Congenital Disorders of Sexual Development

The term “disorders of sexual development” refers to a group of conditions characterized by atypical sexual development in an individual, which may involve abnormalities in the structure and/or function of the internal reproductive organs and/or external genitalia. Typical sex development starts with the chromosomal sex (e.g., 46,XY or 46,XX), which determines the sexual differentiation of the gonads (e.g., testes or ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries), which secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview that determine the phenotype (e.g., male or female). Most disorders of sexual development are due to abnormalities in specific chromosomes, enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, or receptors. Diagnosis typically involves analyzing the karyotype and specific hormone levels. Management can be complex, and often includes psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy, hormone replacement therapy Hormone Replacement Therapy Estrogen and progesterone are the sex hormones produced by the ovaries in premenopausal women. They are used to treat hypogonadism (primary ovarian insufficiency), menopausal symptoms, and gender dysphoria in transgender women. Noncontraceptive Estrogen and Progestins, and/or surgery.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview of Sex Development

Definition

Disorders of sexual development are a group of conditions characterized by atypical sexual development in an individual, involving abnormalities in the structure and/or function of both the internal reproductive organs and/or external genitalia.

Overview of typical sex development

  • Chromosomal sex → determines gonadal sex → determines phenotypic sex
  • Up until 6 weeks of gestation, sex development is identical and nonbinary. The developing structures include:
    • Nonbinary, bipotent, undifferentiated gonads
    • Wolffian and Müllerian ducts (both are present in both sexes initially)
    • Urogenital sinus
    • The genital tubercle, genital swellings, and genital folds 
  • The genes present at fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week will determine how the developing bipotent gonads differentiate (e.g., into a testis or an ovary).
  • The developing gonads will then secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview:
    • The presence and/or absence of specific hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview will determine how the remaining structures differentiate.
    • In general, female organs and structures are the “default” phenotype if specific genes and hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview are not present to stimulate male differentiation.

Sex organs and characteristics

  • Gonads develop based on the karyotype/genes that are present.
    • Testes: 
      • Develop when sex-determining region of the Y chromosome (SRY gene) is present
      • Secrete testosterone and anti-Müllerian hormone (AMH)
    • Ovaries develop when the X chromosome is present and/or the SRY is absent. 
    • Ovotestis: a gonad containing both ovarian and testicular tissue found in patients with true hermaphroditism True hermaphroditism True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. True Hermaphroditism
  • Wolffian structures differentiate from the Wolffian (mesonephric) ducts in the presence of testosterone:
  • Müllerian structures differentiate from the Müllerian (paramesonephric) ducts when AMH is absent:
    • Uterus
    • Fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall
    • Upper ⅓ of the vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
  • External genitalia develop from the undifferentiated genital tubercle, genital swelling, and genital folds based on the presence or absence of testosterone.
    • Male: testosterone → penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis and scrotum
    • Female: lack of testosterone → clitoris, labia majora, labia minora
  • Secondary sexual characteristics develop based on the hormonal milieu at puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty.
    • Androgenic characteristics: due to the presence of testosterone and/or dihydrotestosterone (DHT)
      • Pubic and axillary hair
      • Facial and body hair in an androgenic distribution and quality (dark and coarse)
      • Deepening of the voice
      • ↑ Muscle mass
    • Estrogenic characteristics result from the presence of estrogen:
      • Breast development
      • Wider hips

Typical male development

Male development begins due to the presence of the sex-determining region of the Y chromosome gene (SRY gene).

  • SRY gene → produces SRY protein (also known as testis-determining factor):
    • Stimulates the differentiation of the bipotent gonad into testes 
    • Stimulates development of:
      • Seminiferous tubules
      • Leydig cells
      • Sertoli cells
    • Suppresses the differentiation of ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
  • Testes secrete:
    • AMH
    • Testosterone
    • DHT
  • The above hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview cause:
    • Stimulation of the Wolffian ducts (around the 8th week) to differentiate into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts
    • Regression of the Müllerian ducts
    • Differentiation of the prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands and external genitalia 
  • The process of differentiation is largely completed by 12 weeks of gestation.
Male development

Male development

DHT: dihydrotestosterone
Image by Lecturio.

Typical female development

  • Development of the ovary from the bipotent gonad requires:
    • Absence of the SRY (preventing differentiation into testes)
    • Presence of several genes found on chromosome 1, including:
      • WNT4 
      • R spondin 1 (Rspo1)
    • Begins around 10 weeks of development
  • Differentiation and development of the Müllerian ducts and external genitalia occur when testicular androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and AMH are absent.
  • Embryos develop in the “female hormonal environment” within their mother; thus, it is unclear whether hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview produced by the fetus are required for their development.

