Chapter 539. Disorders of Sexual Development (DSD)

Abnormalities of sex differentiation or disorders of sexual development (DSD) are divided into two broad categories: (1) errors in (primary) sex determination, such as sex chromosome anomalies and gene mutations that interrupt or disrupt normal gonadogenesis, which lead to abnormalities of gonadogenesis, and (2) errors in sex differentiation that cause abnormal development of the somatic sex structures—the genital ducts, urogenital sinus, and external genitalia. Intrinsic or extrinsic factors that adversely affect any of the stages of these mechanisms can cause anomalies of sexual structure. Table 539-1 presents the consensus Classification of Disorders of Sex Development for clinical use. Older terminology used for classification (shown in parentheses in Table 539-1) have been abandoned and replaced by newer designations.1,2 The management approach to these disorders, including discussion of gender determination, is discussed in the final section of this chapter.

Persons with 46,XX disorders of sexual development have a 46,XX karyotype, ovaries, female ducts, and variable degrees of masculine differentiation of the urogenital sinus and external genitalia. The disorders are subdivided into those that are androgen induced and non-androgen induced as shown in Table 539-1.

Congenital Virilizing Adrenal Hyperplasia

This disorder is caused by an inborn error of adrenocortical hormone biosynthesis that results in relative deficiency of cortisol production, increased secretion of corticotropin (ACTH), and relative excess of androgenic hormones and other steroids. Diagnosis and management of these disorders is discussed in greater detail in Chapter 531. Congenital virilizing adrenal hyperplasia accounts for approximately one half of all cases of ambiguous external genitalia with the defect in 21-hydroxylation being by far the most common. The mode of inheritance is autosomal recessive.

At birth the external genitalia of affected girls are, as a rule, conspicuously abnormal, whereas the genitalia of affected boys are normally differentiated. The degree of masculinization can be judged by the size of the clitoris and the completeness of labioscrotal fusion, which determines the size of the urogenital sinus (Fig. 539-1). The phallus is invariably enlarged in the simple virilizing and salt-wasting forms, often approximating the size of a penis (eFig. 539.1). It is generally bound in chordee, behind which a perineal hypospadias is situated. In rare instances, the urethra extends to the tip of the phallus. The labia majora commonly looks like a bifid scrotum. Within the perineal opening of the urogenital sinus lie the orifices of the vagina and the urethra. Greater or lesser degrees of fusion of the labioscrotal folds produce a perineal opening that varies in size from that of a small urethra-like opening to a relatively normal female introitus with a separate urethra and vagina (see Fig. 539-1).

The appearance of the external genitalia is not specific, and the genital abnormality can be indistinguishable from that in other forms of disordered sexual development with bilateral cryptorchidism. Measurement of plasma 17α-hydroxyprogesterone (17OHP) in the plasma is strikingly elevated in patients with 21-hydroxylase deficiency (both salt losers and non-salt-losers) as well as androstenedione and testosterone. Measurement of plasma 17OHP is the most useful diagnostic test, being used in neonatal screening programs for early diagnosis of this disorder (see Chapters 533 and 534).3-5

Other Fetal Sources of Androgen

3β-hydroxysteroid dehydrogenase (3HSD) is a rare disorder that affects both sexes, and female patients may have ambiguous genitalia. Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hypercortisolism, but with manifestations of androgen and mineralocorticoid excess, caused by glucocorticoid receptor gene mutation, and rarely can lead to virilization in females.

Fetoplacental Sources of Androgen

Placental aromatase has a critical role in protecting the female fetus and the mother from exposure to large amounts of testosterone synthesized mainly by the placenta.6-16 When deficient because of mutation in the P450arom gene (CYP19; locus 15q21-OMIM 107910), the concentration of androgen or androgen precursors exceeds the capacity for aromatization. As a consequence, the fetal placenta is unable to convert fetal adrenal androgen precursor to estrogen. This autosomal recessive disorder frequently results in virilization of the mother during pregnancy. The external genitalia may be ambiguous, or in the female there may be clitoromegaly. Wolffian duct derivatives are absent, and müllerian duct derivative are present. The ovaries may be multicystic in infancy and postpubertally. Typical features include hypergonadotropic hypogonadism, multicystic ovaries, osteopenia, delayed bone age, and tall stature after the age of puberty.17,18 Psychosocial orientation is normal, as is a response to estrogen therapy.

Placental Transfer of Androgens from the Mother

In rare instances, a virilizing ovarian or adrenal tumor in the mother during pregnancy partially masculinizes its external genitalia. Therapeutic administration of medications with androgenic activity during pregnancy result in fusion of the labioscrotal folds and formation of a urogenital sinus if given before the 13th week of gestation, but enlargement of the clitoris can follow androgen treatment of the mother at any time during pregnancy.

Nonandrogen Induced XX, Disorders of Sexual Development

In these rare instances, accompanying developmental anomalies of the urinary tract and cloaca, often with atresia of the rectum or rectovaginal fistula, are observed.19 There also may be absence of a fallopian tube or an ovary, and the uterus may be poorly developed. Stenosis of the urethra can cause urinary retention in early infancy.

XY disorders of sexual development result from either the failure of the fetal testis to secrete adequate testosterone to bring about complete masculinization of the somatic sex structures or from defects in androgen-dependent target tissue response to released androgens (see Table 539-1). The karyotype is 46,XY, except in some patients with dysgenetic XY,DSD. Testes are present with variable degrees of ambisexual development of the genital ducts or the urogenital sinus and external genitalia, or both (Fig. 539-2). The appearance of the external genitalia varies from that of a normal girl to that of a boy with a penile urethra and either bilateral or unilateral cryptorchidism. Perineal hypospadias is common. The testes may be inside the abdomen, sometimes in the position of the ovaries, in the inguinal region, or in the labioscrotal folds.

