Disorders of sex development

Summary
Disorders of sex development are a group of congenital conditions that affect the development of the chromosomal, gonadal, or phenotypic sex. The underlying genetic
mutations affect the number and function of sex chromosomes (e.g., in Turner syndrome), lead to structural changes with altered sensitivity of hormone receptors
(e.g., androgen insensitivity syndrome), or alter the function of enzymes responsible for sex hormone synthesis (e.g., congenital adrenal hyperplasia). The most characteristic
clinical feature is the development of a sexual phenotype which does not correspond to the sexual genotype. Other common features include reduced fertility or infertility and
concomitant organ malformations (e.g., cardiac abnormalities). Disorders of sex development can also present with difficulties in gender identification and cause considerable
psychological distress. The diagnosis of these conditions is based on characteristic clinical features, evaluation of hormone levels, and genetic testing. Management
includes hormone substitution, possibly sex reassignment surgery, and psychological counseling.

Congenital adrenal hyperplasia

Summary

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive defects in the enzymes that are responsible for cortisol, aldosterone, and, in very rare
cases, androgen synthesis. All forms of CAH are characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia. The exact clinical manifestations depend
on the enzyme defect. The most common form of CAH is caused by a deficiency of 21β-hydroxylase and manifests with hypotension, ambiguous genitalia, virilization (in the
female genotype), and/or precocious puberty (in both males and females). All newborn infants in the US are screened for 21β-hydroxylase deficiency by measuring 17-
hydroxyprogesterone in a blood sample obtained from a heel prick. CAH treatment involves lifelong glucocorticoid and fludrocortisone replacement therapy. Certain rare forms
of CAH (e.g., 11β-hydroxylase and 17α-hydroxylase deficiencies) manifest with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore
require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Individuals with a virilizing form of CAH have an increased likelihood of
experiencing gender dysphoria. Intersex medical interventions may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal
insufficiency, and failure to thrive.

Pathophysiology
 CAH is caused by autosomal recessive defects in enzymes that are responsible for the production of cortisol.
 There are three subtypes of CAH:
21β-hydroxylase (~ 95% of CAH)
11β-hydroxylase (~ 5% of CAH)
17α-hydroxylase (rare)
 Low levels of cortisol ➜ lack of negative feedback to the pituitary ➜ increased ACTH ➜ adrenal hyperplasia and increased synthesis of adrenal precursor steroids
 Depending on which enzyme is affected, the following endocrine changes are seen:

Enzyme deficiency Cortisol Aldosterone  11-Deoxycorticosterone (DOC)  Androgens

21β-hydroxylase ↓
↑
11β-hydroxylase ↓ ↓
↑
17α-hydroxylase ↓

A deficiency in both 17α-hydroxylase and 11β-hydroxylase tends to result in overproduction of mineralocorticoids like DOC and underproduction of aldosterone.

“1 DOC:” If the deficient enzyme starts with 1 (11β-, 17-), there is increased DOC.
“AND 1:” If the deficient enzyme ends with 1 (21-, 11β-), androgens are increased.

Clinical features

Blood
XX (female) genotype XY (male) genotype
pressure

21β-
 Hypotensio
hydroxylas
n   Female pseudohermaphroditism: clitoromegaly and/or
e
male external genitalia along with a uterus and ovaries   Normal male external genitalia at birth
 Precocious puberty   Precocious puberty 
11β-
 Virilization, irregular menstrual cycles, infertility 
hydroxylas
e
 Hypertensi
on   Male pseudohermaphroditism: female external
17α-  Normal female external genitalia at birth
genitalia with a blind-ending vagina and intra-
hydroxylas  Delayed puberty (primary amenorrhea) or sexual
abdominal testes at birth 
e infantilism 
 Delayed puberty or sexual infantilism
 Hypoglycemia 
 Adrenal crisis ➜ vomiting and diarrhea ➜ dehydration
 Failure to thrive 
 Hyperpigmentation in areas that are not exposed to sunlight (e.g., palm creases, mucous membranes of the oral cavity, genitalia) is a common feature in all forms of CAH. 
Infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life because of severe dehydration due to an adrenal crisis and salt-wasting due
to hypoaldosteronism.
Different types of mutations on the CYP21A2 gene (which codes for 21β-hydroxylase) are associated with different levels of disease severity.

