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Society of fetal urology panel discussion: prenatal diagnosis and treatment of genital anomalies1
PEDIATRIC UROLOGY UPDATE
SOCIETY OF FETAL UROLOGY PANEL DISCUSSION: PRENATAL DIAGNOSIS AND TREATMENT OF GENITAL ANOMALIES LAURENCE S. BASKIN
T
he focus of this panel discussion was the prenatal diagnosis and treatment of genital anomalies. The role of prenatal ultrasound in the management of urologic anomalies remains controversial. Hydronephrosis secondary to obstruction, vesicoureteral reflux, and posterior urethral valves are routinely diagnosed in utero, yet it remains unproven as to whether prenatal intervention is warranted. More recently it has become possible to diagnose genital anomalies in utero.1 In respect to hypospadias, the advantage of prenatal diagnosis remains speculative. Female fetuses with a diagnosis of congenital adrenal hyperplasia, however, can theoretically be diagnosed early in gestation and treated by the administration of maternal steroidal agents, thereby reducing the severity of in utero androgen expsoure. Since the most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is transmitted in an autosomal recessive inheritance pattern, an unborn female sibling in a family with congenital adrenal hyperplasia has a 1 in 8 chance of being affected. The Society of Fetal Urology devoted a morning session to the diagnosis of congenital anomalies in utero followed by a point-counterpoint discussion concerning the risks and benefits of treating a fetus with a presumed diagnosis of congenital adrenal hyperplasia. Felix Conte, Professor of Pediatric Endocrinology at the University of California, San Francisco, started the morning panel discussion by reviewing the latest data on the molecular biology of sexual determination.1 Sexual determination and differentiation are sequential processes that begin at ferThis update reports on a Panel Discussion that took place on October 16, 1998 in San Francisco, California. From the Department of Urology, University of California San Francisco, UCSF Children’s Medical Center, San Francisco, California Reprint requests: Laurence S. Baskin, M.D., Department of Urology, Box 0738, UCSF Children’s Medical Center, 533 Parnassus Avenue, San Francisco, CA 94141 Submitted: December 1, 1998, accepted (with revisions): February 1, 1999 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
tilization with establishment of the chromosomal sex, followed by development of gonadal sex which then regulates the ultimate phenotypic sex. Failure at any of the sequential stages of development can have profound effects on the phenotype and lead to sexual ambiguity or to more subtle abnormalities in function or reproduction. Multiple genes on multiple chromosomes act through a variety of mechanisms that involve hormones, growth factors, and receptors. Early embryos possess indifferent, common primordia that have a tendency to feminize without the action of masculinizing factors. In humans, genes on the Y chromosome induce testis formation and thus male sexual development. An evolutionary conserved gene isolated from the Y chromosome, SRY, is now accepted to be the testis-determining factor.2 SRY, as well as autosomal and X-linked genes, is necessary for testicular development and spermatogenesis. Unlike somatic cells, which have one X chromosome inactivated, female germ cells and oocoytes depend upon the contribution of both X chromosomes. Ovarian differentiation is dependent upon germ cell presence and thus both X chromosomes. In contrast, testicular differentiation can occur in the absence of germ cells, demonstrating that germ cells play no role in male sex determination. In males, spermatogenesis is quiescent during childhood, followed by active mitosis and meiosis. In contrast, the female has a maximal number of germ cells at birth, arrested in the first meiotic division until ovulation. The next presentation reviewed the genital anatomy of the developing male and female (Fig. 1). Genital specimens obtained between weeks 8 and 33 of gestation were serially sectioned and stained for epithelial, smooth muscle, and nerve structures using immunocyotochemical techniques. Selected specimens were reconstructed in three dimensions to better understand the relationship between the nerves, corporal bodies, and urethral spongiosum using NIH imaging and Adobe Photoshop.3 CareUROLOGY 53: 1029–31, 1999 • 0090-4295/99/$20.00 PII S0090-4295(99)00082-5 1029
FIGURE 1. Computer-generated three-dimensional reconstruction. (A) Normal human fetal penis at 25 weeks’ gestation. (B) Normal human fetal clitoris at 24 weeks’ gestation. (C) Hypospadias penis at 33 weeks’ gestation. Note the nerves in blue. In the normal penis (A), the urethral spongiosum has been removed.