Testicular Unresponsiveness to HCG and LH (Leydig Cell Agenesis or Hypoplasia)

Autosomal recessive, homogenous, compound heterozygous mutations in the gene that encodes the hCG-LH receptor (LHGCR; 2p21), a G protein–coupled seven-transmembrane α-helical receptor, cause fetal and postnatal testosterone deficiency. The testes are small and undescended with absent or decreased numbers of Leydig cells. The external genitalia vary from female to ambiguous to hypoplastic male. Müllerian derivatives are absent.20-22 Plasma levels of 17-hydroxyprogesterone, androstenedione, and testosterone are low, and stimulation with hCG evokes little or no increase. Basal FSH and LH levels are elevated in infancy and at puberty.

Inborn Errors of Testosterone Biosynthesis

Figure 531-1 shows the major pathways in testosterone biosynthesis. Each step is associated with an enzymatic defect inherited as an autosomal recessive trait that causes incomplete masculinization of the urogenital sinus or external genitalia (Table 539-1) but not differentiation of müllerian duct structures. The disorders that affect synthesis of corticosteroids and androgens include 3β-hydroxysteroid dehydrogenase-2 deficiency, P450c17 (17α-hydroxylase) deficiency, P450 oxidoreductase deficiency, and Δ7-sterol reductase deficiency (Smith-Lemli-Opitz syndrome), are discussed in more detail in Chapter 533. Enzyme deficiencies that affect testosterone synthesis but not corticosteroid synthesis include 17,20 lyase (P450C17) deficiency and 17β-hydroxysteroid dehydrogenase (HSD 17-β3) type 3 deficiency. In congenital lipoid hyperplasia (StAR deficiency), the Leydig cells are destroyed early in gestation, eliminating testosterone biosynthesis.5 The patients have enormous accumulations of lipid in the cells of the adrenal cortex but surprisingly less in the fetal testis, severe adrenal insufficiency, and death in early infancy if not treated.23,24 Boys have ambiguous external genitalia, a blind vaginal pouch, and undescended testes, and with a severe defect, female external genitalia. The enlarged adrenal glands (with rare exceptions) displace the kidneys caudally. Girls have a normal phenotype but also have life-threatening salt loss and cortisol deficiency. Girls feminize normally at puberty because lipids have not accumulated and destroyed the cells before the pubertal increase in secretion of gonadotropins. In P450 side chain cleavage deficiency genitalia are female, rarely ambiguous. Wolffian duct derivatives are hypoplastic or normal, müllerian duct derivatives are absent. Concomittant adrenal insufficiency is either severe in infancy or milder with onset in childhood. Individuals with P450 oxidoreductase (POR) deficiency have testes with a spectrum of genital abnormalities from ambiguous to hypospadias to normal males. Wolffian duct derivatives are absent or hypoplastic. Features of Antley-Bixler syndrome (craniostenosis, choanalatresia/stenosis, multiple skeletal malformations) are seen in 30% to 65% of individuals with this mutation. 46,XY individuals with 3 β-hydroxysteroid dehydrogenase type II Δ5isomerase deficiency (3βHSD2) have testes with ambiguous external genitalia, or hypospadia, normal wolffian duct derivatives, severe adrenal insufficiency in infancy, poor virilization at puberty with gynecomastia. Patients with CYP17 mutations have impaired synthesis of 17OH-progesterone, 17α-hydroxypregnenolone and their products (androgens, estrogens, and cortisol) caused by an autosomal-recessive mutant gene.25-28 The gene is located on chromosome 10q24.3 and encodes both the adrenal and testicular enzymes that catalyze 17-hydroxylation of pregnenolone and progesterone and removal of the C21 side chain of 17-hydroxypregnenolone (C17-20-lyase) to form C19 steroid DHEA.29 Increased secretion of corticosterone and deoxycorticosterone causes hypokalemic alkalosis and low-renin hypertension. Plasma concentration of gonadal steroids and excretion of urinary 17-ketosteroids are low. Affected boys are incompletely masculinized with hypospadias or may appear to be phenotypic girls, with a blind vaginal. Virilization is poor at puberty and gynecomastia is common.

Individuals with 17,20 lyase (P450C17) deficiency have ambiguous external genitalia and inguinal or intra-abdominal testes. At puberty, incomplete masculinization can occur. Gynecomastia is infrequent. If the disorder is diagnosed in infancy, these patients can be reared as boys and treated with testosterone to induce male secondary characteristics and phallic growth. Plasma levels of testosterone, androstenedione, estradiol, and DHEA are low. After stimulation with hCG, the ratio of C21 steroids (cortisol, 17OHP) to C19 steroids increases. This disorder must be differentiated from 5-reductase-2 deficiency and from 17βHSD-3 deficiency. 46,XY individuals with mutations in the gene encoding 17β-hydroxysteroid dehydrogenase type 3 (or 17-ketosteroid reductase)29-33 have female or ambiguous external genitalia, inguinal testes, male genital duct development, and progressive virilization at puberty, usually with concomitant breast development. The type 3 isozyme, the last enzyme in the biosynthetic pathway for testosterone, is expressed primarily in the testis. Levels of plasma androstenedione and estrone are strikingly elevated because their conversion to testosterone and estradiol is impaired. These patients must be differentiated from those with partial (incomplete) androgen insensitivity syndrome or 5α-reductase-2 deficiency, who have a similar phenotype but not a similar sex steroid pattern.

