Normal sexual development requires a series of sequential and highly regulated events early in fetal development. This sexual differentiation process is regulated through complex interactions from both genetic and hormonal signals. Any disruption in this developmental pathway can lead to a disorder of sex differentiation (DSD).
Neonates born with ambiguous genitalia present a daunting challenge to all involved in health care delivery to the individual patient. An urgent evaluation by appropriate disciplines with discrete and delicate interaction with the family is mandatory. Older and potentially negative and confusing terminology has been replaced and should not be used. A new nomenclature for disorders of sex development, introduced at the 2005 Chicago Consensus Conference,1 is more precise, integrates better the progress in our understanding of the molecular basis of development, and is more sensitive to the concerns of the family and patients (Table 48-1).
Table 48-1Proposed Revised Nomenclature ||Download (.pdf) Table 48-1 Proposed Revised Nomenclature
|Previous ||Proposed |
|Intersex ||Disorders of sex development (DSD) |
|Male pseudohermaphrodite || |
| Undervirilization of an XY male ||46,XY DSD |
| Undermasculinization of an XY male || |
|Female pseudohermaphrodite || |
| Overvirilization of an XX female ||46,XX DSD |
|Masculinization of an XX female || |
| True hermaphrodite ||Ovotesticular DSD |
|XX male or XX sex reversal ||46,XX testicular DSD |
|XY sex reversal ||46,XY complete gonadal dysgenesis |
NORMAL SEXUAL DIFFERENTIATION AND DEVELOPMENT
Undifferentiated Stage of Sexual Differentiation
Normal fetal development of the gonads and the genitalia proceed through 3 sequential stages. The first stage involves the formation of the bipotential gonads from the adrenogonadal ridge at approximately 4 to 5 weeks’ gestation. During this undifferentiated stage, identical structures form in both the XY and XX embryo (Figure 48-1). These structures emanate from the mesonephros and coelomic epithelium. They are the wolffian (precursors to the formation of the seminal vesicles, epididymis, and vas deferens) and müllerian ducts (precursors to the fallopian tubes, uterus, and vagina).
Diagram of the external genitalia in the undifferentiated period. (Reproduced with permission from Diamond.29)
During this phase, the cloaca, which is the terminal portion of the hindgut limited by the cloacal membrane, is partitioned into an anterior urogenital sinus and a posterior anorectal canal. Subsequently, the urogenital sinus becomes the bladder in both sexes and is the precursor for the prostate and proximal urethra in males and the entire urethra and vagina in females.
By the seventh week of gestation, the undifferentiated gonads in a male embryo develop into a testis under the influence of the SRY (sex determining region of the Y chromosome) gene located on the short arm of the Y chromosome. The SRY gene expression causes the primitive sex cords to differentiate into Sertoli cells, which when organized form the seminiferous cords. Primordial germ cells populate near the basement membrane of the cords, while Leydig cells appear in the interstitium between the cords around 8 weeks.
In the female embryo, the undifferentiated gonad does not contain the Y chromosome. Thus, there is no SRY gene production with no resultant differentiation of cells into Sertoli cells. The primitive sex cords degenerate, and secondary sex cords formed from the genital ridge join with primordial germ cells to form the ovarian follicles. At this time, the germ cells differentiate into oogonia and become oocytes following the first meiotic division. Many oocytes at this time are surrounded by a single layer of granulosa cells, becoming primary follicles at around 15 weeks’ gestation. Further meiosis is arrested under puberty when under hormonal influence meiosis resumes. The total population of germ cells reaches an apex of several million by 5 months’ gestation. However, by the time of birth, most cells have undergone apoptosis, leaving approximately 150,000 oocytes in each ovary at birth.
Other Genes Involved in Gonadal Differentiation
The DAX1 gene has been implicated in several cases of XY sex reversal.2 Screening of XY females with a normal SRY gene detected the presence of a submicroscopic duplication of a region designated DDS (dosage-sensitive sex reversal). Within this region, the DAX1 gene was identified. Investigation using a transgenic, XY genotype mouse carrying extra copies of the DAX1 gene led to a phenotypically female mouse in the setting of low expression of the SRY gene.3
The SOX9 gene was found to play a role in sex determination through investigation of patients with campomelic dysplasia (CD).4 In this rare skeletal disorder, a high preponderance of patients were found to have male-to-female sex reversal. Loss-of-function mutations of SOX9 were found in XY females with CD, pointing to a critical role SOX9 likely plays in sex determination.5 While the exact targets of SOX9 are unclear, it is structurally similar to SRY and has been proposed to be responsible for an SRY-negative, XX male patient.6
Steroidogenic factor 1 (SF-1) is a transcription factor that plays a key role in the regulation of endocrine function and development of the adrenal glands and the gonads in both sexes. The results of SF-1 knockout mice models demonstrated a failure of adrenal and gonadal development with XY sex reversal with persistence of the müllerian ducts in males. Ovaries fail to develop in XX female mice lacking the SF-1 gene.7 Clinically, there has been a report of an XY female who was found to have adrenal failure at 2 weeks with a poorly differentiated testis, normal female genitalia, and the presence of a uterus. On evaluation, she was found to have a heterozygous mutation in the DNA-binding domain of SF-1, which was likely the cause of the clinical findings.8
The Wilms tumor 1 (WT1) gene was originally discovered on chromosome 11p13 during efforts to find the oncogene responsible for Wilms tumor.9 Following its discovery, further investigation of WT1 expression in humans and mice models demonstrated a significant relationship between WT1 protein secretion and sex determination. WT1 expression has been found to have a complex role with multiple sites of action, including modulating SF-1 expression, regulating SRY gene actions, and competing with DAX1.10, 11, and 12
Mutations involving WT1 expression are linked to urinary and genital abnormalities in 3 syndromes: WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Denys-Drash syndrome, and Frazier syndrome. Denys-Drash syndrome is a rare genetic disorder associated with gonadal and genital abnormalities, Wilms tumor, and renal failure due to mesangial sclerosis. Frasier syndrome is characterized by male-to-female sex reversal, focal segmental glomerular sclerosis, and Wilms tumor.