ful analysis of the male specimens revealed localization of the nerves dorsally not only at the 11and 1-o’clock positions but extending around the tunica to the junction of the corpus spongiosum and corpora cavernosa, suggesting that penile 1030
straightening procedures may injure these structures (Fig. 1A).3,4 The tunica albuginea showed consistent variations in thickness, with the middorsal 12-o’clock position being the thickest, followed by the 5- and 7-o’clock periurethral positions. The lack of nerves and the thickness of the tunica at the 12-o’clock position have led to the design of penile straightening procedures using plication sutures.5 Analysis of female specimens showed that the normal fetal clitoris consists of two corporal bodies with a midline septum (Fig. 1B). The ultrastructure of the female corporal bodies is analogous to the male counterpart. The glans clitoris forms a cap on top of the distal end of the corporal bodies. Large bundles of nerves course along the corporal bodies, with the greatest density on the dorsal aspect. These anatomic relationships are useful when preserving nerves during feminizing genitoplasty surgery.6 Finally, the ultrastructure of hypospadias has revealed that the nerves and corporal bodies have the same anatomic relationship as the normal penis (Fig. 1C). The most striking difference between the normal penis and the hypospadiac penis is the difference in vascularity. The hypospadic penis has huge endothelial lined vascular channels filled with red blood cells. In contrast, the normal penis has well defined small capillaries around the urethra and fanning into the glans.5 Ellen Shapiro, Professor of Urology at New York University, summarized our current experience with prenatal detection of genital anomalies using ultrasound. Dr. Shapiro reviewed the latest statistics on ultrasound diagnosis of fetal sex. The phallus can be visualized as early as the 10th or 11th week of gestation, yet even at the 24th week of gestation fetal sex remains indeterminate in 10% of fetuses. This is secondary to either fetal lie, placental position, or the close association of the umbilical cord which has internal fluid-filled areas corresponding to three vessels or fetal fingers, both of which can be mistaken for a penis. Dr. Shapiro also presented ultrasound examples of prenatally diagnosed male pseudohermaphroditism, hypospadias, micropenis, cloacal anomalies, penoscrotal transposition, megalourethra, undescended testes, and congenital adrenal hyperplasia. Prenatal ultrasound has also been used to visualize obstructed uterovaginal anomalies such as hydrometrocolpos and/or large ovarian cystic structures including duplication. The fetal female genitalia also have a characteristic finding on sonography. The labia majora and minora are seen by 15 weeks’ gestation to have multiple parallel linear echo patterns. Although the adrenal glands hypertrophy in congenital adrenal hyperplasia, prenatal ultrasound is UROLOGY 53 (5), 1999
not sensitive enough to distinguish all cases of enzyme deficiency. Dr. Phyllis Spieser, from North Shore University Hospital, Manhasset, New York, discussed her extensive clinical experience with the prenatal treatment of congenital adrenal hyperplasia. Dr. Spieser noted that medical treatment of a pregnant woman at risk for carrying a congenital adrenal hyperplasia female can be effective in ameliorating genital ambiguity associated with this condition.7 Whereas data collected in several hundred treated pregnancies over the past two decades show no consistent pattern of major birth defects in these offspring, concern remains over potential subtle disturbances in growth and neurologic and vascular function, which may not manifest for many years. Moreover, because of such uncertainties, the ethics of treating 7 of 8 unaffected pregnancies to prevent genital ambiguity in one affected female should be subjected to further discussion while conducting such studies under scrutiny of an international registry. Dr. Walter Miller, Professor of Pediatrics at the University of California at San Francisco, emphasized the experimental nature and unproven safety of prenatal treatment of congenital adrenal hyperplasia.8 Dr. Miller noted that: (1) the long-term effects and safety for the fetus have not been established; (2) only one in eight treated fetuses stands to gain from the treatment; (3) potential hazardous effects to the fetus may include growth retardation,
UROLOGY 53 (5), 1999
hypertension in the adult years, and emotional effects; and (4) definitive diagnosis of affected XX female fetuses needs to be made in a timely fashion. Both Drs. Spieser and Miller agreed that controlled studies with long-term monitoring are necessary for the safety of both mothers and patients being treated for the prenatal diagnosis of congenital adrenal hyperplasia. REFERENCES 1. Grumbach MM, and Conte FA: Disorders of sex differentiation, in Foster JDWD (Ed): William’s Textbook of Endocrinology. Philadelphia, WB Saunders, 1997, p 853. 2. Koopman P, Gubbay J, Vivian N, et al: Male development of chromosomally female mice transgenic for SRY. Nature 351: 117–121, 1991. 3. Baskin LS, Lee YT, and Cunha GR: Neuroanatomical ontogeny of the human fetal penis. Br J Urol 79: 628 – 640, 1997. 4. Baskin L, Duckett J, and Lue T: Penile curvature. Urology 48: 347–356, 1996. 5. Baskin L, Erol A, Li YW, et al: Anatomical studies of hypospadias. J Urol 160: 1108 –1115, 1998. 6. Baskin LS, Erol A, Li YW, et al: Anatomical studies of the human clitoris. J. Urol (in press). 7. Spieser P, Laforgia N, Kato K, et al: First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 70: 838 – 848, 1990. 8. Miller W: Prenatal treatment of congenital adrenal hyperplasia—a promising experimental therapy of unproven safety. Trends Endocrinol Metab 9: 290 –293, 1998.