Androgen Receptor Defects

The syndrome of complete androgen insensitivity results from a mutation in the X-linked androgen receptor, a ligand-regulated transcription factor that binds both dihydrotestosterone and testosterone (eFig. 539.2). It is estimated to occur in between 1:20,000 and 1:60,000 live male births. Family pedigrees show X-linked inheritance consistent with the location of the androgen receptor gene on Xq11-q12. In addition to transmission from the mother by the mutant gene on the X-chromosome of her oocyte, it is estimated that in about 30% of these individuals the mutation occurs in the postzygotic stage and leads to somatic mosaicism.34-40 The testes secrete testosterone, and at puberty the concentration of plasma testosterone usually is within the normal range for boys. However, both genital and somatic end organs do not respond to androgens in the fetus or at puberty, which leads to female differentiation of the urogenital sinus and external genitalia and to feminization at puberty. The hypothalamic feedback mechanism lacks normal sensitivity to testosterone, which elevates serum levels of luteinizing hormone (LH), but the concentration of follicle-stimulating hormone (FSH) in the serum usually is normal because of circulating inhibin-B and estradiol feedback. These individuals have a normal female appearance so the diagnosis is often not suspected. The testes usually are in the inguinal canal or in the labial folds. In some instances, the clitoris is slightly enlarged and the labioscrotal folds are partially fused. There is a characteristic blind vaginal pouch, absent (or rudimentary, in about 30%) müllerian duct derivatives due to the action of antimüllerian hormone by the fetal testis, and absent or hypoplastic wolffian ducts.41 Development of the genital ducts is variable, but the uterus is absent.

At puberty, estradiol secreted by the testes and synthesized in extragonadal tissues by the aromatization of testosterone bring about feminization of body habitus, development of breasts, and estrogenization of the vaginal mucosa despite elevated testosterone levels, but menstruation does not occur. Mean height is taller than average for women. The discovery of a testis in an inguinal or labial hernia usually is the only clue to the diagnosis in the absence of a familial history. About 1% of females with bilateral inguinal herniae (uncommon in girls) have congenital androgen insensitivity syndrome. The diagnosis is considered when an adolescent girl has primary amenorrhea (it is the third most common cause after gonadal dysgenesis and congenital absence of the vagina) in the presence of otherwise female secondary sexual characteristics (including breast development), especially when associated with absent or sparse sexual hair and unilateral or bilateral hernial masses. Among most patients, pubic and axillary hair are absent or sparse, a manifestation of the impaired response to androgen of the hair follicles that give rise to sexual hair. In the classic form of the syndrome, large amounts of testosterone or dihydrotestosterone do not induce either masculinization or an appropriate degree of protein anabolism. Castration causes a decrease in plasma levels of estradiol and testosterone, an increase in both FSH and LH levels, and menopausal symptoms. There is a low risk for the testes to undergo neoplastic transformation before adulthood. Orchiectomy is recommended in late adolescence or early adulthood after puberty is complete and should be followed by estrogen replacement therapy.

Some patients have a gene mutation that encodes a defective but partially functional androgen receptor—the partial androgen insensitivity syndrome.39,42-44 These individuals have breast development at puberty and undergo variable degrees of masculinization. There is clitoral enlargement at birth, and some patients have ambiguous external genitalia. Phenotypic males with infertility as the sole manifestation of a deficiency of androgen receptors have been described. They represent one extreme of the highly variable phenotype of androgen resistance.39

5α-Reductase Type 2 Deficiency (Pseudovaginal Perineoscrotal Hypospadias

Patients with this syndrome have an XY karyotype but have impaired enzymatic transformation of testosterone to its active hormone (dihydrotestosterone) at testosterone sensitive end organs. The disorder is autosomal recessive and caused by mutations in the 5α-reductase type 2 gene (5RD5A2) on chromosome 2p23. The testes are normally differentiated, internal genital ducts are male, but the external genitalia are ambiguous.45-47 At birth, the phallus usually is small and hypospadiac. There is persistence of the urogenital sinus with a blind vaginal pouch. In severe disease, separate vaginal and urethral orifices are present. At puberty type 1-5α-reductase isoenzyme is expressed (this enzyme is not expressed in the fetus), leading to masculinization including phallus enlargement, growth of axillary and pubic hair, and in many children, male gender identity.48 Acne, facial hair, and temporal recession of the hairline are minimal or absent. Unlike patients with androgen receptor defects, these patients do not have gynecomastia. The diagnosis is suggested by the finding of an abnormally high plasma testosterone to dihydrotestosterone ratio (> 8.5 in infancy) after administration of hCG (1500 IU/m2 intramuscularly daily × 3 doses or every 48 hours × 7 doses with blood sampling 24 hours after the last dose). It is confirmed by assay of 5α-reductase in cultures of skin fibroblasts, detection of an increased 5β/5α ratio of urinary C19 and C21 steroid metabolites, and preferably by DNA analysis of the 5α-reductase type 2 gene. Early diagnosis is critical because selection of male sex assignment necessitates testosterone or dihydrotestosterone therapy to induce growth of the phallus. Repair of hypospadias is performed in early childhood.

Dysgenetic XY,Disorders of Sexual Development

Defective testicular organogenesis results in ambiguous development of the genital ducts, urogenital sinus, and external genitalia. A heterogeneous group of disorders, including 45,X/46,XY mosaicism, structural abnormalities of the Y chromosome, deletions and mutations of the testicular determiner gene (SRY), mutations in autosomal genes, duplication of DSS (dosage sensitive sex) locus on the X chromosome, and the sporadic and heritable forms of XY gonadal dysgenesis manifest defective gonadogenesis and masculinization.

A highly diverse phenotype has been described among patients with XO/XY mosaicism or structural abnormality of the Y chromosome. The appearance can range from a sexually infantile female phenotype with or without the somatic anomalies of Turner syndrome and with bilateral streak gonads, through variable degrees of masculine differentiation of the external genitalia, urogenital sinus, and genital ducts, to almost normal male differentiation of the genital tract.20,48,49 Some patients have a dysgenetic testis on one side and a streak gonad on the other. Short stature and the somatic anomalies of Turner syndrome are inconstant features. The dysgenetic testes must be removed because of the increased tendency toward development of malignant tumors. Patients with an incomplete form of familial XY gonadal dysgenesis are of normal stature and do not have the components of Turner syndrome. The testes are dysgenetic, and there are usually both müllerian and wolffian duct derivatives. The external genitalia are ambiguous. The gonads have variable degrees of dysgenetic testicular differentiation, and some virilization occurs at puberty. Gonadotropin levels are elevated. The defective testes are removed because of the risk of neoplastic transformation. Familial XY gonadal dysgenesis may be transmitted as an X-linked recessive or sex-limited autosomal dominant trait, or owing to a mutant SRY gene. Both the complete form, which has a female phenotype, and the incomplete form can occur in the same pedigree.