Differentiation of the Genital Ducts and External Genitalia
Male Genital Duct Development
By the eighth week of gestation, the developing Sertoli cells secrete müllerian-inhibiting substance (MIS), which causes the müllerian ducts to regress rapidly by the 10th week of gestation. Between the 8th and 12th weeks, Leydig cells secrete testosterone, which stimulates the cranial aspect of the wolffian duct to transform into the epididymis and vas deferens. The caudal portion of the wolffian duct develops into the ejaculatory ducts and seminal vesicles (Figure 48-2).
Fate of the wolffian and müllerian ducts. In the male, the wolffian ducts form the epididymis, vas, and seminal vesicle. In the female, the müllerian ducts form the fallopian tubes, uterus, and upper third of the vagina. at, appendix testis; e, epoöphoron; G, gonad; Gd, Gartner duct; m, mesonephros; md, müllerian duct; um, utriculus masculinus; vmd, vestigial müllerian duct; vwd, vestigial wolffian duct; wd, wolffian duct. (Reproduced with permission from Kelalis P, King LR, Belman AB, et al: The Kelalis-King-Belman textbook of clinical pediatric urology. 5th ed. Abingdon, UK: Informa Healthcare; 2007.)
Female Genital Duct Development
In the female fetus, müllerian duct formation proceeds in the absence of MIS secretion. The müllerian ducts give rise to the fallopian tubes and uterus by the 12th week of gestation. Historically, it was accepted that the upper two-thirds of the vagina originated from the müllerian ducts, with the lower third developing from the posterior urogenital sinus and fusing around 12 weeks’ gestation. Recent small-animal studies have called into question this theory, with genetic molecular work pointing to a complete müllerian vagina.13
Development of the External Genitalia
The early development of the external genitalia is similar in both sexes. Around the fifth week of gestation, a pair of swellings called the cloacal folds joins anterior to the cloacal membrane to form the genital tubercle. The urogenital and labioscrotal folds then appear shortly on either side of the genital tubercle.
Development of Male External Genitalia
In the male fetus, the undifferentiated stage of genital development ends around the ninth week with secretion of testosterone and local conversion to dihydrotestosterone causing an increase in distance between the genital tubercle and anal folds (Figure 48-3). The genital tubercle elongates to become the penis, with the urethral groove forming over the ventrum of the penis. Urethral folds, which are extensions of the urogenital folds, form the lateral margins of the urethral groove. The urethra is then created with the fusion of the urethral folds over the urethral groove. The labioscrotal folds then fuse in the midline to create the scrotum. The urogenital folds fuse over the newly created urethra to provide skin coverage for the penis. This process is completed by the 14th week. The phallus will continue to grow throughout the remainder of gestation. Testicular descent occurs through multiple mechanisms and is typically complete by the third trimester.
Differentiation of the male external genitalia. (Reproduced with permission from Diamond.29)
Development of Female External Genitalia
In the absence of testosterone, the genital tubercle bends inferiorly and forms the clitoris in the female fetus (Figure 48-4). The labioscrotal folds do not fuse in the midline and develop primarily in the caudal portions, forming the labia majora. The urethral folds do not fuse and become the labia minora. The anterior urethral meatus and posterior vaginal orifice form between the labia minora, with this process complete by 14 weeks.
Differentiation of the female external genitalia. (Reproduced with permission from Diamond.29)
Our understanding of human psychosexual differentiation is limited and appears complex and multifactorial. The previously accepted view that humans are psychosexually neutral at birth14 has more recently been questioned by those who support the opposing view that a “neural bias” exists determined primarily by prenatal hormonal exposure.15 Studies in mammals demonstrated a significant role of both testosterone and estrogen exposure prenatally and sexual differentiation of the brain and behavior in utero.16, 17 This relationship between hormone exposure in utero and psychosexual differentiation is less clear in humans. However, the accumulated evidence demonstrates that androgen exposure prenatally has more influence on gender role (aspects of behavior in which males and females appear to differ) than gender identity (identification of oneself as either male or female).18
CLINICAL EVALUATION OF INFANTS WITH AMBIGUOUS GENITALIA
Prenatal suspicion of a DSD occurs most commonly when abnormalities of the genitalia are found on prenatal sonography or when there is a suspected genotype-phenotype mismatch with the karyotype and visualized genitalia or uterus.19 Characteristic findings are seen with ultrasound allowing for accurate prenatal sexual determination. Normal male genital findings on ultrasound include the penis, which is initially visualized as an upwardly projected phallic structure, in contrast to the clitoris, which will have a downward bend.19 Also, fetal penile length can then be measured in terms of a range throughout development.20 The scrotum can also be detected as a distinct structure by the second trimester21 and is sonographically distinct from the developing labia.22 In addition, a nomogram exists for uterine width and circumference measurements, which allows for assessment of normal female genital tract development from the second trimester until birth.23
In the rare situations for which genital abnormalities are suspected prenatally, it is important to follow the fetus longitudinally throughout the pregnancy. Fetal ultrasounds at 13–15 weeks are not good predictors of external genital development.19 The presence of a uterus after 19 weeks is a reliable predictor of internal reproductive organs. Karyotypic or external genital discrepancies based on the presence of a uterus should lead to cautious antenatal counseling, which can include the disciplines of neonatology, pediatric endocrinology, genetic counseling, pediatric urology, and psychology. Certainly, the assignment of sex for the child would be withheld until appropriate postnatal evaluation.
