Campbell-Walsh Urology, 11th Edition

PART XV

Pediatric Urology

SECTION E

Genitalia

150

Disorders of Sexual Development

Etiology, Evaluation, and Medical Management

David Andrew Diamond; Richard Nithiphaisal Yu

Questions

1. Which of the following statements is TRUE about SRY(sex-determining region of the Y-chromosome gene)?
2. It is synonymous with the H-Y antigen.
3. The expressed SRY protein has a characteristic high-mobility group (HMG), DNA-binding domain.
4. It is regulated by SOX9 expression.
5. It was genetically mapped by the study of patients with Klinefelter and Turner syndromes.
6. It is synonymous with Zfyin humans.
7. Which of the following statements is TRUE regarding müllerian-inhibiting substance (MIS)?
8. It acts systemically to produce müllerian regression.
9. It is secreted by the fetal Leydig cells.
10. It functions normally in patients with hernia uteri inguinale.
11. It is secreted at 7 to 8 weeks of gestation, representing the initial endocrine function of the fetal testis.
12. It is secreted by the fetal testis at 10 weeks of gestation, after testosterone production has begun.
13. Which description of WT1is correct?
14. Mutations in WT1can result in either Denys-Drash or Frasier syndrome.
15. Mutations in WT1are associated with adrenocortical carcinoma.
16. Loss of WT1function has not been associated with genitourinary anomalies.
17. Duplication of WT1has been associated with dosage-sensitive sex reversal.
18. The gene was originally isolated in cloning experiments and localized to the X chromosome.
19. Which of the following statements is TRUE regarding fetal testosterone?
20. It results in regression of the müllerian ducts.
21. It is produced primarily by the adrenal gland.
22. It acts locally to virilize the urogenital sinus and genital tubercle.
23. It acts locally to virilize the internal wolffian duct structures.
24. It enters target tissue by active diffusion.
25. Which of the following statements is TRUE regarding dihydrotestosterone (DHT)?
26. It produces virilization of wolffian duct structures.
27. It is converted by 5α-reductase to testosterone in target tissues.
28. It produces virilization of the urogenital sinus.
29. It acts locally to produce regression of müllerian structures.
30. It is secreted in large quantities by the fetal testis.
31. Which of the following statements is TRUE regarding patients with Klinefelter syndrome?
32. They have at least one X and two Y chromosomes.
33. They are at increased risk for development of adenocarcinoma of the breast.
34. They undergo replacement of Leydig cells with hyaline.
35. They are characteristically fertile.
36. They bear little resemblance to XX males.
37. The streak gonad of Turner syndrome:
38. can descend to the scrotum.
39. has a reduced number of oocytes.
40. in the presence of a Y chromosome results in increased risk for development of seminoma.
41. is located in the round ligament.
42. in the presence of a Y chromosome results in risk for development of gonadoblastoma.
43. Which of the following statements is TRUE regarding patients with "pure" gonadal dysgenesis?
44. They frequently have chromosomal anomalies.
45. They are at lesser risk for gonadal tumors than are patients with Turner syndrome.
46. They lack the somatic defects associated with Turner syndrome.
47. They have gonadal histology different from that of patients with Turner syndrome.
48. They derive similar benefit from synthetic growth hormone as do patients with Turner syndrome.
49. What is the common denominator in all cases of Denys-Drash syndrome?
50. Gonadoblastoma
51. Nephropathy with early-onset proteinuria
52. Wilms tumor
53. Calyceal blunting
54. Progressive renal failure
55. Which of the following statements is TRUE regarding patients with embryonic testicular regression or bilateral vanishing testes syndromes?
56. They have normal testosterone and elevated estradiol levels.
57. They have normal testosterone but decreased DHT levels.
58. They have castrate testosterone and elevated gonadotropin levels.
59. They have castrate testosterone and normal gonadotropin levels.
60. They have normal follicle-stimulating hormone but decreased luteinizing hormone levels.
61. Which of the following statements is TRUE regarding the ovotestis in ovotesticular disorders of sexual development (DSDs)?
62. It cannot descend from the retroperitoneum.
63. It is found in the minority of patients.