A variety of gene defects are associated with XY, disorders of sexual development. These include 3 syndromes caused by mutations of the Wilms tumor suppressor gene (WT1).50-54 Denys-Drash syndrome50 is associated with degenerative renal disease (focal and diffuse mesangial sclerosis), early onset nephrotic syndrome with rapid progression to end-stage renal disease, hypertension, and commonly with Wilms tumor at a median age of 18 months. Both the testes and the kidneys are dysgenetic and predisposed to malignant transformation. In Frasier syndrome,51,52 individuals have female or ambiguous external genitalia, later-onset nephropathy (focal and segmental glomerulosclerosis), and a predisposition for gonadoblastoma but not Wilms tumor. In Wilms tumor–aniridia–gonadoblastoma–mental retardation (WAGR) contiguous gene deletion (WT1) syndrome in region chromosome 11p13, affected boys often have ambiguous or hypoplastic male genitalia. Heterozygous mutations in the SOX-9 (SRY-related high-mobility group box) gene are associated with a severe bone dysmorphology syndrome, camptomelic dysplasia, and frequently dysgenetic XY, disorders of sexual development. Other gene mutations associated with disorders of sexual development include desert hedgehog (DHH), TSPYL1 (associated with sudden death in infancy). ARX (associated with X-linked lissencephaly), duplication of the X-linked DAX1 (AHC),60 9p-syndrome (DMRT1); DHCR7 (Smith-Lemli-Opitz syndrome), and XH2 (the ATR-X syndrome: X-linked -thalassemia, mental retardation, small testes, and ambiguous external genitalia.55-61

Defects in Synthesis, Secretion, or Response to Antimullerian Hormone

These disorders result in the persistent müllerian duct syndrome characterized by normal male development of the external genitalia, testes, normal male ducts, and müllerian duct derivatives.62,63 The diagnosis often is made by the finding of a fallopian tube and uterus in a patient undergoing inguinal hernia repair, orchiopexy, or abdominal surgery. The disorder is inherited as a sex-limited autosomal-recessive trait and is caused by mutations in the gene encoding the antimüllerian hormone or its receptor (AMHR2). In the former (in contrast to the latter), the plasma concentration of AMH is low or not detected.

Ovotesticular Disorders of Sexual Development (True Hermaphrodism)

These persons have both an ovary and a testis or, more commonly, one or both gonads are ovotestes.85 Development of the accessory sexual structures is highly variable. Three-fourths of these patients have been reared as boys, but they have variable degrees of hypospadias. Cryptorchidism and an inguinal hernia that contains a gonad or vestigial uterus and fallopian tube are present in 50% of patients. Predominantly masculine or feminine maturation occurs at puberty. Most patients do not have a sex chromosome abnormality. In North America, XX sex chromosome constitution is found in 72% of patients; 21% are sex chromosome mosaics or chimerics, such as XX/XY; and about 7% are XY. Only a small proportion of children with XX ovotesticular disorder of sexual development, including some in pedigrees with XX boys, are SRY positive. The pathogenesis of most cases of XX true hemaphroditism cannot be explained by a Y to X or Y to autosome translocation or by hidden sex chromosome mosaicism or chimerism. The XX/XY chimerism is caused by double fertilization of a binucleate ovum or by fusion of 2 independently fertilized zygotes. Familial cases have been reported that are compatible with an autosomal recessive or sex-limited dominant trait.64,65 Some of these patients are potentially fertile. When the sex of rearing is chosen, an important aim is to preserve the appropriate gonad or gonadal segment, especially if an ovary is present in the mesosalpinx or a testis is attached to its exocrine ducts in the scrotum. There is, however, an increased risk of gonadal neoplasia.

Environmental Chemicals

An increase in the prevalence of hypospadias, cryptorchidism, cancer of the testes, and in some European countries a fall in the sperm count has occurred over the past 30 years.66-104 It has been speculated that the increased prevalence is related to exposure in utero and postnatally to environmental endocrine disrupters, especially compounds with estrogenic activity and agents that bind to the fetal androgen receptors; for example, phthates as well as herbicides and fungicides inhibit androgen action. Further studies on the levels and risks of natural and environmental estrogens and antiandrogens in humans are necessary before the putative increase in prevalence of these abnormalities including the testicular dysgenesis syndrome can be attributed to these agents.

The underlying cause of several abnormalities of sex differentiation is unknown; therefore, they remain categorized as unclassified (see Table 539-1). For example, ambiguous external genitalia are associated with a large number of malformation syndromes such as Aarskog-Scott, CHARGE, and VATER syndromes.66,67

Turner Syndrome

Haploinsufficiency of the X chromosome (45,XO karyotype) results in a female phenotype with associated findings of short stature, sexual infantilism, streak gonads, and a diversity of associated somatic anomalies. It is estimated that about 2% of all zygotes are 45,XO (probably the most common chromosome anomaly in the human), but less than 0.2% of 45,X fetuses survive to term such that about 7% of spontaneous abortions have a 45,X karyotype. The incidence of Turner syndrome is about 1 per 2000 live phenotypic female births; approximately 50% have a 45,X karyotype. Intrauterine growth retardation is common. Maternal age is not advanced. There is increased prevalence of twinning, but familial instances are exceedingly rare. Lymphedema and loose folds of skin around the nape of the neck (Bonnevie-Ullrich syndrome) suggest the diagnosis during the neonatal period (Fig. 539-3) which is then confirmed by genetic testing. Pleural effusion may occur among newborns.