Every newborn must have a careful and complete genital examination. The importance of the examination includes not only assignment of the appropriate gender, but also the accurate diagnosis of more common abnormalities, such as hypospadias, chordee, and undescended testes.
Optimal management of neonates with a suspected DSD as recommended by the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) includes the following: (1) Avoidance of gender assignment before expert evaluation is complete. (2) Evaluation and long-term management must be carried out at center with an experienced multidisciplinarian team. (3) All neonates should receive a gender assignment. (4) Open communication with patients and families is essential, and participation in decision making is encouraged. (5) Patient and family concerns should be respected and addressed in strict confidence.
In the apparent male neonate, the palpability, location, and size of the testis (or ovotestis) should be noted. Ovaries do not descend. The length and diameter of the penis should be measured. Penile length is measured as the stretched length following the reduction of the prepubic fat from the pubic ramus to the tip of glans. Boys with a stretched penile length at term of less than 2 cm in an otherwise physically normal phallus have a micropenis. The location of the urethral meatus should be properly identified. The presence of ventral congenital curvature (chordee) should be documented. Neonates with severe chordee can make obtaining a true stretched penile length difficult. A flat, symmetric scrotum typically indicates bilateral undescended testes. A cleft or bifid scrotum usually occurs in conjunction with a severe penoscrotal or scrotal hypospadias and can look similar to labia.
In the apparent female neonate, the clitoris should be assessed for general size. Clitoromegaly can be dramatic, and in these patients, a stretched length and width should be measured. The urethral location and relationship to a separate vaginal orifice should be carefully assessed. In female fetuses exposed to high levels of testosterone in utero, a common distal stem off the vagina and urethra can occur (urogenital sinus). The os of the urogenital sinus can be located on the perineum or associated with the masculinized clitoris. The labia are normally unfused in females. Fusion, anterior placement of the labia with hyperpigmentation, and absence of labia minora are also signs of in utero androgen exposure. The uterus may be palpable on rectal examination as a cord-like structure anterior to the rectum.
A DSD evaluation should proceed in neonates with the physical findings of (1) overt genital ambiguity; (2) apparent female genitalia with an enlarged clitoris, posterior labial fusion, or an inguinal or labial mass; or (3) apparent male genitalia with bilateral undescended testes, micropenis, isolated perineal hypospadias, or hypospadias (Figure 48-5).
Virilized female genitalia.
Immediate laboratory evaluation of a neonate with a suspected DSD consists of measurement of serum electrolytes, testosterone, and dihydrotestosterone levels and karyotype. Serum 17-hydroxyprogesterone should not be measured until day of life 3 or 4 because elevated levels of this corticosteroid precursor can be found in normal neonates during the first few days of life due to the stress of delivery.24 If 17-hydroxyprogesterone is elevated, 11-deoxycortisol and deoycorticosterone levels are required. LH (luteinizing hormone) levels or a hCG (human chorionic gonadotropin) stimulation test can be performed to determine if functioning testicular tissue is present in the neonate with bilateral nonpalpable testes.
An abdominal and pelvic ultrasound is recommended as the first-line imaging study in the neonate with ambiguous genitalia. The presence of a uterus is accurately seen with pelvic ultrasound.25 Gonads may be seen, but the specificity and sensitivity of ultrasound is poor for nonpalpable testes and the presence of ovaries.26 The absence of visible gonads does not confirm their absence. In experienced hands, adrenal sonography is an accurate adjunct for the diagnosis of congenital adrenal hyperplasia (CAH).27 Studies, such as pelvic magnetic resonance imaging (MRI), flush genitogram, and retrograde urethrogram, are necessary in certain situations, typically dependent on physical examination findings.
CLASSIFICATION OF DISORDERS OF SEXUAL DIFFERENTIATION
Sex Chromosome Disorder of Sex Development
45,X/46,XY (Mixed Gondal Dysgenesis)
Mixed gonadal dysgenesis (MGD) is a group of disorders characterized by a unilateral testis, which is typically undescended; an intra-abdominal contralateral streak gonad, persistent müllerian duct structures; and varying degrees of virilization of the external genitalia.28 Infants typically present with ambiguous genitalia as this condition is the second-most-common cause of a DSD in the newborn period.29 The unilateral testis may be descended but usually is palpable in the groin or nonpalpable when located abdominally.
The uterus is typically rudimentary with bilateral fallopian tubes. In those patients with a well-differentiated testis, the ipsilateral fallopian is commonly absent. A urogenital sinus is present in about one-half of patients.
When the unilateral testis is palpable, it is typically more normal. However, the testicular cellular architecture is consistently abnormal in the adult patient, demonstrating few germ cells and sclerosis of the tubules.30 Wolffian structures are more commonly found on the side of the unilateral testis and usually include only the epididymis, with a well-differentiated vas deferens rarely present.