Summary of Common Disorders of Sexual Development

Table: Common disorders of sexual development
Disorder Pathophysiology Key points
Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome (AIS)
  • Decreased or no response to androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Due to mutations affecting the quantity or function of androgen receptors
  • ↑↑ Serum testosterone levels
  • Affected individuals are 46,XY.
  • Phenotypic female genitalia
  • Testes present (undescended)
  • No Müllerian structures
  • Typically present in adolescence as primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea, well-developed breasts Breasts The breasts are found on the anterior thoracic wall and consist of mammary glands surrounded by connective tissue. The mammary glands are modified apocrine sweat glands that produce milk, which serves as nutrition for infants. Breasts are rudimentary and usually nonfunctioning in men. Breasts, and sparse pubic hair
5-α-reductase deficiency
  • Loss-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in 5-α-reductase gene impairs conversion of testosterone to dihydrotestosterone (DHT).
  • Normal or ↑ testosterone with ↓ DHT
  • Affected individuals are 46,XY.
  • Impaired virilization in utero → ambiguous genitalia at birth
  • Testes present
  • No Müllerian structures
Aromatase deficiency Aromatase deficiency Aromatase deficiency is a very rare genetic condition with autosomal recessive inheritance. Aromatase deficiency is characterized by congenital estrogen deprivation with increased levels of testosterone due to decreased levels of the aromatase enzyme. Aromatase Deficiency
  • ↓ Aromatase → ↓ conversion of testosterone into estrogen
  • Individuals will have:
    • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries
    • ↑ Testosterone
  • 46,XX individuals:
    • Müllerian structures present
    • Virilized/ambiguous genitalia
    • Primary amenorrhea, no breast development, normal pubic hair
  • 46,XY individuals:
    • Normal Wolffian structures and phenotypic male genitalia
    • May have undescended testes, low libido, and/or fertility issues
  • All are prone to effects of ↑ testosterone (e.g., fertility issues, dyslipidemia, glucose intolerance).
Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia
  • Due to deficiencies in 1 of the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in the steroidogenesis pathway
  • 21-Hydroxylase deficiency by far the most common
  • Intermediate substrates are shunted toward testosterone production (see diagram below).
  • Leads to ↓ cortisol, ↓ aldosterone, ↑ ACTH, and ↑ testosterone
  • 46,XX individuals:
    • Müllerian structures present
    • Virilized/ambiguous genitalia
  • 46,XY individuals:
    • Normal Wolffian structures and phenotypic male genitalia
    • Salt-wasting crisis (1-2 weeks of life)
    • Early virilization
  • All are prone to effects of ↑ testosterone and adrenal tumors.
Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome
  • Decreased secretion or lack of gonadotropin-releasing hormone (GnRH)
  • Leads to a lack of all sex hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
  • Affects both sexes
  • Can be due to mutations in a variety of genes
  • Presents with absence of sexual development at puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty due to lack of sex hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
  • Key finding: associated with anosmia (absent sense of smell)
  • Other anomalies may be present, including cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate/ palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, syndactyly, and renal agenesis.
46,XX gonadal dysgenesis 46,XX Gonadal Dysgenesis 46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads with no functional ovarian tissue. It is also called "pure gonadal dysgenesis" to differentiate these patients from those who present with the phenotype of Turner's syndrome. 46,XX Gonadal Dysgenesis
  • Non-functional ovarian tissue → ↓↓ estrogen
  • Due to various mutations affecting ovarian development
  • Affected individuals are 46,XX.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Presents in adolescence with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and lack of all secondary sex characteristics
Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome
  • 46,XY individuals with non-functional gonadal tissue → ↓ testosterone and ↓ estrogen
  • AMH and testosterone are not secreted in developing embryo Embryo The entity of a developing mammal, generally from the cleavage of a zygote to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the fetus. Fertilization and First Week → development of uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall, vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor, and female genitalia
  • Mutations may be on an X, Y (SRY region), or autosomal chromosome.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Undeveloped testes are called “streak gonads” → ↑ risk for tumors:
    • Gonadoblastoma
    • Dysgerminoma
  • Presents in adolescence with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and lack of all secondary sex characteristics
True hermaphroditism
  • Patients have at least 1 ovotestis gonad that contains both ovarian and testicular elements.
  • May have a normal ovary or testis on the contralateral side
  • Karyotype may be either 46,XX (approximately 80%), 46,XY, or 46,XX/XY mosaic (rare).
  • Ambiguous or normal external genitalia at birth
  • Internal structures depend on adjacent gonads:
    • Fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall may develop beside an ovary or ovotestis (60%‒70% of the time).
    • Vas deferens and epididymis develop beside a testicle.
    • Uterus may develop if an ovary is present.
Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome
  • Chromosomal anomaly with a partially or completely missing X chromosome
  • Occurs due to nondisjunction during meiosis Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). Meiosis or mitosis
  • Affected individuals are 45,X0.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Characteristic appearance including short stature, webbed neck, shield chest, and low hairline
  • Multiple medical anomalies involving the cardiac, renal, reproductive, skeletal, and lymphatic systems
  • Most common cause of primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea
Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome
  • Chromosomal anomaly characterized by 1 or more X chromosomes in a male karyotype
  • Most commonly 47,XXY
  • Other possible karyotypes: 48,XXXY and 48,XXYY
  • ↓ Testosterone and ↑ estrogen compared to typical levels in men
  • Phenotypic male genitalia
  • Wolffian structures present; Müllerian structures absent
  • Presents in adolescence with small testes, ↓ body hair, gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
  • Most common cause of hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism in men
21-hydroxylase deficiency

21-hydroxylase deficiency:
Diagram of the pathophysiology of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Image by Lecturio.