In 45,XO patients, ovaries are absent, and streak gonads can be detected with pelvic sonography or coronal MR imaging. Elevated levels of FSH in the serum frequently are detected in infancy and early childhood but not between approximately 4 and 10 years of age.77,78 During adolescence, serum concentrations of FSH and LH and excretion of urinary gonadotropins increase to castrate levels. Persons with Turner syndrome have none of the secondary sexual characteristics caused by secretion of estrogen at puberty, but they do have sexual hair. In rare instances, some degree of feminization occurs at puberty, and some patients have been fertile.

Associated anomalies (see eFigs. 539.2 and 539-3) include atypical facies, broad shield-like chest, low hairline over the nape of the neck, webbed neck (in about 30%), congenital lymphedema of the extremities (especially the hands and feet in about 30%),73 coarctation of the aorta (20%), hypertension, bicuspid aortic valve (unassociated with coarctation [9% to 34%]), aortic root dilatation (8% to 29%),74 short fourth metacarpal (50%), high arched palate, skeletal anomalies (including cubitus valgus and Madelung or bayonet deformity of the wrist, hypoplastic and malformed nails, microthelia), cutaneous (pigmented nevi and predisposition to keloid formation), ocular, recurrent otitis media, sensorineural deafness,75 and renal abnormalities (seen in 50%—most commonly horseshoe kidney). Deficits of space-form recognition and directional sense are common despite a normal intelligence quotient. Skeletal maturation is normal or mildly delayed before puberty. Diminished mineralization of the hands, feet, and elbows is common (see eFigs. 539.2 and 539-3).68,70,71 Awareness of these associated disorders, early diagnosis, and anticipatory guidance are important components of management. Renal ultrasonography is recommended to detect surgically correctable renal anomalies.

The mean mature height is 143 cm (range 133–153 cm). The height deficit is due to a dosage effect associated with loss of the Stature Homeobox Gene (SHOX) on the X chromosome. Therapy is directed at maximizing final height and correcting remediable congenital anomalies and sexual infantilism. Treatment with subcutaneous daily injections of recombinant human GH lead to a mean gain in final height of 9 cm after 3 to 7 years of therapy.80-84 Beginning treatment with rhGH in early childhood is associated with the greatest gains in final height. Among phenotypic girls with elevated urinary levels of gonadotropin, treatment with low-dosage estrogen (eg, transdermal estradiol patch, percutaneous estrogen gel, 0.3 mg conjugated estrogen or less or 2 to 3 µg ethinyl estradiol daily) is initiated at approximately 13 years of age, continues for 6 months, and then is administered cyclically for 3 or 4 weeks to bring about the development of feminine secondary sexual characteristics and estrogen-withdrawal bleeding.85-87 The dose of estrogen should be increased gradually with the aim of administering the minimum dose to maintain secondary sex characteristics and menses and hinder development of involutional osteoporosis. It is useful to administer an oral progestin (eg, medroxyprogesterone acetate, 5 mg daily) during the last 10 days of estrogen therapy.

Associated disorders include Hashimoto thyroiditis, aortic rupture, osteopenia (increased risk of wrist fractures), obesity, inflammatory bowel disease, and rheumatoid arthritis. Turner syndrome carries a 3-fold increase in mortality and a reduction of life expectancy of 6 to 13 years.76 Counseling and monitoring of the patient throughout childhood and adolescence, and of the parents, is a vital part of treatment.88,89 Advances in in vitro fertilization and embryo transplantation have made child bearing achievable,89 but there is the risk of increased maternal mortality.90

Other Genetic Variants of the Syndrome of Gonadal Dysgenesis

Highly diverse expression of the 45,XO phenotype occurs with a variety of modifications of the second sex chromosome due to chromosome mosaicism or structural abnormality of an X or Y chromosome.79 These clinical variants of the syndrome of gonadal dysgenesis usually present with a more normal phenotype compared to the classic form of the syndrome of gonadal dysgenesis associated with a 45,XO karyotype.79 Patients with XO/XX or XO/XX/XXX mosaicism can achieve normal stature and a variable degree of ovarian function, including ovulation and fertility. The associated somatic anomalies may be indistinguishable from those in Turner syndrome, minimal or absent. 45,XO/46,XY mosaicism has a diverse phenotype associated with a variable degree of testicular differentiation, in some cases causing ambisexual development of the external genitalia and in others almost normal male phenotype. Gonadectomy is recommended in 45,XO/46,XY and related forms of mosaicism because of the increased risk of gonadal neoplasm in the presence of a Y chromosome including an occult Y-bearing cell line.

XY Gonadal Dysgenesis

The term XY gonadal dysgenesis is used to describe a female phenotype with an XY karyotype, streak gonads, sexual infantilism, normal or tall stature, and lack of the somatic components of Turner syndrome. The reported pedigrees suggest X-linked recessive or sex-limited autosomal-dominant inheritance. A duplication of the DAX1 gene in chromosome Xp21 is suspected in some familial cases. About 10% to 15% of patients have a deletion or mutation in the SRY gene on the short arm of the Y chromosome. The prevalence of gonadal neoplasms such as seminoma and gonadoblastoma is greatly increased. Familial occurrence is common. In some sets of siblings, an affected sibling has had XY,DSD with dysgenetic testes and ambiguous external genitalia. The prevalence of gonadal neoplasms such as seminoma and gonadoblastoma is greatly increased. Familial occurrence is common. In some sets of siblings, an affected sibling has had XY,DSD with dysgenetic testes and ambiguous external genitalia. Familial occurrence is common. In some sets of siblings, an affected sibling has had XY,DSD with dysgenetic testes and ambiguous external genitalia. The prevalence of gonadal neoplasms, such as seminoma and gonadoblastoma are greatly increased in affected individuals.

Familial XX Gonadal Dysgenesis

These children have a female phenotype, normal stature, sexual infantilism, bilateral streak gonads, normal female external and internal genitalia, primary amenorrhea, elevated levels of gonadotropins, low values of serum and urinary estrogens, and XX karyotypes. The habitus often is eunuchoid, and the somatic anomalies associated with XO gonadal dysgenesis are absent or minimal. Families in which multiple siblings are affected are not uncommon, and the transmission is consistent with autosomal-recessive inheritance. In some families, the gonadal defect is associated with sensorineural deafness. The disorder rarely is recognized before puberty.