47,XXY (Klinefelter Syndrome and Variants)
Klinefelter syndrome is the most common abnormality of sexual differentiation, occurring in approximately 1 in every 600 live newborn males.31 The syndrome is classically characterized by gynecomastia, small testes, absent spermatogenesis, normal-to-moderately reduced Leydig cell function, and increased secretion of follicle-stimulating hormone (FSH).32 It is most commonly associated with the 47,XXY karyotype, but upward of 20% of patients will have higher-grade chromosome aneuploidies, 46XY/47XXY mosaicism, or structurally abnormal X chromosomes.33
The diagnosis is made prenatally in approximately 10% of patients because of genetic screening programs.31 Neonatal diagnosis is rare but can occur during an evaluation for micropenis, severe hypospadias, and undescended or small testes. Typically, the diagnosis is made following puberty when androgen deficiency becomes apparent. Young men with Klinefelter syndrome have sparse body and facial hair. Approximately half of the patients will develop gynecomastia. Adult men have small testes, which rarely exceed 2 cm in length and are atrophic on microscopic examination.
45,X (Turner Syndrome and Variants)
Turner syndrome is associated with an immature female phenotype with short stature, streak gonads, and various congenital anomalies. It is classically and most frequently associated with a missing X chromosome. Variant forms occur less commonly and include partial deletions of the second X chromosome. Various mosaicisms do occur and typically involve the X chromosome. In approximately 5% of patients, a 45,X/46XY mosaicism is found.
Neonates with Turner syndrome do not have ambiguous genitalia but have other somatic features that are noted both antenatally and perinatally, which can lead to the diagnosis (Table 48-2). A clinical guideline pathway exists for those children with a new diagnosis of Turner syndrome. The workup includes a cardiology evaluation, renal ultrasound, hearing testing, and referral to the appropriate support groups. Those patients with a diagnosis missed early in life are typically diagnosed later because of short stature, primary amenorrhea, or lack of secondary sexual development.
Table 48-2Antenatal and Neonatal Features of Turner Syndromea ||Download (.pdf) Table 48-2 Antenatal and Neonatal Features of Turner Syndromea
|Frequency ||Findings |
| ||Low posterior hairline |
| ||Lymphedema |
|Greater than 50% ||Nail dysplasia |
| ||Prominent ears |
| ||Retrognathia |
| ||Narrow palate |
| ||Webbed neck |
| ||Cubitus valgus |
|25%–50% ||Short fourth metacarpals |
| ||Ptosis |
| ||Strabismus |
| ||Multiple nevi |
| ||Epicanthal folds |
| ||Scoliosis |
|10%–25% ||Kyphosis |
| ||Pectus excavatum |
| ||Single palmar crease |
| ||Inverted nipples |
| ||Genu valgum |
|Less than 10% ||Madelung deformity |
| ||Patellar dislocation |
Müllerian structures are well differentiated but remain small. The ovaries are streaks by birth with rare surviving oocytes by adolescence. A small number of pregnancies have been reported. Those children with 45,X/46XY mosaicism and occult Y chromosome material have a 7% to 30% risk of developing a gonadoblastoma.
46,XX/46,XY Chimerism or Ovotesticular Development
Ovotesticular disorder, formerly known as true hermaphroditism, is defined as an individual who has both testicular tissue with seminiferous tubules and ovarian tissue with primordial follicles. The combination of gonads in this disorder includes an ovotestis and ovary (40%), bilateral ovotestes (34%), ovotestis and testis (15%), and ovary and testis (10%).34
Patients predominantly are born with ambiguous genitalia and can have varying karyotypes. Approximately 60% of patients are 46,XX, 33% are either a 46,XX/46,XY chimerism or a 46,XX/46XXY mosaicism, and 7% are 46,XY. Understanding of the signaling pathway for testicular formation in patients with a 46,XX karyotype is not completely elucidated but likely involves an X-linked or autosomal mutation, which causes testicular differentiation downstream of the SRY gene.29
Most have more masculinized genitalia and are raised as males following hypospadias and chordee repair. Children raised as females usually have clitoromegaly and a urogenital sinus. Ovaries are typically in a normal location with an associated fallopian tube and usually found on the left side. Testes or ovotestes are more commonly found on the right and can be found anywhere in the normal testicular descent pathway.35 Testes or an ovotestis with predominantly testicular tissue are more likely to descend. A vas deferens and epididymis are almost always present with a testis. In ovotestes, a fallopian tube is found two-thirds of the time as compared to either a vas deferens or both internal ducts in a third.
Histologically, ovarian tissue is typically normal in the ovotestis with the exception of a reduced number of primordial follicles. In contrast, the testicular component of an ovotestis has tubular atrophy with absent spermatogenesis. Gonadal tumors occur in 2%–3% of these patients.36
46,XY Disorders of Sexual Development
Disorders of Testicular Development
Complete Gonadal Dysgenesis
Children with complete gonadal dysgenesis have a 46,XY karyotype, female-appearing external genitalia, normal müllerian structures, and bilateral streak gonads similar to Turner syndrome.37 The majority of patients present in their teens with absent breast development and amenorrhea. Some patients demonstrate clitoromegaly, thought to be due to the elevated levels of gonadotropins.29 The diagnosis is usually made from the karyotype ordered during the evaluation. Patients with complete gonadal dysgenesis have a 30% risk of developing malignant tumors in their gonads by age 30.38
Partial Gonadal Dysgenesis
Patients with partial gonadal dysgenesis (PGD) present similarly to those patients with MGD except that those with PGD have 2 dysgenetic testes rather than 1 dysgenetic testis and a streak gonad. The genital phenotype can range from ambiguous to either normal male or female. This variance is due to the ability and timing of secretion of testosterone from the dysgenetic testes. Usually, persistent müllerian structures are present, but to varying degrees related to MIS secretion. Similar to patients with complete gonadal dysgenesis, those with PGD are at a high risk for gonadal malignancy.38
Testis Regression and Bilateral Vanishing Testes Syndromes
The testis regression and bilateral vanishing testes syndromes encompass a wide spectrum of phenotypes that occur due to testes that “vanish” antenatally, causing varying degrees of abnormalities of both the external genitalia and internal duct development. Testis regression syndrome usually refers to a loss of testicular tissue within the first trimester, resulting in genital ambiguity. In contrast, bilateral vanishing testes syndrome is thought to occur later in utero, after male sexual differentiation of both the internal ducts and external genital anatomy.39
The etiology of the vanishing testis is not elucidated, but hypotheses include bilateral torsion, a genetic mutation, or a teratogen. Neonates with bilateral vanishing testes syndrome present typically with phallic abnormalities, such as a micropenis or severe chordee, or as a phenotypically normal male with an empty scrotum.40 Newborns have castrate levels of testosterone in the setting of elevated serum LH and FSH and a 46,XY karotype.