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SOCIETY OF FETAL UROLOGY PANEL DISCUSSION: PRENATAL DIAGNOSIS AND TREATMENT OF GENITAL ANOMALIES LAURENCE S. BASKIN
T
he focus of this panel discussion was the prenatal diagnosis and treatment of genital anomalies. The role of prenatal ultrasound in the management of urologic anomalies remains controversial. Hydronephrosis secondary to obstruction, vesicoureteral reflux, and posterior urethral valves are routinely diagnosed in utero, yet it remains unproven as to whether prenatal intervention is warranted. More recently it has become possible to diagnose genital anomalies in utero.1 In respect to hypospadias, the advantage of prenatal diagnosis remains speculative. Female fetuses with a diagnosis of congenital adrenal hyperplasia, however, can theoretically be diagnosed early in gestation and treated by the administration of maternal steroidal agents, thereby reducing the severity of in utero androgen expsoure. Since the most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is transmitted in an autosomal recessive inheritance pattern, an unborn female sibling in a family with congenital adrenal hyperplasia has a 1 in 8 chance of being affected. The Society of Fetal Urology devoted a morning session to the diagnosis of congenital anomalies in utero followed by a point-counterpoint discussion concerning the risks and benefits of treating a fetus with a presumed diagnosis of congenital adrenal hyperplasia. Felix Conte, Professor of Pediatric Endocrinology at the University of California, San Francisco, started the morning panel discussion by reviewing the latest data on the molecular biology of sexual determination.1 Sexual determination and differentiation are sequential processes that begin at ferThis update reports on a Panel Discussion that took place on October 16, 1998 in San Francisco, California. From the Department of Urology, University of California San Francisco, UCSF Children’s Medical Center, San Francisco, California Reprint requests: Laurence S. Baskin, M.D., Department of Urology, Box 0738, UCSF Children’s Medical Center, 533 Parnassus Avenue, San Francisco, CA 94141 Submitted: December 1, 1998, accepted (with revisions): February 1, 1999 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
tilization with establishment of the chromosomal sex, followed by development of gonadal sex which then regulates the ultimate phenotypic sex. Failure at any of the sequential stages of development can have profound effects on the phenotype and lead to sexual ambiguity or to more subtle abnormalities in function or reproduction. Multiple genes on multiple chromosomes act through a variety of mechanisms that involve hormones, growth factors, and receptors. Early embryos possess indifferent, common primordia that have a tendency to feminize without the action of masculinizing factors. In humans, genes on the Y chromosome induce testis formation and thus male sexual development. An evolutionary conserved gene isolated from the Y chromosome, SRY, is now accepted to be the testis-determining factor.2 SRY, as well as autosomal and X-linked genes, is necessary for testicular development and spermatogenesis. Unlike somatic cells, which have one X chromosome inactivated, female germ cells and oocoytes depend upon the contribution of both X chromosomes. Ovarian differentiation is dependent upon germ cell presence and thus both X chromosomes. In contrast, testicular differentiation can occur in the absence of germ cells, demonstrating that germ cells play no role in male sex determination. In males, spermatogenesis is quiescent during childhood, followed by active mitosis and meiosis. In contrast, the female has a maximal number of germ cells at birth, arrested in the first meiotic division until ovulation. The next presentation reviewed the genital anatomy of the developing male and female (Fig. 1). Genital specimens obtained between weeks 8 and 33 of gestation were serially sectioned and stained for epithelial, smooth muscle, and nerve structures using immunocyotochemical techniques. Selected specimens were reconstructed in three dimensions to better understand the relationship between the nerves, corporal bodies, and urethral spongiosum using NIH imaging and Adobe Photoshop.3 CareUROLOGY 53: 1029–31, 1999 • 0090-4295/99/$20.00 PII S0090-4295(99)00082-5 1029
FIGURE 1. Computer-generated three-dimensional reconstruction. (A) Normal human fetal penis at 25 weeks’ gestation. (B) Normal human fetal clitoris at 24 weeks’ gestation. (C) Hypospadias penis at 33 weeks’ gestation. Note the nerves in blue. In the normal penis (A), the urethral spongiosum has been removed.