XX and XY Turner Phenotype (Noonan Syndrome)

A distinctive syndrome with a prevalence of about 1 in 2000 live births was first recognized in males who had a phenotype somewhat similar to Turner syndrome, thus known as male Turner syndrome or Noonan syndrome. Now this distinct syndrome is also described in females. About half the patients studied have mutations in the PTPN11 gene91 that encodes protein tyrosine phosphatase SHP2 (locus 12q24.1). A small proportion of affected individuals have a mutation in the KRAS gene. Familial examples of autosomal-dominant transmission of this disorder are well documented.

Patients with Noonan syndrome have characteristic facies—ptosis; antimongoloid palpebral slant; broad, flat nose; webbed neck; short stature92; high arched palate; and malformed ears (eFig. 539.3 and eFig. 539.4). Congenital heart disease (most commonly atrial septal defect or pulmonic stenosis but rarely coarctation of the aorta) is a cardinal but not invariable feature. Hypertrophic cardiomyopathy, sometimes with subaortic or subpulmonic stenosis, is common. Pectus excavatum, cubitus valgus, and impaired mental development are frequent associated findings. In boys, one or both testes may be undescended. Some boys have germinal cell aplasia, hypoplasia of the testis, and evidence of androgen deficiency. Girls have functioning ovaries. In both sexes the karyotype is normal, and gonadal differentiation is consistent with the chromosomal and phenotypic sex.

Dysgenesis of the Seminiferous Tubules (Klinefelter Syndrome)

The most common human sex chromosomal aberration, a 47,XXY karyotype, is associated with Klinefelter syndrome,93-95 a common cause of primary hypogonadism and infertility among men. In surveys of newborn infants, the 47,XXY abnormality has a frequency of 0.9 in 1000, and 0.15 in 1000 are 46,XY/47,XXY mosaics. About 50% of XXY fetuses die in utero. Forty-two percent of male XXY arise from meiotic nondisjunction during oogenesis which is associated with advanced maternal age. In 53% of cases, the nondisjunction occurs during spermatogenesis at the first meiotic division; 5% of cases are caused by mitotic nondisjunction in an early division of the fertilized zygote.

The histopathologic features of the testis vary. Among XXY infants, testicular structure can be normal, but the prepubertal testis has a diminished number of germ cells. During late gestation and early infancy, a striking loss of spermatogonia occurs, quite likely because of exaggeration of the normal apoptosis in neonatal life. With the onset of puberty, and associated with the action of pituitary gonadotropins, the characteristic testicular defect is evident: irreversible and progressive hyalinization and atrophy of seminiferous tubules, absence of peritubular elastic tissue, aggregation and pseudoadenomatous groupings of Leydig cells, and occasional tubules lined by Sertoli cells.97 In rare instances, spermatogenesis occurs in isolated tubules.

The diagnosis should be suspected when an adolescent boy has disproportionately long legs, small, firm testes, gynecomastia, and poorly developed male secondary sex characteristics. Often, the long legs are the only feature noted before puberty. Epiphyseal fusion is not delayed, and osseous development follows the male pattern. Most XXY boys need help in reading and spelling. Mean IQ is between 85 and 99, but there is wide variation. Severe mental retardation is rare. Poor motor skills and delayed emotional development are common, but most patients do not have behavioral disorders. As a group, men with Klinefelter syndrome are little different from other men with hypogonadism in terms of education, employment, socioeconomic status, social adjustment, and criminal behavior.

During or after puberty, the variable features of gynecomastia and androgen deficiency with signs of eunuchoidism are present in more than one half of patients; gynecomastia occurs in about 90% of patients. The concentration of FSH and LH in the serum is elevated after 12 to 13 years of age. Testosterone concentrations are normal or low, whereas the concentration of plasma estradiol is normal or high. These patients tend to grow tall (mean adult height at the 75th percentile). The prevalence of germ cell neoplasms, often that secrete hCG (eg, teratoma), especially in the mediastinum, is significantly increased. About 20% of male patients with primary mediastinal germ cell tumors have Klinefelter syndrome.96 Down syndrome and, among adults, chronic pulmonary disease, varicose veins, and mild diabetes mellitus also occur with increased frequency in this disorder. Carcinoma of the breast is 20 times more frequent than among other men.

The androgen deficiency that occurs with Klinefelter syndrome is treated at adolescence to enhance secondary sex characteristics and to improve general well-being. Therapy is initiated with a long-acting repository preparation such as testosterone enanthate in oil, 50 to 100 mg intramuscularly every 4 weeks, and gradually increased to the adult dose of 200 mg every 2 weeks or with a transdermal testosterone patch or percutaneous testosterone gel.85 Testosterone therapy can decrease gynecomastia. Once gynecomastia is advanced, it is rarely improved by hormonal treatment, and reduction mammoplasty may be necessary for psychological and cosmetic reasons. About one half of men with Klinefelter syndrome father successful pregnancies after testicular sperm extraction and intracytoplasmic sperm injection into the oocyte. There is, of course, a risk of sex chromosome aneuploidy in the offspring.

There is an increased risk for the development of premalignant tumors and cancer, especially of germ cell tumors in disorders of sexual development, especially in dysgenetic XY males.98,99 Even though the incidence of gonadoblastomas and seminomas increases near the time of puberty, neoplasms are sometimes discovered during the first decade. In disorders in which there is a well-recognized risk of malignant degeneration, it is prudent to proceed with gonadectomy concurrently with the initial repair of the external genitalia, often by laparoscopy. eTable 539.1 provides current evidence of the risk of germ cell tumors in individuals with various types of DSD. Notable is the relatively low risk for gonadal neoplasm in patients with complete androgen insensitivity syndrome, lower than previously appreciated. In others, orchiectomy can be deferred until late adolescence or early adulthood when the patient can participate in the decision.