Patients with bilateral vanishing testes syndrome present with ambiguous genitalia or as a phenotypically normal female, depending on the in utero timing of the insult. In severe cases, a 46,XY female is diagnosed at puberty with no müllerian or wolffian structures. This is thought to occur due to the secretion of MIS from the testes prior to regression before androgen secretion.
Disorders in Androgen Synthesis or Action
Androgen Biosynthesis Defect
A defect in any of the steps involved in the synthesis of testosterone from cholesterol will result in absent or decreased production of androgens and resultant 46,XY DSD. There are 6 specific steps involved in this process, 5 involving enzymes (Figure 48-6). Three of these enzymes are required also for cortisol production (cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase), and their defect will lead to impaired cortisol and possibly mineralocorticoid production. All 5 of these enzyme deficiencies are inherited in an autosomal recessive pattern.
Steroidogenic pathways. Substrates, products, and genes involved in adrenal, ovarian, testicular, and placental steroidogenesis. Genes are 17α-hydroxylase/17,20-lyase (CYP17), 3β-hydroxysteroid dehydrogenase (HSD3B2), 21-hydroxylase (CYP21), 11β-hydroxylase (CYP11B1), aldosterone synthase (CPY11B2), aromatase (CYP19), 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1), 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3), 5α-reductase type 2 (SRD5A2), sulfotransferase (SULT2A1), and steroid sulftase/arylsulfatase C (ARSC1). CYP3A7 is a cytochrome P450 enzyme expressed in fetal liver, where it catalyzes the 16α-hydroxylation of estrone (E1) and DHEA (dehydroepiandrosterone). Its expression decreases postnatally. Steroidogenic enzymes that utilize P450 oxidoreductase to transfer electrons are indicated by hatched arrows. DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; DOC, 11-deoxycortisol. (Reproduced from Witchel and Lee.68)
StAR Deficiency (Congenital Lipoid Adrenal Hyperplasia). The first step in steroidogenesis involves the transport of cholesterol into the mitochondria. This defect in steroidogenic acute regulator (StAR) protein leads to significant feminization of the genitalia with either completely female features or ambiguous genitalia. Patients have testes located in the abdomen, inguinal canal, or labia. Rudimentary wolffian structures are present with an absence of müllerian ducts. Neonates develop adrenal insufficiency. In some cases, this is life-threatening, affecting newborns as young as 1–2 days old. Other newborns have a milder presentation and present at an older age (2–4 weeks). Patients with this disorder have an enormous accumulation of lipid in the adrenal gland as seen on abdominal imaging, alternatively giving the name congenital lipoid adrenal hyperplasia.
Cholesterol Side-Chain Cleavage Enzyme Deficiency. The second step in steroid hormone synthesis is the conversion of cholesterol to pregnenolone by cholesterol side-chain cleavage enzyme. A deficiency in this enzyme leads to ambiguous genitalia in affected XY males. Corticosteroid and mineralocorticoid production is also impaired, requiring prompt identification and treatment.
3β-Hydroxysteroid Dehydrogenase Deficiency. The 3β-hydroxysteroid dehydrogenase enzyme is found early in the pathway for steroidogenesis and is required for formation of all steroids. Its deficiency affects production of glucocorticoids, mineralocorticoids, and the sex steroids. Boys with 3β-hydroxysteroid dehydrogenase insufficiency have incomplete masculinization of the external genitalia, with findings of a small phallus with hypospadias, a urogenital sinus with blind-ending vaginal pouch, and scrotal testes on examination. Patients have normal wolffian and no müllerian ducts. Salt wasting occurs because of the impaired production of cortisol and aldosterone.
17α-Hydroxylase Deficiency. Patients with 17α-hydroxylase deficiency disorder have absent or only slight masculinization of the external genitalia. Many have normal female genitalia with a blind-ending vaginal pouch and intra-abdominal testes. The deficiency of 17α-hydroxylase leads to the accumulation of desoxycorticosterone, corticosterone, and 18-hydroxycorticosterone in the adrenals, which leads to salt and water retention, hypokalemia, and hypertension.
17,20-Lyase Deficiency. Newborns with deficiency of 17,20-lyase can have a wide spectrum of genital abnormalities, but usually present with ambiguous genitalia. If the diagnosis is not made as an infant, patients present at puberty because of a lack of secondary sexual characteristics.