64. It can be unilateral or bilateral.
65. It has testicular and ovarian elements randomly distributed.
66. It is impossible to cleave surgically.
67. An important consideration for gender assignment in the ovotesticular DSD patient is:
68. the potential for fertility.
69. the impossibility of precisely dividing an ovotestis surgically.
70. that malignant degeneration of gonads does not occur.
71. the familial pattern of inheritance of the disorder.
72. the unresponsiveness of the external genitalia to testosterone.
73. Which of the following statements is TRUE regarding the 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH)?
74. It accounts for 99% of CAH cases.
75. It occurs as a result of CYP21Agene inactivation in the majority of cases.
76. It occurs with simple virilization in 75% of cases and salt wasting in 25% of cases.
77. It occurs with a predictable phenotype.
78. It is transmitted in an autosomal dominant pattern.
79. Prenatal treatment of patients with CAH with dexamethasone:
80. is appropriate therapy in seven of eight at-risk fetuses.
81. is initiated after a diagnosis of CAH is confirmed.
82. is of no risk to the fetus.
83. is demonstrated to be effective.
84. acts by suppressing maternal corticotropin.
85. Which of the following statements is TRUE regarding enzymatic disorders of testosterone biosynthesis?
86. They are transmitted in an autosomal dominant pattern.
87. They are associated with persistent müllerian structures.
88. They appear clinically with a predictable phenotype.
89. They may involve impaired glucocorticoid and mineralocorticoid synthesis.
90. They may be associated with fertility.
91. Which of the following statements is TRUE regarding patients with complete androgen insensitivity?
92. They are appropriately raised as female.
93. They have normal wolffian duct structures.
94. They have persistent müllerian duct structures.
95. They should undergo orchiectomy as early as possible.
96. They have a 2% incidence of inguinal hernia.
97. What is Reifenstein syndrome?
98. The group of defects in testosterone biosynthesis that results in male pseudohermaphroditism
99. A form of 5α-reductase deficiency
100. Defects of MIS elaboration in utero
101. A disorder of androgen receptor quantity or function
102. An autosomal recessively transmitted disorder
103. Which of the following statements is TRUE regarding patients with 5α-reductase deficiency?
104. Fertility is an important issue in gender assignment.
105. Isoenzymes 1 and 2 are abnormal.
106. Serum testosterone levels are normal, but there is a decreased testosterone/DHT ratio.
107. Masculinization occurs at puberty.
108. Prostatic enlargement occurs at puberty.
109. Which of the following statements is TRUE regarding patients with persistent müllerian duct syndrome?
110. They have absent wolffian duct structures.
111. They represent a homogeneous disorder of involving the MIS receptor.
112. They should undergo routine removal of müllerian structures.
113. They experience a high incidence of transverse testicular ectopia.
114. They are uniformly infertile.
115. Which of the following statements is TRUE regarding Mayer-Rokitansky-Küster-Hauser syndrome?
116. It presents most commonly as infertility.
117. It is a homogeneous disorder entailing congenital absence of the uterus and vagina.
118. It is associated with a spectrum of ovarian abnormalities.
119. It has associated upper urinary tract anomalies, primarily with the atypical disorder.
120. It is associated with persistent wolffian duct structures.
121. In an unambiguous neonate with hypospadias and a unilateral cryptorchid testis:
122. midshaft location of the urethral meatus is an important risk factor for disorder of sexual differentiation.
123. impalpability of the cryptorchid testis carries a 50% risk of a disorder of sexual differentiation.
124. palpability of the cryptorchid testis effectively rules out disorder of sexual differentiation.
125. perineal hypospadias is not a risk factor for a disorder of sexual differentiation.
126. difference in tissue texture of the poles of the cryptorchid gonad is suggestive of tumor.
127. Gender identity:
128. is synonymous with gender role.
129. is primarily determined by prenatal exposure to androgens.
130. is primarily determined by postnatal environmental influences.
131. is defined as the identification of self as either male or female.
132. does not play a role in gender dysphoria.

