurs in all infants with classical CAH. resulting in the phenotype associated with CAH begins before It may lead to hypoglycemia, apnea, seizures, vascular insta­ and/or as normal sexual differentiation takes place; the exter­ bility and collapse, hypotension, hyperpigmentation, and an nal genitals can be masculinized by androgens beginning at 1 2 inability to deal with stress or illness. Approximately 75% of 6-9 weeks gestation. · The development of external genitalia CAH patients have the SW-CAH subtype, wherein the dual is normally controlled by the presence or absence of fetal defect in cortisol and aldosterone biosynthesis results in the androgens of gonadal origin. The indifferent gonads appear reduction of sodium reabsorption by the renal tubules and during the 5th week of development. Testes develop at approx­ imately 43-50 days and descend into the scrotal sac during therefore an inability to conserve sodium and to excrete potas­ sium and hydrogen ions. This leads to hyponatremia, hyper­ the 3rd to the 9th month. The ovaries differentiate a few weeks after the testes and descend into the pelvic cavity from the 7th kalemia, dehydration, hypotension, acidosis, and further 3 9 to the 9th month. The adrenal cortex is derived from the hypovolemia. · Most girls with SW-CAH are noted at birth coelomic mesothelium, first detected at approximately 7 weeks because of their genital ambiguity. Males affected with SW­ gestation; steroid production by the fetal zone begins in the CAH may not be detected at birth, but are diagnosed in the latter half of the first trimester. 3 Sexual differentiation nor­ newborn period when they present with failure to thrive, vom­ mally occurs between the 9th and 13th weeks, 2 and pheno­ iting, dehydration, and electrolyte abnormalities. If children 6 typic sex is established at the end of the first trimester. 4 are not treated quickly, shock and even death can occur. In cases with the SV-CAH subtype, sufficient mineralo­ PHENOTYPIC FORMS OF CAM corticoid is synthesized to prevent salt-losing. 10 These infants 3 11 Females with the classical form of CAH, which includes will not have neonatal electrolyte disturbances. · As with the both the salt-wasting (SW-CAH) and simple virilizing (SV­ SW-CAH subtype, most girls are diagnosed in the neonatal CAH) subtypes, exhibit genital ambiguity ranging in severity period because of clitoromegaly. Boys may not be diagnosed 1 5 through five stages, as described by Prader. • Females may until much later, when they present with signs of androgen present at birth with an enlarged clitoris; fusion of labioscro- excess (early pubic hair development, phallic enlargement, Fnnn the .'lhpnrtlllCIIIS oFA!t'dJ(!Ilcruull!umuu < .cnt'ilt"\ L?nil'cr>lll'O/ CIJJcuxo. CJHt"ilgn, ll., acne, and rapid growth). and o( Pcdwtrics, Hntoh '.- I 'luldrcu ·_, und L of Hnti.'h Columfn11 PHYSIOLOGY Both the classical and nonclassical forms of CAH are caused kt'cc·n·cd: full' 30, l!.J99 by deficiency of the same 21-0 H enzyme. This steroidogenic A(ccptcd: Auxust 6, 1999 224 GenetiC!! IN Medicine Antenatal treatment of CAH 11 enzyme belongs to the cytochrome P450 group of oxidases. 12 The gene that encodes 21-0H, CYP21, is located at 6p21.3. 21-0H is one of a number of enzymes in the steroidogenic This gene is linked to the major histocompatibility complex 6 pathway, which results in the synthesis of cortisol (the prin­ between HLA-B and HLA-DR, and near HLA class Ill. Two cipal glucocorticoid in man) from cholesterol. The cortisol CYP21 genes flank the 3' end ofC4A and C4B, which encode biosynthetic pathway is stimulated first by corticotropin­ members of the complement cascade. Each CYP21 gene con­ releasing hormone (CRH) from the hypothalamus and then tains 10 exons 11 that span 3kb of DNA and share 98% homol­ by adrenocorticotropic hormone (ACTH) from the pituitary. ogy with each other. 