10: Disorders of sexual development Flashcards

Question

Which of the following is a possible cause of ambiguous genitalia in a newborn? a. Postnatal exposure to exogenous hormones b. Overweight mother during pregnancy c. High neonatal weight d. Congenital adrenal hyperplasia

Answer 1

d. Congenital adrenal hyperplasia

Answer 2

c. History of diabetes

Answer 3

Consanguinity refers to the degree of blood relationship between two individuals, such as first cousins or siblings. In some cultures and populations, consanguineous marriages are more common, which can increase the likelihood of certain genetic disorders being passed down through generations. A family history of consanguinity may be relevant in the evaluation of a newborn with ambiguous genitalia.

Answer 4

Ambiguous genitalia in newborns refers to a condition in which the genitalia are not clearly male or female. This can be due to a variety of factors, including genetic abnormalities, hormonal imbalances, and environmental factors. Some possible causes include congenital adrenal hyperplasia, androgen insensitivity syndrome, and abnormalities in the production or response to hormones such as testosterone or estrogen.

Answer 5

A thorough history is important in the diagnosis and management of newborns with ambiguous genitalia because it can provide important information about possible causes and guide further testing and management. Factors such as level of prematurity, exposure to exogenous hormones by mother, and prenatal testing such as fetal karyotype or appearance of genitalia on sonogram can all provide important clues. Family history is also important, as certain conditions such as congenital adrenal hyperplasia may be inherited and may affect multiple family members.

Answer 6

In the family history of a newborn with ambiguous genitalia, it is important to assess for a variety of factors that may provide important clues to the underlying cause. These may include neonatal deaths (suggestive of congenital adrenal hyperplasia [CAH]), urologic diagnoses in children or adults, precocious puberty, infertility, amenorrhea, hirsutism, or consanguinity. By assessing these factors, healthcare providers may be able to better identify possible causes and guide further testing and management.

Answer 7

C. A palpable gonad in the inguinal canal or scrotum is highly suggestive of the presence of a testicle.

Answer 8

D. Stretched penile length should be measured during phallic examination.

Answer 9

B. The presence of a uterus can sometimes be determined on physical exam by palpation of an anterior midline cordlike structure on rectal examination.

Answer 10

Bilaterally nonpalpable testicles or a unilateral nonpalpable testis in the presence of any degree of hypospadias should be treated as disorders of sexual development (DSD) until proven otherwise. This is because these findings suggest an underlying hormonal or genetic abnormality that may require further evaluation and management.

Answer 11

In addition to genital examination, it is important to note other dysmorphic features suggestive of genetic disorders, such as short, broad neck associated with Turner syndrome. This is because DSD can be associated with various genetic disorders and other systemic abnormalities that may require further evaluation and management.

Answer 12

An ovotestis is a rare condition in which both ovarian and testicular tissue are present in the same gonad. In some cases, an ovotestis may undergo descent and be palpable in the inguinal canal or scrotum. However, the diagnosis of an ovotestis usually requires histological examination of the gonad after surgical removal.

Answer 13

d. Prostate-specific antigen (PSA) Explanation: The immediate serum laboratory evaluation for newborns with ambiguous genitalia includes karyotype, serum electrolytes, 17-hydroxyprogesterone, testosterone, LH, and FSH. PSA is not part of the evaluation.

Answer 14

a. To determine the presence of testicular tissue Explanation: The hCG stimulation test is used to determine the presence or absence of testicular tissue in newborns with ambiguous genitalia. A failure to respond to hCG in combination with other laboratory findings can indicate functional anorchia.

Answer 15

d. Magnetic resonance imaging (MRI) Explanation: Pelvic ultrasound or MRI can be helpful in determining the presence of Müllerian structures and/or gonads in newborns with ambiguous genitalia.

Answer 16

Answer: Karyotyping is an important part of the evaluation of newborns with ambiguous genitalia, as it can help to identify X and Y chromosome material and determine the genetic sex of the baby. This information can be used to guide further evaluation and management.

Answer 17

Answer: b) Ambiguous genitalia

Answer 18

e) All of the above

Answer 19

b) Diagnosis

Answer 20

c) Based on diagnosis, anatomy, and functional potential of the genital and reproductive tract

Answer 21

The most common causes of DSD in the newborn are congenital adrenal hyperplasia (CAH), androgen insensitivity syndrome (AIS), and 5-alpha-reductase deficiency. Diagnosis involves a combination of clinical examination, imaging studies, and laboratory testing. Treatment of CAH involves hormone replacement therapy, while AIS and 5-alpha-reductase deficiency may require surgery to reconstruct the external genitalia.