17β-Hydroxysteroid Oxireductate Deficiency. Newborns with deficiency of 17β-hydroxysteroid oxireductate appear to have a normal phenotype and are typically raised female. These patients have intra-abdominal, inguinal, or labial located testes with normal wolffian and absent müllerian ducts. The diagnosis may be made during repair of an inguinal hernia but typically is made at puberty when there is significant phallic growth and development of male secondary sexual characteristics. Pubertal increases in gonadotropin production lead to a spike in androstenedione production, which overcomes the enzymatic defect and raises testosterone levels into the low-normal range.
Androgen Receptor and Postreceptor Defects
Androgen Insensitivity Syndromes. Patients with both complete and partial androgen receptor defects characteristically have a 46,XY karyotype with bilateral testes. Abnormalities of androgen receptor function represent the most common definable cause of the undervirilized male and are transmitted as an X-linked trait.29 Those with complete androgen insensitivity syndrome have no associated or limited derivatives of wolffian structures.41 These patients have a female phenotype and no müllerian structures. Diagnosis is rare before puberty unless a karyotype is performed during pregnancy or if testes are found in the groin or labia on physical examination or during repair of an inguinal hernia. Otherwise, these patients present at puberty with primary amenorrhea and development of secondary female sexual characteristics due to the conversion of testosterone to estradiol.
Newborns with partial androgen insensitivity syndrome have incomplete masculinization of their external genitalia. On examination, there is a wide spectrum of findings, but patients usually have hypospadias, bilateral undescended testes, and rudimentary wolffian structures. Multiple mutations of the androgen receptor gene exist, but in general, the abnormality exists as a reduced number of normally functioning receptors or a normal receptor number but decreased binding affinity.42
Disorders of Androgen Action. 5α-Reductase is an enzyme that converts testosterone to dihydrotestosterone. The absence of the enzyme is transmitted in an autosomal recessive pattern, with only homozygous males affected. These children have normal formation of testes and male internal genital duct through the action of testosterone. However, without dihydrotestosterone, normal male external genitalia do not occur. Neonates with this condition present with severe hypospadias or more commonly with ambiguous genitalia. Patients undiagnosed as newborns with bilateral nonpalpable testes can present in a very unusual fashion at puberty with significant phallic development and subsequent gender reversal due to markedly high levels of testosterone.43
Luteinizing Hormone Receptor Abnormality. LH receptor abnormality or Leydig cell aplasia is found typically during an evaluation for a delay in puberty in an adolescent girl. Younger patients may present with this condition with a palpable testis in the inguinal canal or labia. This disorder is characterized by a normal 46,XY karyotype with no wolffian or müllerian structures and a short vagina. It is transmitted as an autosomal recessive trait. Laboratory examination is classic for a low basal level of testosterone, which does not respond to hCG stimulation. Testicular cellular architecture demonstrates an absence or severe reduction in the number of Leydig cells but normal Sertoli cells.
Antimüllerian Hormone and Receptor Abnormality. The condition of antimüllerian hormone and receptor (AMR) abnormality, also known as persistent müllerian duct syndrome or as classically described hernia uteri inguinale,44 has characteristic features of a normal-appearing 46,XY male with internal müllerian structures. Patients usually have bilateral fallopian tubes, a uterus, a vagina draining into a prostatic utricle, and either unilateral or bilateral undescended testes. Most frequently, this condition is found during an inguinal hernia repair or orchiopexy when müllerian structures are encountered.
Antimüllerian hormone and receptor abnormality appears to be a heterogeneous genetic disorder affecting the production of either AMH or its receptor. Its transmission occurs as a sporadic mutation or as an X-linked trait. Several clinical forms have been described. The majority of patients (60%–70%) have bilateral intra-abdominal testes similar in location to ovaries. The next-most-common presentation (20% to 30%) is when 1 testis is partially descended and a uterus and fallopian tube are encountered during the inguinal hernia repair, the classic hernia uteri inguinale presentation. The least commonly seen group (10%) is when both testes are found in the same hernia sac with fallopian tubes and uterus due to transverse testicular ectopia.45
46,XX Disorders of Sex Development
Disorders of Ovarian Development
Children with 46,XX gonadal dysgenesis have findings similar to Turner syndrome: bilateral streak gonads, normal müllerian structures with absence of wolffian structures, and normal external genitalia. They differ as these patients have a normal karyotype and stature without other classic physical findings seen in Turner syndrome. Familial cases do occur, which may include include renal disorders, neurologic abnormalities, and sensorineural hearing loss.46
Testicular Disorder of Sex Development (46,XX Male)
The classic presentation of an individual with testicular disorder of sex development (46,XX male) is a normal male phenotype with a 46,XX karyotype. Nonclassic forms occur around 10%–20% percent of the time in neonates with varying degrees of sexual ambiguity and a 46,XX karyotype.47 Patients with this condition have normal testes at birth that under the influence of the second X chromosome, deteriorate by adulthood as demonstrated by small testicular volume, an absence of spermatogonia, and hyalinization of the seminiferous tubules. Approximately 90% of boys of with this disorder result from an abnormal Y-to-X translocation involving the SRY gene during meiosis.48 Those with more SRY gene material are typically more virilized.
46,XX Ovotesticular Disorder
For discussion of 46,XX ovotesticular disorder, refer to the previous section on 46,XX/46,XY (chimerism or ovotesticular disorder).
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is the leading cause for a masculinized female and most common DSD in general. Of the 5 enzymatic deficiencies that cause CAH, only abnormalities in 21-hydroxylase (21HD), 11β-hydroxylase, and to a lesser extent 3β-hydroxysteroid dehydrogenase lead to virilization of the female genitalia.