13 The first CYP21 gene encodes an active Cortisol from the adrenal glands binds to glucocorticoid recep­ protein, whereas the second gene is an inactive pseudogene 11 14 15 tors in the hypothalamus and pituitary, and exerts a negative known as CYP21P. · · feedback on the secretion of CRH and ACTH. When there is At least 44 different disease-causing sequence aberrations a deficiency of the 21-0H enzyme, cortisol secretion is inad­ in 21-0H CAH have been identified. 16 In 95% of cases, inac­ equate to turn off CRH and ACTH secretion. 21-0H is also tivation of CYP21 is caused by a transfer of deleterious sequences involved in the synthesis of aldosterone (the principal min­ (a "gene conversion") between CYP21 P and CYP21; this results eralocorticoid) from cholesterol; this pathway is primarily reg­ in CYP21 becoming defective or nonfunctional. 1 (Large CYP21 ulated renally by the renin( angiotension mechanism. In CAH, deletions and an intron 2 splice mutation [I2] account for 3 precursor steroids proximal to the blocked step (most notably approximately 50% of classical mutations. ) The majority of 17 -hydroxyprogesterone, or 17 -OHP) accumulate and are other mutations are point mutations found within the coding shunted into other steroidogenic pathways, particularly andro­ region of CYP21, with a 2% prevalence of de novo mutations gen biosynthesis; the adrenal androgen androstenedione can CAH is not a homogenous disorder; studies report good cor­ be converted peripherally to the much more potent testos­ relation between genotype and phenotype. In compound het­ terone (Figure 1 ). 6 erozygotes, the disease severity corresponds most often to the 6 least deleterious mutation presentL ; a mild mutation on one INHERITANCE AND MOLECULAR BASIS allele allows for 20-50% of normal 21-0H enzyme activity. 1 CAH is inherited in an autosomal recessive pattern, hav­ Differences in phenotypes in patients with identical genotypes 3 10 ing a worldwide incidence of approximately 1: 14000. • Within are most likely due to environmental factors and constitutional the Caucasian population, the classical form of CAH is seen differences in other aspects of steroid metabolism and home­ at a frequency of 1:5000-15000,6 for a carrier frequency of ostasis such as androgen sensitivity, metabolic clearance, 2 or 1:60-1:123. 10 other non-CYP21 enzymes with 21-0H-like activity. Dihydroepiandrosterone I \ndm<tenedione _ _.!.7_--"_ Testosterone /' OH P<egn\"' 3 Cholesterol -..Pregnenolone OH p 17 - rogesterone 2 \ I 11-Deoxyco,ti,ol _ __,4_--".,_ Cortisol Pmg"'"""'\ ocoxr:rco"""": Corticosterone ---•18-0H corticosterone __6 _ _,.,_Aldosterone Fig. 1 Adrenal steroidogenesis. ', 21-hydroxylase; I, 17 -hydroxylase; 2, 313-hydroxysteroid dehydrogenase; 3, 17, 20 Lvase; 4, 11 13-hvdroxvlase; 5, \8-hvdrowla-e· " _dYdr _ ·I s 18 0 dehydrogenase; 7, 1713-hydroxylsteroid dehydrogenase. · · · · · · · - " a.e 19GQ ·Vol. 1 • No. e Travitz and Metzger TREATMENT 17 -OHP in mid-trimester reveals a markedly increased level 7 18 Children who are born with either subtype of classic CAH in SW-CAH affected fetuses. • The normal concentration of need to be managed by lifelong hormonal replacement ther­ 17-0HP in amniotic fluid ranges between 18-270 ng/dl, and 19 20 apy to allow normal growth and pubertal development while the concentration of an affected fetus is> 300 ng/dl. • Amni­ ensuring good healthY Treatment for both SW-CAH and SV­ otic fluid androstenedione and testosterone are also increased CAH includes glucocorticoid therapy (usually hydrocorti­ in affected female pregnancies, but testosterone is within the 18 sone) to suppress ACTH secretion and return adrenal androgen upper normal limits with affected males. 17 -OHP and production to normal. Those with SW-CAH are also placed androstenedione are less sensitive in detecting CAH subtypes 19 on mineralocorticoid replacement therapy (usually oral flu­ other than SW-CAH. These amniotic fluid levels may mea­ drocortisone ), 6 and they may require sodium chloride replace­ sure within the normal range in the SV-CAH and NC-CAH 18 19 ment, which can take the form of table salt or ad lib intake of affected.
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