Answer 22

b) Klinefelter syndrome

Answer 23

c) Seminiferous tubules degeneration

Answer 24

c) Both a) and b)

Answer 25

c) 40%-50%

Answer 26

Klinefelter syndrome is characterized by the presence of at least one Y chromosome and at least two X chromosomes. This results in testicular dysgenesis, where seminiferous tubules degenerate and are replaced by hyaline, leading to small and firm testicles. The decreased testosterone levels and increased estrogen levels result in gynecomastia, breast carcinoma, and extragonadal germ cell tumors. The majority of patients are infertile with azoospermia.

Answer 27

Patients with Klinefelter syndrome may present with small and firm testicles, gynecomastia, reduced body hair, decreased libido, and infertility. They are also at an increased risk for breast carcinoma, extragonadal germ cell tumors, and Leydig/Sertoli cell tumors.

Answer 28

The diagnosis of Klinefelter syndrome is confirmed by a karyotype analysis, which typically shows a 47,XXY chromosomal pattern. The serum testosterone levels are low-normal, while the gonadotropins and estradiol levels are elevated. Imaging studies, such as testicular ultrasound or magnetic resonance imaging, may reveal small and firm testicles.

Answer 29

Treatment for Klinefelter syndrome includes androgen supplementation to improve libido and reduce gynecomastia. Reduction mammoplasty may also be necessary for severe cases of gynecomastia. Assisted reproductive technology, such as microdissection testicular sperm extraction and intracytoplasmic sperm injection, may be used for nonmosaic patients who desire to have children. Patients should also undergo regular surveillance for breast carcinoma and other malignancies.

Answer 30

Nonmosaic patients are those with Klinefelter syndrome who have the same chromosomal pattern in all of their cells. In contrast, mosaic patients have more than one chromosomal pattern in their cells, meaning that only some cells in their body have the extra X chromosome. The distinction between mosaic and nonmosaic Klinefelter syndrome can impact the severity of the condition and the success of treatments such as assisted reproductive technology.

Answer 31

What is the pathophysiology of 46,XX male and how does it present clinically? 46,XX male is a disorder of gonadal differentiation and development characterized by testicular development in individuals with no Y chromosome. The hypothesized mechanism is translocation of Y chromosome material, including SRY, to the X chromosome. This leads to the expression of SRY, which is responsible for initiating male gonadal differentiation. Most individuals with 46,XX male have normal male external genitalia or hypospadias, but all are infertile due to lack of germ cells.

Answer 32

Diagnosis of 46,XX male is based on karyotyping, which reveals the presence of two X chromosomes and no Y chromosome. In terms of endocrinologic profile, individuals with 46,XX male have high testosterone levels and low LH and FSH levels, similar to Klinefelter syndrome.

Answer 33

The management of 46,XX male involves correcting the endocrinologic imbalances through hormonal treatment, which is similar to the treatment of Klinefelter syndrome. Testosterone replacement therapy can be used to maintain normal male secondary sexual characteristics and bone health. However, because of the lack of germ cells, there is no role for sperm retrieval. Hormonal treatment is important for long-term health and well-being of individuals with 46,XX male.

Answer 34

a. Lack of development of secondary sex characteristics.

Answer 35

b. 10-12%.

Answer 36

Turner syndrome is characterized by one normal functioning X chromosome and one absent, abnormal, or mosaic sex chromosome. By birth, gonads are mostly devoid of oocytes, resulting in characteristic streak gonads. The lack of oocytes and the absence of estrogen production lead to a lack of pubertal development of the external genitalia and lack of development of secondary sex characteristics.

Answer 37

Manifestations of 45,X type may include short stature, broad chest, widespread nipples, webbing of the neck, peripheral edema at birth, short fourth metacarpal, hypoplastic nails, multiple pigmented nevi, coarctation of the aorta, bicuspid aortic valve, and renal anomalies.

Answer 38

The diagnosis should be considered in any infant with lymphedema or young woman with short stature, lack of secondary sex characteristics, or primary amenorrhea. Karyotype analysis is required to confirm the diagnosis.

Answer 39

Risk of gonadoblastoma is estimated at 12%–20% and has been reported as early as 5 months of age. Determination of Y chromosome material in Turner syndrome is critical because it predisposes to masculinization and gonadoblastoma. Prophylactic gonadectomy in the Y mosaic Turner syndrome patient is advised but not required in the 45,XO patient.