Table 539-2 lists the historical and physical features that should alert the physician to consider an anomaly of sex. Early diagnosis is important among infants with ambisexual development to assure recognition and treatment of the salt-losing form of congenital adrenal hyperplasia, and for psychological and social reasons. The history may reveal other siblings with congenital virilizing adrenal hyperplasia, signs of progressive virilization, or dehydration, vomiting, and collapse suggestive of an addisonian-like electrolyte disorder, or perinatal death. This disorder is particularly important to recognize due to the risks of delayed treatment.

Physical Examination

In infants and children with ambiguous genitalia, the physical examination should include a detailed description of the physical signs described in Table 539-3. Table 539-4 indicates the normal values for penile size. Table 539-5 describes the normal values for clitoral size, and the anogenital ratio AF/AC (anus to fourchette and anus to base of clitoris), an index of virilization. Disorders of sexual development should be considered in children with abnormal phallic size or chordee, nonpalpable chordee or hypospadias. In these disorders, the appearance of the external genitalia can be highly variable; in some instances, the phallus resembles a large clitoris. Usually, however, there is some fusion of the labioscrotal folds and only a single perineal orifice. The presence of a palpable gonad in a labioscrotal fold or in the carefully palpated and “milked” groin is a strong point against the diagnosis of XX,DSD. In some forms of disorders of sexual development, the external genitalia appearance is not ambiguous but is female as in children with XY,DSD and complete androgen resistance syndrome (Fig. 539-2). In children with XX, DSD, the orifice of the urogenital sinus is located at or close to the tip of the phallus and can have the appearance of boys with cryptorchidism (eFig. 539.1). If an infant with a female phenotype has a firm mass in the inguinal region or labium majus, a diagnosis of the syndrome of complete androgen insensitivity should be suspected. Phenotypic female infants with prominent edema of the hands and feet and loose folds of skin over the nape of the neck may have the syndrome of gonadal dysgenesis (Turner syndrome with Bonnevie-Ullrich complex). Facial and skeletal dysplasia are features of P450 oxidoreductase and the Smith-Lemli-Opitz syndrome.

Diagnostic Testing

Figure 539-4 summarizes the diagnostic procedures of value in the differential diagnosis of ambiguous external genitalia due to disorders of sexual development. Evaluation of the karyotype is essential. Physical examination alone is inadequate for diagnosis of those disorders that require urgent early diagnosis because the external genitalia are not distinctive in XY,DSD compared with other forms of DSD in which there is bilateral cryptorchidism. In virilizing congenital adrenal hyperplasia, in which there is a defect in 21-hydroxylation, concentration of 17OHP in the plasma is strikingly elevated; an ACTH test is useful for characterizing 21-hydroxylase deficiency and other forms of adrenal enzymatic defects (see Chapter 531). Initial studies in an infant with ambiguous genitalia are listed in Table 539-6.

Patients who are 46,XX and have normal values for steroids in the plasma may have either ovotesticular DSD or nonadrenal XX,DSD, a distinction that can be based on the clinical features or for the former after assessing serum inhibin B and antimüllerian hormone and, if available, an rhFSH challenge with measurement of estradiol and an hCG test for the testosterone response. XX individuals whose mothers received potential masculinizing agents during pregnancy or who have evidence of a virilizing tumor, placental aromatase, or P450 oxidoreductase (POR) deficiency do not need surgical exploration. Sonography and MR imaging of the pelvis and perineum are performed to identify the urogenital sinus when separate urethral and vaginal orifices cannot be identified with inspection and to search for a uterus and gonads in the abdomen. Müllerian duct derivatives are absent in testicular biosynthetic defects, androgen insensitivity, and 5α-reductase-2 deficiency. A renal sonogram is of value for detecting anomalies of the urinary tract.

Persons who are XY and have abnormal external genitalia may have either XY,DSD (including dysgenetic XY,DSD) or ovotesticular DSD. Studies of plasma levels of sex steroids before and after the administration of hCG and ACTH, plasma antimüllerian hormone and inhibin B, the karyotype, assessment of the response in phallic length to a 3-month course of testosterone if partial androgen insensitivity syndrome is suspected,105,106 and DNA analysis usually provide a specific diagnosis. Laparoscopy or exploratory laparotomy and bilateral gonadal biopsy are necessary in selected instances for a definitive diagnosis. Before operation, the anatomic findings are defined with imaging studies including a urethrogram, pelvic sonography, and, if needed, an MRI. Urethroscopic examination is performed at surgery.

Psychosexual Differentiation, Sex and Gender

Previous decisions regarding gender assignment for infants with disorders of sexual development were based largely upon the Money hypothesis of sexual neutrality at birth107,108; that genes and androgens were not important, only nurtureæexperience, environment, and instinct lead to psychosexual differentiation. Accordingly, sex assignment in infants with a DSD depended heavily on surgical considerations. At the time, feminine genitoplasty was favored for technical considerations. However, evolving data, and the long-term outcomes of such gender assignment approaches, suggest a substantial effect of prenatal brain exposure to androgens and the role of genes on the sex chromosomes (Y and X) on differential expression on autosomes (“brain/mind sex”) in gender identity.109-134

It is important to appreciate the differences between sex and gender, terms that are inappropriately used by some interchangeably. Sex is a biologic identity that classifies as male or female according to reproductive organs and functions that derive from the chromosomal complement. Gender exists in a social construct and is a person’s self-representation as male or female, or how a person is responded to by social institutions based upon the individual’s gender presentation. Components of psychosexual differentiation include gender identity, gender role, gender orientation, and cognitive differences. Gender identity, the identification of self as either male or female, remains an incompletely understood dimorphic phenomenon. No one component is solely deterministic; genes, sex hormones, or nurture (environment) do not act independently, such that both nature and nurture, biological and psychosocial factors, are critical determinants of gender identity. However, clinical experience indicates that in a given infant with a disorder of sexual development, there is uncertainty about whether either nature or nurture will be deterministic in establishing gender identity. Figure 539-5 summarizes the percentage of patients with various SD opting to change sex.135-137