ful analysis of the male specimens revealed localization of the nerves dorsally not only at the 11and 1-o’clock positions but extending around the tunica to the junction of the corpus spongiosum and corpora cavernosa, suggesting that penile 1030
straightening procedures may injure these structures (Fig. 1A).3,4 The tunica albuginea showed consistent variations in thickness, with the middorsal 12-o’clock position being the thickest, followed by the 5- and 7-o’clock periurethral positions. The lack of nerves and the thickness of the tunica at the 12-o’clock position have led to the design of penile straightening procedures using plication sutures.5 Analysis of female specimens showed that the normal fetal clitoris consists of two corporal bodies with a midline septum (Fig. 1B). The ultrastructure of the female corporal bodies is analogous to the male counterpart. The glans clitoris forms a cap on top of the distal end of the corporal bodies. Large bundles of nerves course along the corporal bodies, with the greatest density on the dorsal aspect. These anatomic relationships are useful when preserving nerves during feminizing genitoplasty surgery.6 Finally, the ultrastructure of hypospadias has revealed that the nerves and corporal bodies have the same anatomic relationship as the normal penis (Fig. 1C). The most striking difference between the normal penis and the hypospadiac penis is the difference in vascularity. The hypospadic penis has huge endothelial lined vascular channels filled with red blood cells. In contrast, the normal penis has well defined small capillaries around the urethra and fanning into the glans.5 Ellen Shapiro, Professor of Urology at New York University, summarized our current experience with prenatal detection of genital anomalies using ultrasound. Dr. Shapiro reviewed the latest statistics on ultrasound diagnosis of fetal sex. The phallus can be visualized as early as the 10th or 11th week of gestation, yet even at the 24th week of gestation fetal sex remains indeterminate in 10% of fetuses. This is secondary to either fetal lie, placental position, or the close association of the umbilical cord which has internal fluid-filled areas corresponding to three vessels or fetal fingers, both of which can be mistaken for a penis. Dr. Shapiro also presented ultrasound examples of prenatally diagnosed male pseudohermaphroditism, hypospadias, micropenis, cloacal anomalies, penoscrotal transposition, megalourethra, undescended testes, and congenital adrenal hyperplasia. Prenatal ultrasound has also been used to visualize obstructed uterovaginal anomalies such as hydrometrocolpos and/or large ovarian cystic structures including duplication. The fetal female genitalia also have a characteristic finding on sonography. The labia majora and minora are seen by 15 weeks’ gestation to have multiple parallel linear echo patterns. Although the adrenal glands hypertrophy in congenital adrenal hyperplasia, prenatal ultrasound is UROLOGY 53 (5), 1999
not sensitive enough to distinguish all cases of enzyme deficiency. Dr. Phyllis Spieser, from North Shore University Hospital, Manhasset, New York, discussed her extensive clinical experience with the prenatal treatment of congenital adrenal hyperplasia. Dr. Spieser noted that medical treatment of a pregnant woman at risk for carrying a congenital adrenal hyperplasia female can be effective in ameliorating genital ambiguity associated with this condition.7 Whereas data collected in several hundred treated pregnancies over the past two decades show no consistent pattern of major birth defects in these offspring, concern remains over potential subtle disturbances in growth and neurologic and vascular function, which may not manifest for many years. Moreover, because of such uncertainties, the ethics of treating 7 of 8 unaffected pregnancies to prevent genital ambiguity in one affected female should be subjected to further discussion while conducting such studies under scrutiny of an international registry. Dr. Walter Miller, Professor of Pediatrics at the University of California at San Francisco, emphasized the experimental nature and unproven safety of prenatal treatment of congenital adrenal hyperplasia.8 Dr. Miller noted that: (1) the long-term effects and safety for the fetus have not been established; (2) only one in eight treated fetuses stands to gain from the treatment; (3) potential hazardous effects to the fetus may include growth retardation,
UROLOGY 53 (5), 1999
hypertension in the adult years, and emotional effects; and (4) definitive diagnosis of affected XX female fetuses needs to be made in a timely fashion. Both Drs. Spieser and Miller agreed that controlled studies with long-term monitoring are necessary for the safety of both mothers and patients being treated for the prenatal diagnosis of congenital adrenal hyperplasia. REFERENCES 1. Grumbach MM, and Conte FA: Disorders of sex differentiation, in Foster JDWD (Ed): William’s Textbook of Endocrinology. Philadelphia, WB Saunders, 1997, p 853. 2. Koopman P, Gubbay J, Vivian N, et al: Male development of chromosomally female mice transgenic for SRY. Nature 351: 117–121, 1991. 3. Baskin LS, Lee YT, and Cunha GR: Neuroanatomical ontogeny of the human fetal penis. Br J Urol 79: 628 – 640, 1997. 4. Baskin L, Duckett J, and Lue T: Penile curvature. Urology 48: 347–356, 1996. 5. Baskin L, Erol A, Li YW, et al: Anatomical studies of hypospadias. J Urol 160: 1108 –1115, 1998. 6. Baskin LS, Erol A, Li YW, et al: Anatomical studies of the human clitoris. J. Urol (in press). 7. Spieser P, Laforgia N, Kato K, et al: First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 70: 838 – 848, 1990. 8. Miller W: Prenatal treatment of congenital adrenal hyperplasia—a promising experimental therapy of unproven safety. Trends Endocrinol Metab 9: 290 –293, 1998.
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