Principles of Diagnosis

The differential diagnosis for disorders of sexual development typically includes many of the conditions listed above. The general diagnostic approach to help determine the appropriate diagnosis is listed below.

Exam

  • Genital examination:
    • Ambiguous genitalia is likely due to ↑ testosterone/DHT in individuals without SRY (e.g., 46,XX) or ↓ testosterone in individuals with SRY (e.g., 46,XY)
    • Assess the size and descent of testes.
  • Internal pelvic examination on phenotypic females:
    • Is a cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Posterior Abdominal Wall visible?
    • Is the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall palpable?
  • Assessment of secondary sex characteristics in adolescents/adults:
    • Breast development = estrogen present
    • Pubic and axillary hair = testosterone present
    • Facial/body hair, deepening of the voice = testosterone present
  • Look for findings associated with specific syndromes (e.g., webbed neck in Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome).

Laboratory

  • Karyotype with FISH to assess the presence or absences of the SRY gene
  • Testosterone: 
    • Decreases in Kallman, Swyer, and Klinefelter syndromes
    • Increases or is normal in androgen insensitivity syndrome (AIS), 5α-reductase deficiency, aromatase deficiency, and congenital adrenal hyperplasia
  • DHT: 
    • Decreases with 5α-reductase deficiency 
    • Increases in AIS
  • Follicle stimulating hormone (FSH) and luteinizing hormone (LH): 
    • Decrease in Kallman syndrome (due to ↓ gonadotropin-releasing hormone (GnRH))
    • Increase in 46,XX gonadal dysgenesis 46,XX Gonadal Dysgenesis 46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads with no functional ovarian tissue. It is also called "pure gonadal dysgenesis" to differentiate these patients from those who present with the phenotype of Turner's syndrome. 46,XX Gonadal Dysgenesis and Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome (normal GnRH function with non-responsive gonads)
  • 17-Hydroxyprogesterone: ↑ in congenital adrenal hyperplasia

Imaging

Abdominal pelvic ultrasound to assess the internal organs:

  • Presence or absence of a uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall
  • Assessment of the gonads

Consider imaging of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract, as abnormalities in the reproductive organs are frequently associated with renal/urinary anomalies.

Principles of Management

  • Factors affecting management:
    • Age of presentation (infant, adolescent, versus adult)
    • Gender identity and preferences of the patient
    • Hormone status
  • Psychotherapy/counseling: All patients (and potentially family members) should be referred for therapy.
  • Hormone replacement therapy (HRT) may be indicated in patients with hormonal deficiencies (e.g., testosterone and/or estrogen).
  • Surgery:
    • Abnormal gonads, especially gonadoblastomas and dysgerminomas, pose a high risk for malignancy → surgical excision recommended
    • Reconstructive or reassignment surgery

References

  1. Patel, N., Zafar Gondal, A. (2020). Embryology, Mullerian-inhibiting Factor. StatPearls. Retrieved May 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544351/
  2. Chan, Y., Levitsky, L.L. (2020). Causes of differences of sex development. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/causes-of-differences-of-sex-development?source=history_widget
  3. Hiort, O. (2020). Typical sex development. UpToDate. Retrieved May 13, 2021, from https://www.uptodate.com/contents/typical-sex-development?source=history_widget#H1048687515
  4. Chan, Y., Levitsky, L.L. (2020). Evaluation of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/evaluation-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
  5. Houk, C.P., Baskin, L.S., Levitsky, L.L. (2020). Management of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/management-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
  6. Nieman, L.K. (2020). Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2021, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
  7. Merke, D.P., Auchus, R.J. (2020). Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency-in-infants-and-children
  8. Medline Plus. (2020). Swyer syndrome. Retrieved January 21, 2021, from https://medlineplus.gov/genetics/condition/swyer-syndrome/
  9. Ostrer, H. (2019). Swyer syndrome. National Organization for Rare Disorders. Retrieved January 21, 2021, from https://rarediseases.org/rare-diseases/swyer-syndrome/
  10. Moshiri, M., Chapman, T., Fechner, P.Y., et al. (2012). Evaluation and management of disorders of sex development: Multidisciplinary approach to a complex diagnosis. RadioGraphics. 32(6),1599–1618. https://pubmed.ncbi.nlm.nih.gov/23065160/
  11. Hiort, O., Bohring, A. (2011). 46, XX gonadal dysgenesis. Orphanet. Retrieved January 22, 2021, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=243&lng=EN

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details