Answer 40

Endocrinologic evaluation is needed. Growth hormone or sex hormones may be needed for growth and development. Although spontaneous fertility is rare, pregnancy is a possibility for some patients with spontaneous menses. Regular follow-up and monitoring of cardiac and renal function is also recommended.

Answer 41

c. Elevated serum gonadotropins Explanation: Patients with 46,XX “pure” gonadal dysgenesis have normal female external genitalia, normal Müllerian ducts with the absence of wolffian structures, normal height, and bilateral streak gonads. Due to the presence of streak gonads, they have elevated serum gonadotropins. Management involves estrogen and progesterone replacement and gonadectomy is not recommended.

Answer 42

d. Estrogen and progesterone replacement Explanation: Management of 46,XX “pure” gonadal dysgenesis involves estrogen and progesterone replacement since there is no Y chromosome material and gonadectomy is not recommended.

Answer 43

Gonadal dysgenesis refers to a group of conditions characterized by abnormal gonadal development. There are several types of gonadal dysgenesis, including: 45,X (Turner syndrome) 46,XY gonadal dysgenesis 46,XX gonadal dysgenesis 46,XX/46,XY gonadal dysgenesis (mixed gonadal dysgenesis)

Answer 44

C. Mixed Gonadal Dysgenesis

Answer 45

B. 15%-35%

Answer 46

A. Denys-Drash Syndrome

Answer 47

Mixed Gonadal Dysgenesis (MGD) is a disorder of sexual development characterized by a unilateral testis, a contralateral streak gonad, and persistent Müllerian structures associated with varying degrees of masculinization. Most patients with MGD have a 45,XO/46,XY karyotype. MGD can also present with phenotypic internal asymmetry, where a dysgenetic or streak gonad on one side will be associated with an ipsilateral uterus and fallopian tube, and a testicle on the contralateral side can be associated with wolffian duct structures (e.g., epididymis, vas deferens). This underscores the effects of local testosterone and AMH secretion. MGD is the second most common cause of ambiguous genitalia in the neonatal period.

Answer 48

The risk of gonadoblastoma or dysgerminoma in patients with mixed gonadal dysgenesis is 15%-35%. Denys-Drash syndrome and Frasier syndrome are associated with mutations in the Wilms tumor suppressor gene and are associated with mixed gonadal dysgenesis. Denys-Drash syndrome is associated with nephropathy, genital ambiguity, and Wilms tumor. The risk of gonadal tumor in patients with Denys-Drash syndrome is up to 40%. Frasier syndrome is not associated with an increased risk of Wilms tumor but a 60% risk of gonadoblastoma in the presence of Y chromosome material.

Answer 49

Sex assignment, gonadectomy if indicated, and screening for Wilms tumor are the primary considerations for the management of mixed gonadal dysgenesis. If male gender is selected and the testicle can be brought to the scrotum, physical exam and ultrasound screening for gonadoblastoma must be weighed against prophylactic gonadectomy and androgen replacement. Screening recommendations for patients with mixed gonadal dysgenesis include regular abdominal ultrasounds for Wilms tumor and periodic evaluation of sex hormone levels.

Answer 50

b) Only one dysgenetic testis

Answer 51

c) More than 40%

Answer 52

d) Similar to mixed gonadal dysgenesis

Answer 53

Partial gonadal dysgenesis is a disorder of gonadal differentiation and development that is characterized by two dysgenetic testes and variable phenotypic presentation. Individuals typically have a 45,X/46,XY or 46,XY karyotype.

Answer 54

The phenotype of partial gonadal dysgenesis is variable, depending on the production of anti-Müllerian hormone (AMH) and testosterone. Some common features include ambiguous genitalia, undescended testes, and infertility. Other features may include shortened stature, hearing loss, and skeletal abnormalities.

Answer 55

The risk of gonadal malignancy has been estimated to be more than 40% by 40 years of age. Therefore, regular monitoring with physical examination, imaging studies, and tumor markers is recommended. The management approach is similar to that of mixed gonadal dysgenesis, which may involve surgical removal of the dysgenetic testes. Hormonal replacement therapy may also be necessary. Genetic counseling is recommended for affected individuals and their families.

Answer 56

a. Lack of testis formation despite a Y chromosome, with bilateral streak gonads, normal female genitalia, and well-developed Müllerian structures.

Answer 57

a. Delayed puberty and amenorrhea.