Classic CAH Nonclassic CAH

21β-hydroxylase deficie
 Severe  Mild
ncy

Detection by neonatal
 Yes  No
screening
 Classic CAH Nonclassic CAH

Prevalence  Less common  More common

 Late onset (manifests during late

Onset of symptoms  Early onset (during the neonatal period or early infancy)
childhood, adolescence, or adulthood)

 Salt-wasting type
~67% of all classic forms  Normal external genitalia at birth in
7–14 days after birth, males present with failure to both genotypes
thrive, dehydration, vomiting, and shock.  Precocious puberty
Females present with ambiguous genitalia.  Acne
Clinical manifestations
 Non-salt-wasting type (simple virilizing)  Infertility
~33% of all classic forms  Females may also have irregular menstrual
No signs of shock cycles and hirsutism.
Males present with precocious puberty at age 2–4.  May even be asymptomatic
Females present with ambiguous genitalia.

Ethnic predisposition  Inuit and Alaska native populations  Ashkenazi and white populations
Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria.
Differential diagnoses
 Precocious pseudopuberty
 Primary adrenal insufficiency
 PCOS
 Hyperprolactinemia
 Cushing Syndrome
The differential diagnoses listed here are not exhaustive.
Diagnostics
 Increased specific steroid precursors in blood and/or urine samples (see the table below)
Screening is conducted by measuring 17-hydroxyprogesterone (also for newborns). 
If steroid precursors are not elevated at baseline but CAH is still suspected, administer exogenous ACTH (cosyntropin) and measure again (see ACTH stimulation test). 
 Hypocortisolism is seen in all forms of CAH, and cortisol levels remain low even after administration of cosyntropin.
 Specific patterns of electrolyte and/or acid-base disorders are associated with specific enzyme deficiencies.

Adrenal enzyme deficiencies
Laboratory findings
21β-hydroxylase 11β-hydroxylase 17α-hydroxylase

17-Hydroxyprogesterone  ↑↑ ↑ ↓

11-Deoxycorticosterone (DOC) ↓  ↑↑ ↑

Corticosterone ↓ ↓  ↑↑

Sodium ↓ ↑ ↑

Potassium ↑ ↓ ↓

Acid-base disorders  Metabolic acidosis  Metabolic alkalosis  Metabolic alkalosis

All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample.
Treatment
 General approach
Therapy aims to replace deficient hormones and reduce excess androgen production.
Glucocorticoid replacement therapy is indicated in all forms of CAH. 
 Lifelong daily regimen
Hydrocortisone in neonates and children
Prednisolone or dexamethasone in adolescents and adults
 Steroid stress dosing
 Specific treatment
21β-hydroxylase deficiency
 Lifelong fludrocortisone therapy (aldosterone substitution)
 Sodium chloride (salt) supplements, especially during infancy and childhood
11β-hydroxylase deficiency
 Spironolactone to block mineralocorticoid receptors
 Reduced dietary sodium intake
17α-hydroxylase deficiency
 Spironolactone to block mineralocorticoid receptors
 Estrogen replacement therapy for female genotype; may be started in early puberty
 Reduced dietary sodium intake
Salt-wasting CAH
 Fluid resuscitation with intravenous normal saline
 Intravenous dextrose in patients with significant hypoglycemia
 Immediate administration of glucocorticoid replacement therapy
Nonclassic CAH
 Symptomatic children: hydrocortisone replacement therapy until 2-3 years postmenarche for girls and early to mid-puberty for boys
 Women: combined oral contraceptives are first-line treatment (alternatively glucorticoid therapy)
 Men: usually no treatment required
 Additional considerations
Intersex medical intervention may be considered in children with ambiguous genitalia.
Patients that experience gender dysphoria may benefit from counseling.
The dose of glucocorticoids must be increased during severe infection, critical illness, and perioperatively to meet increased demands to prevent adrenal crisis.
Prenatal diagnosis and treatment of CAH
 Prenatal testing is recommended in mothers who have previously given birth to a child with 21β-hydroxylase deficiency.
Chorionic villus sampling 
Increased 17α-hydroxyprogesterone in amniotic fluid 
 If a defect in 21β-hydroxylase is diagnosed prenatally:
Prophylactic treatment of the mother with dexamethasone soon after conception 
Dexamethasone therapy should be discontinued if the fetus has a male genotype (revealed by karyotyping).

Androgen insensitivity syndrome

 Incidence:approx. 1:20,000 genetically male individuals in the US
 Etiology: X-linked recessive mutation of the gene encoding the androgen receptor
 Karyotype: 46,XY
 Pathophysiology: Defects in the androgen receptor result in varying degrees of end-organ insensitivity to androgens.
 Clinical features
Complete androgen insensitivity
 Female external genitalia and physique
Attributed to increased aromatization of androgens to estrogens
Includes testicular feminization and female breast development
 Blind-ended vaginal pouch, uterine agenesis (due to anti-Mullerian hormone secretion)
 Absent male internal genitalia (with the exception of the testes) 
 Cryptorchid testes: intra-labial, inguinal or abdominal localization of undescended testicles 
 Scant or no pubic hair
 Primary amenorrhea, infertility (no menarche)
Partial androgen insensitivity: various phenotypes, depending on the degree of androgen insensitivity
 Diagnosis
Clinical presentation
Before puberty: ↑ testosterone
After puberty: ↑ LH, ↑ estrogen, and normal/↑ testosterone levels (no virilization) 
Genetic testing
 Treatment: depends on receptor status as well as on the patient's phenotype and gender identity
Hormone treatment
 Complete androgen insensitivity: estrogen replacement 
 Partial androgen insensitivity: high-dose androgen therapy can be used in patients with male gender identity 
Gonadectomy for intra-abdominal/intra-labial testicles
 Typically performed after puberty
 Prevents malignant transformation of the abnormally localized gonads
Psychological support