Assignment of Sex of Rearing

Advances in the understanding of the pathogenesis of DSD, greater insight into the effect on the brain of exposure of the fetus to androgens, and new insight into sex-specific effects (eg, differential expression of brain genes independent of sex steroids, and by the voice of nonprofessional support groups, psychologists, ethicists, and social scientists) has led to less certainty of approach. Much of the available follow-up data on adults with DSD do not reflect current management practices that guide decisions on sex assignment. The responsibility and goal of physicians in the management of patients with ambiguous genitalia are to establish a diagnosis promptly, and with the informed consent of the parents, assign a sex of rearing that is most compatible with a well-adjusted life and sexual adequacy (Table 539-7). Early diagnosis and skillful management obviate many of the serious psychological and social problems of the patients and their parents, as well as the difficult decisions that may face the physician when the diagnosis is incorrect or the selection of sex is indecisive or delayed until childhood. Parents need to be assured that with modern diagnostic tests, a definitive diagnosis can be made expeditiously, but that naming the baby, sending out birth announcements, and filling out the birth certificate should be delayed.138,139 Repeated, lucid, simple, but comprehensive discussions with the parents about the cause of their child’s “atypical” genitalia, the natural history of other patients with similar pathophysiology, and the possible hormonal and therapeutic options available are critical for an informed decision on the sex of rearing of their infant.

Goals in the management of infants and children with DSD include attaining a stable gender identity; providing age-appropriate education about the disorder; if feasible, maintaining the potential for reproduction; achieving good sexual function; achieving a sex-appropriate appearance; and minimizing surgical procedures and genital examinations. A multidisciplinary team consisting of a pediatric endocrinologist, pediatric surgeon or urologist experienced and skilled in genitoplasty, psychiatrist/psychologist with knowledge of the functional and behavioral issues, pediatric nurse, social worker, and if appropriate, religious counselor is a critical component of the immediate and future care of the patient. It must be clearly stated that anatomical abnormalities can be surgically repaired, that hormone therapy can be given at an appropriate time, and that psychosocial support is available. The physician and consultants recommend sex assignment, but the ultimate decision is that of well-informed parents. These discussions must take into account parental concerns, religious views, cultural factors,140-142 social mores, and the parents’ level of understanding. It is critical to discuss with the parents what is known and what is not known about the long-term follow-up of patients with DSD and the results of reconstructive genital surgery in terms of genital sensitivity and sexual gratification and reproductive potential. Comparison and transparency by the team are essential in helping the parents make the decision about sex assignment of their infant.

Reassignment of sex in infancy and childhood is always a difficult challenge for the patient, the parents, and the physicians involved. Although easier in infancy than after 1 year of age, it should only be undertaken after deliberation and with provision for long-term psychiatric/psychological and clinical supervision and counseling. Current recommendations are to initiate plastic repair of the external genitalia as soon as feasible by surgeons experienced in the field who recommend 1 stage repair by 4 to 6 months of age143-150 (Table 539-8). However, iHHit has been suggested by some “intersex” societies that surgery, except that which is medically necessary, be deferred until the child is able to give her or his informed consent, although there are no data of patients with ambiguous genitalia using this approach. In children raised as females, the clitoris should be repaired by modern clitoroplasty techniques performed by experienced pediatric surgeons/urologists. Clitoroplasty is not recommended for mild to moderate clitoromegaly (Prader stage 1 or 2) and uncommonly in Prader stage 3.151 All surgical procedures should strive to preserve the functional capacity of all genital structures. This consideration should outweigh cosmetic appearance. A management approach for common disorders of sexual development is shown in Table 539-8.

Removal of gonads in children with Y chromosome material and gonadal dysgenesis should be performed at the time of initial repair of the external genitalia because gonadoblastoma, seminoma, and germinoma can occur during the first decade.152 In a patient with complete androgen resistance, the gonads may be left in situ (provided they are not situated in the labia majora) to provide estrogen until late adolescence or early adulthood. The patient may then choose to undergo prophylactic castration, having had her female identity reinforced by normal feminization at puberty. In this circumstance, sex steroid replacement therapy at the time of puberty is useful. In patients with incomplete androgen resistance reared as females or in patients with errors of testosterone biosynthesis in whom some degree of masculinization occurs at puberty, orchidectomy is recommended performed before puberty. Cyclic oral estrogen or estradiol dermal patch and progestin are used in individuals reared as females in whom a uterus is present.87 In males, masculinization is achieved by the administration of a repository preparation of testosterone or the use of the testosterone dermal patch.85

In infants with XX,disorders of sexual development, gender assignment as girls, and the repair of their external genitalia by 4 to 6 months of age is recommended. Genital reconstruction of the urogenital sinus and vagina are usually deferred until requested by the patient or parents. Because these patients have ovaries, fallopian tubes, and uterus, they are potentially fertile. Among infants with XY,disorders of sexual development, the basis for deciding on the sex of rearing is more complex, and many aspects remain controversial. Male sex assignment for patients with a phallus that can respond to testosterone therapy is most often chosen. This includes infants with LH/hCG unresponsiveness, biosynthetic errors in testosterone biosynthesis, or 5α-reductase 2 deficiency and XY dysgenetic DSD. The care of patients with partial androgen resistance is more complex.153-164 For some patients with ambiguous external genitalia, high-dose testosterone therapy can increase phallus size to allow for sexual function. Because these patients are sterile, fertility usually is not a consideration.

The recommendation for sex assignment in ovotesticular DSD is based on the morphologic features of the external genitalia and gonads. When the ambiguity of the genital structures is such that the child can be reared as a male or female, consideration of the selection of sex depends on whether the ovarian or testicular elements are better developed, the risk of malignant disease in dysgenetic-appearing testicular elements, and on the potential for fertility in the ovarian constituent. The gonad contrary to the selected sex is removed before puberty.