Answers

1. b. The expressed SRY protein has a characteristic high-mobility group (HMG), DNA-binding domain.This domain can induce significant DNA binding when bound to the regulatory regions of target genes. The SRY gene is located on the short arm of the Y chromosome adjacent to the pseudoautosomal boundary. Deletion maps based on the genomes of these individuals were constructed by a number of laboratories, and SRY was mapped to the most distal aspect of the Y-unique region of the short arm of the Y chromosome, adjacent to the pseudoautosomal boundary. SRY expression leads to induction of SOX9 during gonadal differentiation.
2. d. It is secreted at 7 to 8 weeks of gestation, representing the initial endocrine function of the fetal testis. The initial endocrine function of the fetal testes is the secretion of MIS by the Sertoli cells at 7 to 8 weeks of gestation.
3. a. Mutations in WT1can result in either Denys-Drash or Frasier syndrome. Denys-Drash syndrome is characterized by a triad of Wilms tumor, congenital nephropathy, and disorder of sexual development (DSD), whereas Frasier syndrome is associated with gonadal dysgenesis, gonadoblastoma, and congenital nephropathy. WT1 is located on chromosome 11 and is not associated with dosage-sensitive sex reversal.
4. d. It acts locally to virilize the internal wolffian duct structures. It was clearly demonstrated that androgen is essential for virilization of wolffian duct structures, the urogenital sinus, and genital tubercle. Testosterone, the major androgen secreted by the testes, enters target tissues by passive diffusion. The local source of androgen is important for wolffian duct development, which does not occur if testosterone is supplied only via the peripheral circulation.
5. c. It produces virilization of the urogenital sinus.In some cells, such as those in the urogenital sinus, testosterone is converted to DHT by intracellular 5α-reductase. Testosterone or DHT then binds to a high-affinity intracellular receptor protein, and this complex enters the nucleus, where it binds to acceptor sites on DNA, resulting in target gene activation and protein synthesis. Therefore, in tissues equipped with 5α-reductase at the time of sexual differentiation, such as prostate, urogenital sinus, and external genitalia, DHT is the active androgen.
6. b. They are at increased risk for development of adenocarcinoma of the breast.Gynecomastia, which can be quite marked, is a common pubertal development in patients with Klinefelter syndrome. As a result, these patients are at eight times the risk for developing breast carcinoma relative to normal males. Males with Klinefelter syndrome have one Y chromosome and at least two X chromosomes. Seminiferous tubular cells undergo replacement with hyaline after pubertal development.
7. e. In the presence of a Y chromosome results in risk for development of gonadoblastoma. In patients with occult Y chromosomal material, the risk of gonadoblastoma, an in situ germ cell cancer, is approximately 30%. The streak gonad is usually abdominal in location, is hypoplastic, and predominantly consists of fibrous tissue.
8. c. They lack the somatic defects associated with Turner syndrome(e.g., broad chest, neck webbing, cardiac and renal anomalies, and short stature). However, patients with 46,XX "pure" gonadal dysgenesis are closely related to those with Turner syndrome. Because these patients exhibit none of the somatic stigmata associated with Turner syndrome, and their condition entails gonadal dysgenesis only, this type has been regarded by some authors as pure.
9. b. Nephropathy with early-onset proteinuria. The full triad of the syndrome includes nephropathy, characterized by the early onset of proteinuria, and hypertension and progressive renal failure in the majority. Because incomplete forms of the syndrome may occur, the nephropathy has become regarded as the common denominator of the syndrome.
10. c. They have castrate testosterone and elevated gonadotropin levels.The diagnosis can be made on the basis of a 46,XY karyotype and castrate levels of testosterone, despite persistently elevated serum luteinizing hormone and follicle-stimulating hormone levels. Serum MIS is a useful marker for the presence of testicular tissue and is undetectable in these males.
11. c. It can be unilateral or bilateral.Ovotesticular DSD patients are individuals having both testicular tissue with well-developed seminiferous tubules and ovarian tissue with primordial follicles, which may take the form of one ovary and one testis or, more commonly, one or two ovotestes. Histopathology of the ovotestis will typically demonstrate well-developed ovarian tissue and a dysgenetic testicular component.
12. a. The potential for fertility.The most important aspect of management in ovotesticular DSD is gender assignment.
13. b. It occurs as a result of gene inactivation in the majority of cases.Mutations leading to gene conversion of the active CYP21A gene into the inactive gene occur in 65% to 90% of cases of the classic disorder (salt wasting and simple virilizing) and all cases of nonclassic 21-hydroxylase deficiency. 21-Hydroxylase deficiency accounts for 95% of CAH cases, with 75% of patients presenting with salt wasting and 25% with simple virilization.
14. d. Is demonstrated to be effective.Treatment should be initiated before 9 weeks after the last menstrual period, once pregnancy is confirmed. A number of series have established the effectiveness of prenatal treatment of CAH with dexamethasone, which suppresses fetal secretion of adrenocorticotropic hormone. However, a diagnosis of CAH cannot be confirmed before therapy is initiated because the diagnosis is usually made by chorionic villus sampling or amniocentesis. Therefore, if treatment is initiated for all at-risk fetuses, seven of eight may be treated unnecessarily before confirmatory diagnosis.
15. d. They may involve impaired glucocorticoid and mineralocorticoid synthesis.A defect in any of the five enzymes required for the conversion of cholesterol to testosterone can cause incomplete (or absent) virilization of the male fetus during embryogenesis. The first three enzymes (cholesterol side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase) are present in both the adrenals and the testes. Therefore their deficiency results in impaired synthesis of glucocorticoids and mineralocorticoids in addition to testosterone.
16. a. They are appropriately raised as female.It is of great interest that, currently, all studies of patients with complete androgen insensitivity support an unequivocal female gender identity, consistent with androgen resistance of brain tissue as well. To date there has been no report of a patient raised as a female who needed gender reassignment to male. Development of wolffian duct structures is androgen dependent. Sertoli cells are present and produce MIS, which results in the regression of müllerian duct structures.
17. d. A disorder of androgen receptor quantity or function.Androgen receptor studies in cultured fibroblasts have demonstrated two forms of receptor defect in the partial androgen insensitivity syndrome. These include a reduced number of normally functioning androgen receptors and normal receptor number but decreased binding affinity.
18. d. Masculinization occurs at puberty.At puberty, partial masculinization occurs with an increase in muscle mass, development of male body habitus, increase in phallic size, and onset of erections. The type 2 isoenzyme is affected in patients with 5α-reductase deficiency, resulting in an increased testosterone/DHT ratio owing to a reduced testosterone-to-DHT conversion rate.
19. d. They experience a high incidence of transverse testicular ectopia.Persistent müllerian duct syndrome is thought to be etiologically important in transverse testicular ectopia, occurring in 30% to 50% of cases. Aberrant MIS function may be secondary to defects in the gene for MIS or in the gene for the MIS receptor.
20. d. It has associated upper urinary tract anomalies, primarily with the atypical disorder.Urinary tract anomalies occur more commonly in patients with the atypical form of the disorder than in patients with the typical syndrome. Patients with Mayer-Rokitansky-Küster- Hauser syndrome typically present with primary amenorrhea.
21. b. Impalpability of the cryptorchid testis carries a 50% risk of a disorder of sexual differentiation.With a unilateral cryptorchid testis, the incidence of a disorder of sexual differentiation was 30% overall, 15% if the undescended testis was palpable, and 50% if it was impalpable.
22. d. Is defined as the identification of self as either male or female.Gender role refers to aspects of behavior that distinguish males and females. The development of gender identity is poorly understood, but is influenced by prenatal and postnatal factors. Individual conflicts with gender identity are central to the concept of gender dysphoria.

