The clinical features of patients with disorders of gonadal and phenotypic sex are divided into the underandrogenization of 46,XY males (46,XY DSD) and the excess androgenization of 46,XX females (46,XX DSD) (Table 349-1). These disorders cover a spectrum of phenotypes ranging from "46,XY phenotypic females" or "46,XX males" to individuals with ambiguous genitalia.
46,Xy DSD (Underandrogenized Males)
Underandrogenization of the 46,XY fetus (formerly called male pseudohermaphroditism) reflects defects in androgen production or action. It can result from disorders of testis development, defects of androgen synthesis, or resistance to testosterone and DHT (Table 349-1).
Disorders of Testis Development
Patients with pure (or complete) gonadal dysgenesis (Swyer syndrome) have streak gonads, müllerian structures (due to insufficient AMH/MIS secretion), and a complete absence of androgenization. Serum AMH/MIS is low, and testosterone response to human chorionic gonadotropin (hCG) stimulation is impaired. Patients with partial gonadal dysgenesis (dysgenetic testes) may produce enough MIS to regress the uterus and, sometimes, sufficient testosterone for partial androgenization. Gonadal dysgenesis can result from mutations or deletions of testis-promoting genes (WT1, SF1, SRY, SOX9, DHH, ATRX, ARX, DMRT) or duplication of chromosomal loci containing "antitestis" genes (e.g., WNT4/RSPO1, DAX1) (Table 349-3). Among these, deletions or mutations of SRY and heterozygous mutations of SF1 (NR5A1) appear to be most common but still account collectively for <25% of cases. Associated clinical features may be present, reflecting additional functional roles for these genes. For example, renal dysfunction occurs in patients with specific WT1 mutations (Denys-Drash and Fraser's syndromes), primary adrenal failure occurs in some patients with SF1 mutations, and severe cartilage abnormalities (campomelic dysplasia) are the predominant clinical feature of SOX9 mutations. A family history of DSD or premature ovarian insufficiency is important (e.g., SF1/NR5A1). Intraabdominal dysgenetic testes should be removed to prevent malignancy, and estrogens can be used to induce secondary sex characteristics in 46,XY individuals raised as females. Absent (vanishing) testis syndrome (bilateral anorchia) reflects regression of the testis during development. The etiology is unknown, but the absence of müllerian structures indicates adequate secretion of AMH in utero. Early testicular regression causes impaired androgenization in utero, and in most cases, androgenization of the external genitalia is either normal or slightly impaired (e.g., small penis, hypospadias). These individuals can be offered testicular prostheses and should receive androgen replacement in adolescence.
Table 349-3 Selected Genetic Causes of Underandrogenization of Karyotypic Males (46,XY DSD) |Favorite Table|Download (.pdf)
Table 349-3 Selected Genetic Causes of Underandrogenization of Karyotypic Males (46,XY DSD)
|Gene||Inheritance||Gonad||Uterus||External Genitalia||Associated Features|
|Disorders of Testis Development|
|WT1||AD||Dysgenetic testis||+/−||Female or ambiguous||Wilms' tumor, renal abnormalities, gonadal tumors (WAGR, Denys-Drash and Fraser's syndromes)|
|SF1||AR/AD||Dysgenetic testis/Leydig's dysfunction||+/−||Female or ambiguous||Primary adrenal failure; primary ovarian insufficiency in female (46,XX) relatives|
|SRY||Y||Dysgenetic testis or ovotestis||+/−||Female or ambiguous|
|SOX9||AD||Dysgenetic testis or ovotestis||+/−||Female or ambiguous||Campomelic dysplasia|
|DHH||AR||Dysgenetic testis||+||Female||Minifascicular neuropathy|
|ATRX||X||Dysgenetic testis||−||Female or ambiguous||α Thalassemia, developmental delay|
|ARX||X||Dysgenetic testis||−||Male or ambiguous||Developmental delay; X-linked lissencephaly|
|MAMLD1||X||Dysgenetic testis/Leydig's dysfunction||−||Hypospadias|
|DAX1||dupXp21||Dysgenetic testis||+/−||Female or ambiguous|
|Disorders of Androgen Synthesis|
|LHR||AR||Testis||−||Female, ambiguous or micropenis||Leydig's cell hypoplasia|
|DHCR7||AR||Testis||−||Variable||Smith-Lemli-Opitz syndrome: coarse facies, second-third toe syndactyly, failure to thrive, developmental delay, cardiac and visceral abnormalities|
|StAR||AR||Testis||−||Female or ambiguous||Congenital lipoid adrenal hyperplasia (primary adrenal failure)|
|CYP11A1||AR||Testis||−||Ambiguous||Primary adrenal failure|
|HSD3β2||AR||Testis||−||Ambiguous||CAH, primary adrenal failure ± salt loss, partial androgenization due to ↑ DHEA|