Answer 58

Swyer Syndrome is a disorder of gonadal differentiation and development. It is characterized by a lack of testis formation despite having a Y chromosome. Bilateral streak gonads are present, and the individual has normal female genitalia and well-developed Müllerian structures. The absence of testis formation is due to mutations in genes that regulate the differentiation and development of the gonads.

Answer 59

The majority of individuals with Swyer Syndrome present in adolescence with delayed puberty and amenorrhea. There is no genital ambiguity, but there is sexual infantilism. High levels of serum gonadotropins are observed, which can lead to elevated androgen levels and clitoromegaly in some individuals. In addition, there may be other associated features such as short stature and osteoporosis.

Answer 60

The risk of germ cell tumors in Swyer Syndrome is up to 35% by 30 years of age. Therefore, management includes gonadectomy and cyclic hormone replacement therapy. The gonads are removed to prevent the development of tumors. Hormone replacement therapy is given to induce puberty and to replace the hormones that are normally produced by the gonads. Counseling and support may also be necessary to help individuals cope with the psychological and social issues associated with the disorder.

Answer 61

A) Genetic mutation, teratogen, or bilateral testicular torsion Explanation: The etiology of Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome is postulated to be caused by a genetic mutation, teratogen, or bilateral testicular torsion.

Answer 62

D) Range from typical female to ambiguous to male Explanation: The phenotype range of patients with Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome ranges from typical female to ambiguous to male.

Answer 63

C) Karyotype, castrate levels of testosterone, and elevated gonadotropins during mini-puberty from 2-6 months of age Explanation: Diagnosis for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome can be made with karyotype, castrate levels of testosterone, and elevated gonadotropins during mini-puberty from 2-6 months of age.

Answer 64

C) Individualized Explanation: Treatment for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome is individualized.

Answer 65

Ovotesticular DSD is a condition where individuals have both testicular and ovarian tissue. The gonads may take the form of one ovary and one testis, or more commonly, one or two ovotestes. The chromosomal makeup in order of frequency is 46,XX, mosaicism with Y chromosome material, and 46,XY.

Answer 66

The differentiation of both the external and internal genitalia is variable and related to the function of the ipsilateral gonad. In most, the genitalia are ambiguous. The ovary, most commonly found on the left side, is usually orthotopic. Testes and ovotestes, more commonly found on the right side, can lie anywhere in the path of testicular descent. Fallopian tubes are consistently present along with the ovary, and vas deferens alongside the testis. Ovotestes can have fallopian tube, vas deferens, or both structures. In most patients, a uterus is present. Frequently, the ovarian portion of an ovostestis is normal while the testicular component is dysgenetic.

Answer 67

Although both gonadoblastoma and dysgerminoma have been described, the incidence is low. Gender assignment is based on functional potential of external and internal genital

Answer 68

b) Congenital adrenal hyperplasia Explanation: Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in newborns.

Answer 69

c) 21-hydroxylase deficiency Explanation: A deficiency in 21-hydroxylase is responsible for 95% of cases of congenital adrenal hyperplasia.

Answer 70

c) Hydrocortisone administration Explanation: Treatment of congenital adrenal hyperplasia consists of hydrocortisone administration in childhood and adolescence.

Answer 71

d) All of the above Explanation: Maternal ingestion of progestins or androgens, aromatase deficiency in the mother, and maternal tumor with virilizing effects on a female fetus are all potential sources of increased maternal androgens leading to 46,XX DSD.

Answer 72

46,XX DSD is a phenotypic abnormality of sexual development in which individuals with no chromosomal abnormalities and ovaries have some degree of external masculinization and ambiguous genitalia. The condition presents with variable degrees of clitoromegaly and labial fusion in females, and a common urogenital sinus. Müllerian structures are usually normal.

Answer 73

CAH is caused by a defect in one of five enzymes involved in the cortisol biosynthetic pathway, resulting in impaired production of hydrocortisone and a compensatory increase in secretion of adrenocorticotrophic hormone (ACTH). A deficiency in 21-hydroxylase is responsible for 95% of cases, while a deficiency in 11β-hydroxylase accounts for approximately 5% of cases. The most common presentation of CAH is ambiguous genitalia in the newborn, with varying degrees of virilization in females. Patients with 21-hydroxylase deficiency exhibit one of three presentations: salt wasting and virilization, simple virilization without salt wasting, and those without evidence of either. In the salt-losing variant, failure to regain birth weight, weight loss, and dehydration occur in the first few weeks of life, and in severe cases, adrenal crises can occur within the first 10-21 days of life. In males with CAH, there is sexual precocity within the first 2-3 years of life.