Aromatase deficiency
 Karyotype: 46 XX or 46 XY (normal sex development)
 Pathophysiology: Mutations in the CYP19A1 gene which encodes for the enzyme aromatase  ➜ ↓ serum estrogen and ↑ serum testosterone
 Clinical features
Females (46 XX)
 Birth: Ambiguous genitalia despite normal internal genital organs
 Puberty
Impaired maturation of secondary sexual characteristics
Primary amenorrhea 
Virilization (e.g., hirsutism, severe acne)
Both males and females
 Childhood
Tall stature
Osteoporosis (e.g., fractures following minimal trauma)
Mothers of affected children may experience virilization during pregnancy (may start at 12 weeks' gestation and typically disappear after delivery)
 Treatment
Estrogen and progesterone replacement therapy
Calcium and vitamin D supplementation
Surgical correction of ambiguous genitalia

5-alpha-reductase deficiency
 Synonym: pseudovaginal perineoscrotal hypospadias (PPSH)
 Etiology: rare autosomal recessive loss-of-function mutation of chromosome 2
 Karyotype: 46,XY
 Pathophysiology
Normal testosterone production
Defective 5-alpha-reductase: testosterone not converted into dihydrotestosterone (DHT) ➜ DHT-dependent virilization of genitalia does not occur 
 Clinical features
Female external genitalia at birth, sometimes with pseudovaginal perineoscrotal hypospadias 
Internal urogenital organs are male 
In puberty, increasing synthesis of testosterone leads to virilization (phallic growth, testicular descent, development of male gender identity).
 Diagnostics
Hormone levels: n/↑ testosterone, ↓ DHT (elevated testosterone-to-DHT ratio) 
Genetic testing for definitive diagnosis
 Therapy
Female gender identity: gonadectomy; estrogen substitution therapy upon completion of longitudinal growth
Male gender identity: testosterone substitution
Klinefelter syndrome
 Karyotype: 47 XXY, rarely 48 XXXY and 48 XXYY 
 Incidence: approximately 1:600 children 
 Etiology: most commonly due to nondisjunction of sex chromosomes during meiosis of parental germ cells
 Clinical features
Male phenotype; symptoms rarely observed during childhood
Testicular dysgenesis and subsequent testosterone deficiency become apparent at the onset of puberty.
 Eunuchoid growth pattern : tall, slim stature with long extremities [7]
 Gynecomastia, reduced body hair
 Testicular hypoplasia with a normal sized penis
 Reduced fertility, frequent azoospermia
 Osteoporosis frequently observed in adulthood
Associations:
 Mitral valve prolapse
 Diagnostics: primarily a clinical diagnosis; karyotyping confirms the diagnosis
 Complications: Increased risk of breast cancer development due to decreased levels of testosterone and increased levels of estrogen.
Testicular hypoplasia ➜ ↓ testosterone ➜ loss of negative feedback on gonadotropins ➜ ↑ FSH ➜ ↑ aromatase activity ➜ ↑ testosterone to estradiol conversion
 Therapy: life-long testosterone substitution 

Ovotesticular disorder of sex development

 Karyotype
Typically normal (46 XX > 46 XY)
 Incidence: rare
 Pathophysiology
Both ovarian and testicular tissue are present (true hermaphroditism)
 Bilateral (50%) or unilateral (20%) ovotestes 
The descent and position of the ovotestes depends on the amount of testicular tissue present in the ovotestes
 50% are found intra-abdominally
 25% in the inguinal region
 25% in the labio-scrotal region
 Unilateral testes and contralateral ovary (30%)
The type of internal genitalia depends on the nature of the adjacent gonad
 Fallopian tube develops beside the ovary and vas deferens with an epididymis develops beside the testicle
 In the case of ovotestes, fallopian tubes develop in 60–70% of cases
 A uterus can develop in the case of a unilateral ovotestis with a contralateral ovary
 Clinical features
At birth: most patients have ambiguous genitalia 
 Male karyotype
Hypospadias
Cryptorchidism
 Female karyotype
Labial fusion
Urogenital sinus
Puberty and adulthood
 Male karyotype
Gynecomastia
Recurrent groin or scrotal pain
Testicular enlargement
Infertility
 Female karyotype
Primary amenorrhea if the uterus does not form
Infertility