|CYP17||AR||Testis||−||Female or ambiguous||CAH, hypertension due to ↑ corticosterone and 11-deoxycorticosterone, except in isolated 17,20 lyase deficiency|
|POR||AR||Testis||−||Ambiguous or male||Mixed features of 21-hydroxylase deficiency and 17α-hydroxylase/17,20 lyase deficiency, sometimes associated with Antley-Bixler craniosynostosis|
|HSD17β3||AR||Testis||−||Female or ambiguous||Partial androgenization at puberty, ↑ androstenedione: testosterone ratio|
|SRD5A2||AR||Testis||−||Ambiguous or micropenis||Partial androgenization at puberty, ↑ testosterone: dihydrotestosterone ratio|
|Disorders of Androgen Action|
|Androgen receptor||X||Testis||−||Female, ambiguous, micropenis or normal male||Phenotypic spectrum from complete androgen insensitivity syndrome (female external genitalia) and partial androgen insensitivity (ambiguous) to normal male genitalia and infertility|
Disorders of Androgen Synthesis
Defects in the pathway that regulates androgen synthesis (Fig. 349-4) cause underandrogenization of the male fetus (Table 349-1). Müllerian regression is unaffected because Sertoli cell function is preserved.
Simplified overview of glucocorticoid and androgen synthesis pathways. Defects in CYP21A2 and CYP11B1 shunt steroid precursors into the androgen pathway and cause androgenization of 46,XX females. Testosterone is synthesized in the testicular Leydig's cells and converted to dihydrotestosterone peripherally. Defects in enzymes involved in androgen synthesis result in underandrogenization of 46,XY males. StAR, steroidogenic acute regulatory protein. [After E Braunwald et al (eds): Harrison's Principles of Internal Medicine, 15th ed. New York, McGraw-Hill, 2001.]
Mutations in the LH receptor (LHCGR) cause Leydig's cell hypoplasia and androgen deficiency. Defects of LH receptor synthesis or function preclude hCG stimulation of Leydig's cells in utero, as well as LH stimulation of Leydig's cells late in gestation and during the neonatal period. As a result, testosterone and DHT synthesis are insufficient for normal androgenization of the internal and external genitalia, causing a spectrum of phenotypes that range from complete underandrogenization to micropenis, depending on the severity of the mutation.
Steroidogenic Enzyme Pathways
Mutations in steroidogenic acute regulatory protein (StAR) and CYP11A1 affect both adrenal and gonadal steroidogenesis (Chap. 342). Affected individuals (46,XY) usually have severe early-onset salt-losing adrenal failure and a female phenotype, although later-onset milder variants have been reported. Defects in 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2) also cause adrenal insufficiency in severe cases, but the accumulation of dehydroepiandrosterone (DHEA) has a mild androgenizing effect, resulting in ambiguous genitalia or hypospadias. Patients with CAH due to 17α-hydroxylase (CYP17) deficiency have variable underandrogenization and develop hypertension and hypokalemia due to the potent salt-retaining effects of corticosterone and 11-deoxycorticosterone. Patients with complete loss of 17α-hydroxylase function often present as phenotypic females who fail to enter puberty and are found to have inguinal testes and hypertension in adolescence. Some mutations in CYP17 selectively impair 17,20 lyase activity without altering 17α-hydroxylase activity, leading to underandrogenization without mineralocorticoid excess and hypertension. Mutations in P450 oxidoreductase (POR) affect multiple steroidogenic enzymes, leading to impaired androgenization and a biochemical pattern of apparent combined 21-hydroxylase and 17α-hydroxylase deficiency, sometimes with skeletal abnormalities (Antley-Bixler craniosynostosis). Defects in 17β-hydroxysteroid dehydrogenase type 3 (HSD17β3) and 5α-reductase type 2 (SRD5A2) interfere with the synthesis of testosterone and DHT, respectively. These conditions are characterized by minimal or absent androgenization in utero, but some phallic development can occur during adolescence due to the action of other enzyme isoforms. Individuals with 5α-reductase type 2 deficiency have normal wolffian structures and usually do not develop breast tissue. At puberty, the increase in testosterone induces muscle mass and other virilizing features despite DHT deficiency. Some individuals change gender from female to male at puberty. Thus, the management of this disorder is challenging. DHT cream can improve prepubertal phallic growth in patients raised as male. Gonadectomy before adolescence and estrogen replacement at puberty can be considered in individuals raised as females.