Answer 74

Evaluation of CAH includes testing for serum electrolytes, serum renin, and cortisol levels. Pelvic ultrasound may be used to demonstrate Müllerian structures in classic 21-hydroxylase deficiency. Management of CAH consists of hydrocortisone administration in childhood and adolescence. Those with the salt-wasting variant require increased salt intake and mineralocorticoid treatment indefinitely. Surgical management in CAH patients is controversial and can include urethroplasty and vaginoplasty to create separate orifices and enlarge the vaginal introitus, clitoroplasty with reduction in size and creation of a clitoral hood, and feminizing vulvoplasty/labioplasty. Proper hormonal supplementation can lead to long-term fertility in males and feminization and menstruation in females.

Answer 75

46,XX DSD secondary to increased maternal androgens is a rare diagnosis, historically caused by maternal ingestion of progestins or androgens, aromatase deficiency in the mother, or a maternal tumor with virilizing effects on a female fetus. The diagnosis is recognized postnatally by a normal hormonal profile, and genital reconstruction, if desired, is the only treatment.

Answer 76

E Explanation: All of the mentioned enzymes are required for testosterone biosynthesis. Deficiencies in any of these enzymes not only result in abnormal testosterone production but also impaired production of glucocorticoids and mineralocorticoids.

Answer 77

B Explanation: Syndrome of complete androgen insensitivity (CAIS) is characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of Müllerian derivatives (due to AMH secretion). A mutation in the gene for the androgen receptor is identified in 95% of cases.

Answer 78

B Explanation: Management of Müllerian structures in PMDS is controversial, as the vasa deferentia are in close proximity to the uterus and proximal vagina, and preservation of structures to prevent vas injury has been recommended. However, malignancies have been reported in up to 8% of Müllerian remnants, supporting careful excision.

Answer 79

Leydig cell aplasia is a rare autosomal recessive trait in males that yields absence of Leydig cells or abnormalities of the LH receptor on Leydig cells. The phenotype varies with bilateral testes. Absent rise of serum testosterone after hCG stimulation is characteristic. Histology of the testicles shows absence of Leydig cells with normal Sertoli cells. The diagnosis is made through genetic testing and hormonal evaluation. Management of Leydig cell aplasia is variable and dependent on the enzymatic abnormality determined by genetic testing.

Answer 80

5α-reductase deficiency is caused by an autosomal recessive mutation in the 5α-reductase type II isoenzyme, which catalyzes conversion of testosterone to DHT. This mutation is expressed at high levels in the prostate and external genitalia. The phenotype of 5α-reductase deficiency ranges from female, to ambiguous genitalia, to penoscrotal hypospadias. The diagnosis is made through genetic testing and hormonal evaluation. Individuals with 5α-reductase deficiency have normal plasma testosterone but low DHT. After hCG stimulation, the testosterone/DHT ratio increases markedly (20:1). This diagnosis is associated with gender reversal at puberty, specifically in a pedigree study from the Dominican Republic, individuals known as guevedoces (“testicles at 12,” or “penis at 12”). Male gender assignment is usually favored, but studies supporting this were performed in a unique sociologic environment.

Answer 81

d. Irregular menstrual cycles Explanation: The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Answer 82

d. Irregular menstrual cycles Explanation: The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Answer 83

c. Absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics Explanation: MRKH is associated with congenital absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics. Normal ovaries and fallopian tubes are present, but only uterine remnants remain, along with a shallow vaginal pouch.

Answer 84

c. Renal agenesis, pelvic kidney, and horseshoe kidney Explanation: Upper tract urinary anomalies occur in one third of patients with MRKH, including renal agenesis, pelvic kidney, and horseshoe kidney.

Answer 85

Mayer Rokitansky Küster hauser syndrome (MRKH) is a congenital disorder that is associated with the absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics. Normal ovaries and fallopian tubes are present, but only uterine remnants remain, along with a shallow vaginal pouch. Upper tract urinary anomalies occur in one third of patients, including renal agenesis, pelvic kidney, and horseshoe kidney. The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Answer 86

MRKH is evaluated using abdominal ultrasound or MRI to demonstrate an absent uterus. Hormonal profile can also be used to demonstrate normal female parameters. Management of MRKH involves the creation of a neovagina with dilation or surgery. If present, a hemiuterus should be removed or hormonally suppressed. Upper tract urinary anomalies may also require further management. Psychological counseling and support may also be beneficial for individuals with MRKH.

10: Disorders of sexual development Flashcards

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