Turner syndrome
 Karyotype
Nondisjunction during meiosis ➜ complete sex chromosomal monosomy ➜ 45 XO, no Barr body
Nondisjunction during mitosis of an embryonic cell ➜ sex chromosomal mosaicism (45,XO/46,XX); Barr body may be present in cells with 46,XX karyotype ➜
mild phenotype
 Incidence: 1:2000 children 
 Clinical features
Female phenotype
Lymphedema in the neonatal period affecting the hands and feet (due to abnormal development of the lymphatic system)
Short stature, shield chest, widely spaced nipples, cubitus valgus 
 , nail dysplasia, short fourth metacarpals/metatarsals
High arched palate, low-set posterior hairline
Webbed neck: skin folds along the side of the neck between the mastoid process and the acromion 
Hypertension (even in children)
Gonadal dysgenesis with streak gonads : insufficient hormone production ➜ estrogen and progestogen deficiency
 Delayed puberty
 Primary amenorrhea 
 Infertility: Pregnancy is still possible through IVF using donor oocytes, with similar rates of success to that of the general population 
Associations:
 Cardiovascular abnormalities
Bicuspid aortic valve
 Increased risk of premature aortic stenosis and/or insufficiency
 Coarctation of the aorta 
Aortic dissection and rupture 
 Kidney and ureter malformations (especially horseshoe kidney; possibly agenesis, rotational anomalies, obstructions)
 Osteoporosis and pathologic fractures 
 Diagnostics:
Hypergonadotropic hypogonadism ➜ ↓ estrogen, ↓ androgens, ↑ follicle stimulating hormone, ↑ luteinizing hormone
Karyotyping confirms the diagnosis
 Therapy: estrogen and progestogen substitution
 Prognosis: life expectancy is significantly reduced (> 10 years)

Swyer syndrome
 Karyotype: 46 XY
 Pathophysiology: normal development until the 8th embryonic week ➜ SRY gene mutation ➜ gonads do not develop into testes ➜ no production of testosterone and anti-
Mü llerian hormone (AMH) ➜ male genital organs do not develop ➜ uterus and vagina develop despite the presence of XY chromosomes
 Clinical features
Female phenotype
Childhood: normal female development without evidence of a chromosomal aberration
Puberty: estrogen deficiency due to the absence of functional ovaries (streak gonads)
 Primary amenorrhea
 Infertility
 Therapy
Lifelong estrogen and progestogen substitution 
Removal of streak gonads 

Pure gonadal dysgenesis

 Karyotype: 46 XX
 Pathophysiology: Various mutations lead to impaired ovarian development or premature depletion of ovarian follicles ➜ impaired estrogen secretion ➜ secondary sexual
characteristics do not develop
 Clinical features
Female phenotype
Childhood: normal development of female genital organs (uterus and vagina)
Puberty:
 Impaired maturation of secondary sexual characteristics
 Primary (rarely secondary) amenorrhea
 Infertility
 Treatment: lifelong estrogen and progestogen substitution 

Kallmann syndrome
 Definition: a form of hypogonadotropic hypogonadism, associated with hyposmia/anosmia 
 Incidence: most common in male individuals (♂:♀ = 4: 1)
 Karyotype: 46,XY or 46,XX
 Etiology: associated with more than 20 different gene mutations
 Pathophysiology↑↓
Defective migration of GnRH-releasing neurons from the olfactory bulbs to the hypothalamic preoptic nuclei ➜ ↓ GnRH secretion and underdevelopment of the olfactory
bulbs
↓ GnRH ➜ ↓ pituitary secretion of FSH and LH ➜ ↓ testosterone in male individuals and ↓ estrogen in female individuals
 Clinical features
Anosmia or hyposmia
Infertility
 In male individuals: cryptorchidism and low sperm count
 In female individuals: primary amenorrhea
Absent or attenuated pubertal changes (e.g., absent thelarche in female individuals, decreased growth spurt)
Associated disorders
 Renal agenesis
 Cleft lip/palate
 Diagnosis
Clinical presentation
Hormone levels: low levels of GnRH, FSH, LH, estrogen/testosterone (otherwise normal pituitary function)
 Treatment
Hormone replacement therapy is given in puberty to stimulate the development of secondary sexual characteristics.
 For men: testosterone
 For women: estrogen and progesterone combination therapy
Gonadotropins or pulsatile GnRH therapy is used to increase fertility.
 In men: stimulates testicular growth and sperm production
 In women: stimulates ovulation