21-Hydroxylase Deficiency. By far the most common cause of CAH is a deficiency of 21HD, which catalyzes the conversion of 17-OH progesterone to 11-deoxycortisol, a precursor of cortisol. It is transmitted in an autosomal recessive pattern and occurs in approximately 1:15,000 live births. 21HD deficiency is responsible for 95% of CAH cases.49
There are 2 forms of 21HD deficiency. The most common classic presentation is an infant with both salt wasting and virilization (75%). Twenty-five percent of newborns only virilize.50 The nonclassic form is milder, with patients presenting in adolescence and adulthood with androgen excess.
Newborns present with varying degrees of virilization. Girls have enlargement of their clitoris, labia fusion, and a common urogenital sinus. In severe cases, the clitoris appears completely phallic. Prader classified the degrees of masculinization of the external genitalia in females with CAH51 (Figure 48-7). Müllerian structures and ovaries are typically normal. Without treatment, progressive virilization of the genitalia will continue, with early development of secondary sexual characteristics, premature epiphyseal closure, and short stature.
Classification of masculinization of genitalia in girls with congenital adrenal hyperplasia as described by Prader. (Reproduced with permission from Incidence of congenital adrenogenital syndrome. Helv Paediatr Acta. 1958;13(5):426–431.)
In neonates with the salt-wasting variant, symptoms become evident within the first several weeks of life. These include nausea, vomiting, dehydration, and progressive weight loss. In some patients, adrenal crisis can occur. Often, this condition is confused with pyloric stenosis. Without rapid and appropriate resuscitation, death can occur due to hyperkalemia, dehydration, and shock.
Affected males, without the salt variant, present with sexual precocity. Characteristic signs can be seen as early as 2 years and include significant phallic enlargement, pubic hair, deepening of the voice, acne, and advanced bone age. The term little Hercules has been used to physically describe these boys.
11β-Hydroxylase Deficiency. 11β-Hydroxylase deficiency is the second-most-likely enzymatic deficiency leading to virilization in patients with CAH.52 Both classic and nonclassic forms are seen. The classic presentation of 11β-hydroxylase deficiency is similar to the classic presentation of 21HD deficiency with marked virilization. In contrast to 21HD deficiency, hypertension is found in the classic form due to the increased serum levels of desoxycorticosterone. Patients with the nonclassic variant present in childhood or adolescence with early virilization. Similar to 21HD, 11β-hydroxylase deficiency is inherited as an autosomal recessive disorder.
3β-Hydroxysteroid Dehydrogenase Deficiency. 3β-Hydroxysteroid dehydrogenase deficiency is the least-common enzyme deficiency causing virilization in CAH. Similar to 21HD deficiency, neonates present with virilization and can have issues with salt wasting. However, genital virilization is usually less in this condition than in children with 21HD deficiency.53
Cytochrome P450 Oxidoreductase Deficiency. The cytochrome P450 oxidorecductase enzyme acts as a cofactor for the P450 microsomal enzymes, which include 17α-hydroxylase, 17,20-lyase, and 21HD. Deficiencies in this enzyme can lead to a wide spectrum of both genital abnormalities and cortisol insufficiency.54 Most neonates with this condition also have Antley-Bixler syndrome (craniosynostosis, hydrocephalus, distinct facies, low-set ears, multiple skeletal anomalies, renal abnormalities, and developmental delay).
Maternal Androgen Excess. Maternal androgen excess is a rare cause of masculinization of the female fetus. Historically, the administration of exogenous androgens or progestational agents during pregnancy caused virilization of the female fetus. Maternal ovarian or adrenal tumors during pregnancy are also rare causes of masculinization. Normal cytochrome P450 aromatase in the placenta converts weak fetal adrenal androgens to estrogens. Its deficiency can lead to virilization of both mother and the female, fetus which resolves following birth.
The exstrophy-epispadias complex of birth defects is considered a spectrum of embryologic malformations that include abnormalities of the genitalia in both sexes. Boys in particular can have a wide variability in genital anatomy, at times looking ambiguous. In males with epispadias, the urethra is open partially or completely over the dorsum of the penis. The penis is small with significant dorsal chordee. Boys with classic bladder exstrophy similarly have short, dorsally tethered penises but have no urethra, with the bladder opening on the lower abdominal wall. Male newborns with cloacal exstrophy have widely divergent, short corporal bodies, which may be asymmetric or absent unilaterally, giving a bizarre genital appearance. Adding to the confusion, males with cloacal exstrophy commonly have undescended testes.
Hypospadias is a common congenital abnormality of the male external genitalia. It occurs in approximately 1 in 250 male newborns. Boys with hypospadias usually have 3 anomalies of the penis: (1) abnormal ventral opening of the urethra; (2) abnormal ventral curvature of the penis; and (3) deficient ventral shaft skin with a redundant prepuce over the dorsum (dorsal hood). Most males have a mild form. Patients with severe hypospadias may have a perineal or scrotal meatus with severe foreshortening and dorsal curvature of the penis giving an ambiguous appearance to the genitalia (Figure 48-8). Undescended testes are common (7%–9%) in boys with hypospadias and can make sexual determination difficult.
Boy with severe hypospadias and bifid scrotum.