Chapter review

1. SRYinitiates testicular organogenesis. The SRY gene is located on the short arm of the Y chromosome.
2. The prostate, urogenital sinus, and external genitalia are all sensitive to dihydrotestosterone.
3. Estrogens are not required for normal female differentiation.
4. Patients with Klinefelter syndrome have eunuchoidism, gynecomastia, azoospermia, and small testes and are tall for their age. Muscle development is poor.
5. Patients with Turner syndrome (XO) have sexual infantilism, web neck, and cubitus valgus; are of the female phenotype; are short in stature; and lack secondary sexual characteristics.
6. In patients with Turner syndrome, any Y-chromosome material increases the risk for the streak gonad developing a gonadoblastoma; these patients also have increased incidence of abnormalities of the kidney, including horseshoe kidney.
7. The diagnosis CAH of the salt-wasting variety is made by obtaining a serum 17-hydroxyprogesterone value 3 to 4 days after birth. If it is elevated, the patient has CAH.
8. In patients who have severe forms of CAH difficult to control medically, bilateral adrenalectomy may be the most effective approach.
9. A distinctly palpable gonad along the pathway of descent is highly suggestive of a testis or rarely of an ovotestis.
10. Patients with bilateral impalpable testes or a unilateral impalpable testis and hypospadias should be regarded as having a disorder of sexual development until proven otherwise whether or not the genitalia appear ambiguous. They should have a karyotype.
11. For normal ovarian development there must be two X chromosomes.
12. In the developing embryo, MIS and testosterone act locally and unilaterally.
13. Mixed gonadal dysgenesis is the second most common cause of DSD after CAH, and it is characterized by a unilateral testis, a contralateral streak gonad, and persistent müllerian structures with varying degrees of inadequate masculinization.
14. The syndrome of complete androgen insensitivity is characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of müllerian structures; the testes are prone to tumors, which usually occur after puberty in 1% to 2% of affected individuals.
15. Persistent müllerian duct syndrome is due to absence of MIS in patients with 46,XY karyotype who have normal male external genitalia and internal müllerian duct structures (fallopian tubes, uterus and upper vagina).
16. The finding of a palpable gonad in a newborn with ambiguous genitalia effectively rules out overt masculinization of the female (congenital adrenal hyperplasia).
17. Patients with Klinefelter syndrome are at 8 times the risk for breast carcinoma relative to normal males.
18. Serum MIS is a useful marker for the presence of testicular tissue in the newborn period.
19. Histopathology of the ovotestis will typically demonstrate well-developed ovarian tissue and a dysgenetic testicular component.
20. Patients with complete androgen insensitivity support an unequivocal female gender identity,