Disorders of Androgen Action
Androgen Insensitivity Syndrome
Mutations in the androgen receptor (AR) cause resistance to androgen (testosterone, DHT) action or the androgen insensitivity syndrome (AIS). AIS is a spectrum of disorders that affects at least 1 in 100,000 46,XY individuals. Because the androgen receptor is X-linked, only 46,XY offspring are affected if the mother is a carrier of a mutation. XY individuals with complete AIS (formerly called testicular feminization syndrome) have a female phenotype, normal breast development (due to aromatization of testosterone), a short vagina but no uterus (because MIS production is normal), scanty pubic and axillary hair, and a female psychosexual orientation. Gonadotropins and testosterone levels can be low, normal, or elevated, depending on the degree of androgen resistance and the contribution of estradiol to feedback inhibition of the hypothalamic-pituitary-gonadal axis. AMH/MIS levels in childhood are normal or high. Most patients present with inguinal hernias (containing testes) in childhood or with primary amenorrhea in adulthood. Gonadectomy sometimes is performed, as there is a low risk of malignancy, and estrogen replacement is prescribed. Alternatively, the gonads can be left in situ until breast development is complete. The use of graded dilators in adolescence is usually sufficient to dilate the vagina and permit sexual intercourse.
Partial AIS (Reifenstein's syndrome) results from less severe AR mutations. Patients often present in infancy with perineoscrotal hypospadias and small undescended testes and with gynecomastia at the time of puberty. Those individuals raised as males require hypospadias repair in childhood and breast reduction in adolescence. Supplemental testosterone rarely enhances androgenization significantly, as endogenous testosterone is already increased. More severely underandrogenized patients present with clitoral enlargement and labial fusion and may be raised as females. The surgical and psychosexual management of these patients is complex and requires active involvement of the parents and the patient during the appropriate stages of development. Azoospermia and male-factor infertility also have been described in association with mild loss-of-function mutations in the androgen receptor.
Other Disorders Affecting 46, XY Males
Persistent müllerian duct syndrome is the presence of a uterus in an otherwise normal male. This condition can result from mutations in AMH or its receptor (AMHR2). The uterus may be removed, but damage to the vasa deferentia must be avoided. Isolated hypospadias occurs in ˜1 in 200 males and is treated by surgical repair. Most cases are idiopathic, although evidence of penoscrotal hypospadias, poor phallic development, and/or bilateral cryptorchidism require investigation for an underlying disorder of sex development (e.g., partial gonadal dysgenesis, mild defect in testosterone action, or even severe forms of 46,XX CAH). Unilateral undescended testes (cryptorchidism) affects more than 3% of boys at birth. Orchidopexy should be considered if the testis has not descended by 6 to 9 months of age. Bilateral cryptorchidism occurs less frequently and should raise suspicion of gonadotropin deficiency or DSD. A small subset of patients with cryptorchidism may have mutations in the insulin-like 3 (INSL3) gene or its receptor LGR8 (also known as GREAT), which mediates normal testicular descent. Ascending testis is being recognized increasingly as a distinct condition for which management is currently unclear. Syndromic associations and intrauterine growth retardation also occur relatively frequently in association with impaired testicular function or target tissue responsiveness, but the underlying etiology of many of these conditions is unknown.
46,XX DSD (Androgenized Females)
Inappropriate androgenization of females (formerly called female pseudohermaphroditism) occurs when the gonad (ovary) contains androgen-secreting testicular material or after increased androgen exposure, which is usually adrenal in origin (Table 349-1).
46,XX Testicular/Ovotesticular DSD
Testicular tissue can develop in 46,XX testicular DSD (46,XX males) after translocation of SRY or duplication of SOX9 or defects in RSPO1 (Table 349-4).