Prenatal treatment with dexamethasone is available for those fetuses at high risk for CAH and is aimed at reducing congenital virilization of the female genitalia. This therapy is initiated in pregnant mothers with a history of a previous child with CAH and is highly successful at preventing virilization in 85% of female fetuses.55 Because genital differentiation occurs between 8 and 12 weeks postconception, oral dexamethasone should be started as soon as pregnancy is determined. Unfortunately, because sex determination cannot be made before this time period with routine methods (chorionic villus sampling at 10 weeks), 7 of 8 fetuses are unnecessarily exposed to corticosteroids because of the autosomal recessive nature of genetic transmission. New noninvasive testing using cell-free fetal DNA from maternal plasma is accurate at determining fetal sex as early 5 weeks postconception and once widely available will likely become part of the workup prior to corticosteroid therapy.56
Prenatal administration of dexamethasone may lead to growth retardation, disruption of the hypothalamic-pituitary-adrenal axis, behavioral issues, and developmental delays in children.57 Maternal exposure may cause abnormal glucose tolerance, hypertension, osteoporosis, cataracts, and increased risk for infection during treatment.58 Because of these factors and other ethical and sociological concerns, prenatal treatment with dexamethasone continues to be a controversial subject and is considered experimental therapy.59
The management of a newborn with ambiguous genitalia requires great sensitivity. An experienced group of physicians from the disciplines of neonatology, endocrinology, medical genetics, pediatric urology, and psychiatry/psychology is best from an experienced center in managing these patients. It is paramount that the team works collectively to make a precise and appropriate diagnosis and includes the parents in this process. In addition, all caregivers and ancillary staff should be made aware of the sensitive aspect of the situation.
When treating children with a DSD, it is good to consider the parameters of optimal gender policy as described by Meyer-Bahlburg.60 These include (1) reproductive potential (if attainable at all); (2) good sexual function; (3) minimal medical procedures; (4) an overall gender-appropriate appearance; (5) a stable gender identity; and (6) contentment in life.
Once the diagnosis of a DSD is made, stabilization of the neonate is the priority during the evaluation. Particular attention should be paid to the newborn’s general condition, feeding status, heart rate, blood pressure, and urine output. Daily electrolyte testing is recommended until screening studies return in those neonates with concerns for having CAH.
In neonates in an acute salt-wasting crisis, aggressive fluid replacement with 0.9% saline at 20 mL/kg body weight is initiated with administration of both glucocorticoids (50–100 mg/m2 of hydrocortisone) and mineralocorticoids (Florinef® acetate 0.1 to 0.2 mg orally every 12 to 24 hours).61 Electrolyte and metabolic derangements are commonly seen in these patients and should be corrected aggressively.
Once stabilized, cortisol replacement should be decreased to a range to suppress corticotropin (ACTH) secretion, usually between 12 and 20 mg/m2 daily. Florinef dosing often can be titrated downward based on the child’s blood pressure and renin levels. Routine salt administration is rarely required after the newborn period. Information on the dosing of hydrocortisone during periods of illness or stress should be explained in detail to the parents prior to discharge.
Testosterone therapy may be administered in infant males with a micropenis or those with a small penis prior to reconstructive surgery. However, in the vast majority of patients with hypogonadism, exogenous hormonal therapy is initiated to induce puberty at a time determined by the patient, family, and endocrinologist. Hormonal therapy then leads to a cascade of both physical and emotional changes that requires routine adherence for a lifetime.
Gender uncertainty is stressful for families of the newborn. Gender assignment requires a thorough evaluation and discussion with the multidisciplinary team. Factors involved in the decision include diagnosis, genital appearance, surgical options, need for lifelong replacement therapy, potential for fertility, views of the family, and cultural practices.62 Family participation is essential in the decision-making process. While the decision should be made deliberately, gender assignment should be made as early as possible, preferably in the newborn period. Some have advocated for the deferment of the decision until the patient can provide informed consent. However, cultural norms and practices make this approach difficult.
Surgery in patients with DSD can be complex and challenging. Only surgeons with specific training in genital reconstruction surgery should perform these procedures.
It is generally accepted that clitoroplasty is best performed in the first few months of life. Waiting several months allows for stabilization of the child from an endocrine and metabolic standpoint. Corticosteroid replacement therapy typically leads to some improvement of the virilization of the external genitalia. All current techniques have preservation of the clitoral sensation and function as their cornerstone.
In contrast to timing of clitoral reconstruction, the optimal age for vaginal reconstruction is more controversial. Benefits of proceeding at a younger age include improved tissue transfer and reduced scarring secondary to estrogen stimulation, minimization of parental anxiety over the child’s condition, and earlier self-acceptance of the child’s gender identity and genital anatomy.63 Others have advocated a delayed approach because of the need for subsequent surgery for vaginal stenosis in children who had early vaginal reconstruction.64
One of the major factors in determining gender assignment is potential phallic adequacy in adulthood. Today, most genital reconstruction is performed with respect to genetic sex. However, in some situations with severe phallic insufficiency, gender conversion may be appropriate. Reasonable and expected outcomes following surgery are an important part of the discussion with the parents.
Penile surgery should occur around 6 months of age or older and may proceed as part of a staged procedure.65 Preoperative testosterone is a useful adjunct in boys with small penises and is typically administered intramuscularly about a month prior to surgery. Persistent müllerian remnants are usually not excised unless the child becomes clinically symptomatic.
Prophylactic gonadectomy or removal of streak goads is generally recommended to prevent malignancy in patients raised as girls with Y genetic material. This is usually performed at the time of reconstructive surgery or within the first year of life. In girls with complete androgen insensitivity, gonadectomy may be deferred until the teenage years or not be performed because of the low malignant potential of the testes.66 Children raised as males with MGD or PGD should in general have streak gonads and intra-abdominal gonads removed. Testes with mostly normal architecture can be brought down into the scrotum and can be managed with close surveillance.29
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