Table 349-4 Selected Genetic Causes of Androgenization of Karyotypic Females (46,XX DSD) |Favorite Table|Download (.pdf)
Table 349-4 Selected Genetic Causes of Androgenization of Karyotypic Females (46,XX DSD)
|Gene||Inheritance||Gonad||Uterus||External Genitalia||Associated Features|
|SRY||Translocation||Testis or ovotestis||−||Male or ambiguous|
|SOX9||dup17q24||Unknown||−||Male or ambiguous|
|RSPO1||AR||Testis or ovotestis||±||Male or ambiguous||Palmar plantar hyperkeratosis, squamous cell skin carcinoma|
|WNT4||AR||Testis or ovotestis||−||Male or ambiguous||SERKAL syndrome (renal dysgenesis, adrenal and lung hypoplasia)|
|Increased Androgen Synthesis|
|HSD3β2||AR||Ovary||+||Clitoromegaly||CAH, primary adrenal failure, mild androgenization due to ↑ DHEA|
|CYP21A2||AR||Ovary||+||Ambiguous||CAH, phenotypic spectrum from severe salt-losing forms associated with adrenal failure to simple virilizing forms with compensated adrenal function, ↑ 17-hydroxyprogesterone|
|POR||AR||Ovary||+||Ambiguous or female||Mixed features of 21-hydroxylase deficiency and 17α -hydroxylase/17,20 lyase deficiency, sometimes associated with Antley-Bixler craniosynostosis|
|CYP11B1||AR||Ovary||+||Ambiguous||CAH, hypertension due to ↑ 11-deoxycortisol and 11-deoxycorticosterone|
|CYP19||AR||Ovary||+||Ambiguous||Maternal virilization during pregnancy, absent breast development at puberty|
|Glucocorticoid receptor||AR||Ovary||+||Ambiguous||↑ ACTH, 17-hydroxyprogesterone and cortisol; failure of dexamethasone suppression|
Increased Androgen Exposure
21-Hydroxylase Deficiency (Congenital Adrenal Hyperplasia)
The classic form of 21-hydroxylase deficiency (21-OHD) is the most common cause of CAH (Chap. 342). It has an incidence between 1 in 10,000 and 1 in 15,000 and is the most common cause of androgenization in chromosomal 46,XX females (Table 349-4). Affected individuals are homozygous or compound heterozygous for severe mutations in the enzyme 21-hydroxylase (CYP21A2). This mutation causes a block in adrenal glucocorticoid and mineralocorticoid synthesis, increasing 17-hydroxyprogesterone and shunting steroid precursors into the androgen synthesis pathway (Fig. 349-4). Glucocorticoid insufficiency causes a compensatory elevation of adrenocorticotropin (ACTH), resulting in adrenal hyperplasia and additional synthesis of steroid precursors proximal to the enzymatic block. Increased androgen synthesis in utero causes androgenization of the female fetus in the first trimester. Ambiguous genitalia are seen at birth, with varying degrees of clitoral enlargement and labial fusion. Excess androgen production causes gonadotropin-independent precocious puberty in males with 21-OHD.
The salt-wasting form of 21-OHD results from severe combined glucocorticoid and mineralocorticoid deficiency. A salt-wasting crisis usually manifests between 7 and 21 days of life and is a potentially life-threatening event that requires urgent fluid resuscitation and steroid treatment. Thus, a diagnosis of 21-OHD should be considered in any baby with ambiguous genitalia with bilateral nonpalpable gonads. Males (46,XY) with 21-OHD have no genital abnormalities at birth but are equally susceptible to adrenal insufficiency and salt-losing crises.
Females with the classic simple virilizing form of 21-OHD also present with genital ambiguity. They have impaired cortisol biosynthesis but do not develop salt loss. Patients with nonclassic 21-OHD produce normal amounts of cortisol and aldosterone, but at the expense of producing excess androgens. Hirsutism (60%), oligomenorrhea (50%), and acne (30%) are the most common presenting features. This is one of the most common recessive disorders in humans, with an incidence as high as 1 in 100 to 500 in many populations and 1 in 27 in Ashkenazi Jews of Eastern European origin.
Biochemical features of acute salt-wasting 21-OHD are hyponatremia, hyperkalemia, hypoglycemia, low cortisol and aldosterone, and elevated 17-hydroxyprogesterone, ACTH, and plasma renin activity. Presymptomatic diagnosis of classic 21-OHD is now made by neonatal screening tests for increased 17-hydroxyprogesterone in many centers. In most cases, 17-hydroxyprogesterone is markedly increased. In adults, ACTH stimulation (0.25 mg cosyntropin IV) with assays for 17-hydroxyprogesterone at 0 and 30 min can be useful for detecting nonclassic 21-OHD and heterozygotes (Chap. 342).
Treatment: Congenital Adrenal Hyperplasia
Acute salt-wasting crises require fluid resuscitation, IV hydrocortisone, and correction of hypoglycemia. Once the patient is stabilized, glucocorticoids must be given to correct the cortisol insufficiency and suppress ACTH stimulation, thereby preventing further virilization, rapid skeletal maturation, and the development of polycystic ovaries. Typically, hydrocortisone (10–15 mg/m2 per day in three divided doses) is used in childhood with a goal of partially suppressing 17-hydroxyprogesterone (100–<1000 ng/dL). The aim of treatment is to use the lowest glucocorticoid dose that adequately suppresses adrenal androgen production without causing signs of glucocorticoid excess such as impaired growth and obesity. Salt-wasting conditions are treated with mineralocorticoid replacement. Infants usually need salt supplements up to the first year of life. Plasma renin activity and electrolytes are used to monitor mineralocorticoid replacement. Some patients with simple virilizing 21-OHD also benefit from mineralocorticoid supplements. Newer therapeutic approaches such as antiandrogens and aromatase inhibitors (to block premature epiphyseal closure) are under evaluation. Parents and patients should be aware of the need for increased doses of steroids during sickness, and patients should carry medic alert systems.
Older adolescents and adults often are treated with prednisolone or with dexamethasone at night to provide more complete ACTH suppression. Steroid doses should be adjusted to individual requirements as overtreatment results in weight gain and hypertension and can affect bone turnover. Androstenedione and testosterone may be useful measurements of long-term control, with less fluctuation than 17-hydroxyprogesterone. Mineralocorticoid requirements often decrease in adulthood, and doses should be reduced to avoid hypertension. In very severe cases, adrenalectomy has been advocated but incurs the risks of surgery and total adrenal insufficiency.
Girls with significant genital androgenization due to classic 21-OHD usually undergo vaginal reconstruction and clitoral reduction (maintaining the glans and nerve supply), but the optimal timing of these procedures is debated, as is the need for the individual to be able to consent. There is a higher threshold for undertaking clitoral surgery in some centers as long-term sensation and ability to achieve orgasm can be affected, but the long-term results of newer techniques are not yet known. If surgery is performed in infancy, surgical revision or regular vaginal dilatation may be needed in adolescence or adulthood, and long-term psychological support and psychosexual counseling may be appropriate. Women with 21-OHD frequently develop polycystic ovaries and have reduced fertility, especially when control is poor. Fecundity is achieved in up to 90% of women, but ovulation induction (or even adrenalectomy) is frequently required. Dexamethasone should be avoided in pregnancy. Men with poorly controlled 21-OHD may develop testicular adrenal rests and are at risk for reduced fertility. Prenatal treatment of 21-OHD by the administration of dexamethasone to mothers is still under evaluation. However, treatment of the mother and child must be started ideally before 6 to 7 weeks; long-term effects of prenatal dexamethasone exposure on fetal development are still under evaluation.
The treatment of other forms of CAH includes mineralocorticoid and glucocorticoid replacement for salt-losing conditions (e.g., StAR, CYP11A1, HSD3β2), suppression of ACTH drive with glucocorticoids in disorders associated with hypertension (e.g., CYP17, CYP11B1), and appropriate sex-hormone replacement in adolescence and adulthood, when necessary.
Increased androgen synthesis can also occur in CAH due to defects in POR, 11β-hydroxylase (CYP11B1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2) and with mutations in the genes encoding aromatase (CYP19) and the glucocorticoid receptor. Increased androgen exposure in utero can occur with maternal virilizing tumors and with ingestion of androgenic compounds.
Other Disorders Affecting 46,XX Females
Congenital absence of the vagina occurs in association with müllerian agenesis or hypoplasia as part of the Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome (rarely caused by WNT4 mutations). This diagnosis should be considered in otherwise phenotypically normal females with primary amenorrhea. Associated features include renal (agenesis) and cervical spinal abnormalities.
The approach to a child or adolescent with ambiguous genitalia or another DSD requires cultural sensitivity, as the concepts of sex and gender vary widely. Rare genetic DSDs can occur more frequently in specific populations (e.g., 5β-reductase type 2 in the Dominican Republic). Different forms of CAH also show ethnic and geographic variability. In many countries, appropriate biochemical tests may not be readily available, and access to appropriate forms of surgery or treatment may be limited.