Disorders of Sexual Development PDF

Disorders of Sexual Development Genetic mutations Developmental issues during fetal development Hormone insufficiency - baby does not make enough hormones or respond to them Exposure to certain hormones Medications during pregnancy (testosterone antagonist) Sex Chromosome Disorders Aneuploidy of sex...

Disorders of Sexual Development Genetic mutations Developmental issues during fetal development Hormone insufficiency - baby does not make enough hormones or respond to them Exposure to certain hormones Medications during pregnancy (testosterone antagonist) Sex Chromosome Disorders Aneuploidy of sex chromosomes (abnormal number of chromosomes): o Turner syndrome (45 X) o Klinefelter syndrome (47 XXY) o Double Y males (47 XYY) § Normal appearing male § Normal fertility § Tall § Sometimes severe acne § Learning disability, autism Disorders of Sexual Development (DSD) The normal number of chromosomes Congenital discrepancy between: o Chromosomal sex (46XX/46XY) o Gonads (testes/ovaries) o External genitalia Clinical Presentation Ambiguous genitalia - external genitals do not appear to be clearly either male or female o Common presentations of DSD o XX female exposed to excessive androgens o XY male with insufficient androgens Female external genitalia o XY male with a lack of androgen activity o Often discovered at puberty Sexual Development Default genital development is female Male development requires special factors: o Testosterone o Dihydrotestosterone (DHT) o Mullerian inhibiting factor Disorders of sexual development o Presence of male factors in XX (female) o Absence of male factors in XY (male) Key test: Karyotype Ovotesticular DSD – Hermaphroditism A combination of male and female physical characteristics Baby born with both ovarian and testicular tissue o Separate ovaries and testes o Ovotestes (both tissue types in one structure) 46, XX > 46, XY 80% of cases in 46, XX individual Diagnosis by gonadal biopsy Range of male/female genital development o Abnormal vagina o Hypoplastic uterus o Undescended testes (cryptorchidism) o Abnormal penis Puberty: breast development, menstruation may occur Treatment : Genital reassignment surgery Most individuals infertile Types: 46, XX DSD 46, XY DSD 46, XX DSD o Genetic female with abnormal sexual development o Presence of male factors in XX (female) o Ovaries usually present o External genitalia ambiguous o Female baby exposed to androgens in utero o Fetus vulnerable 7-12 weeks gestation o 2 classic causes: § Congenital adrenal hyperplasia (CAH) § Gestational hyperandrogenism 46, XY DSD o Genetic male with abnormal sexual development o Absence of male factors in XY (male) o Testes present o External genitalia ambiguous or female o Male baby under-exposed to androgens o Many potential causes § Gonadal dysgenesis § 5-α reductase deficiency § Androgen insensitivity § Rare forms of CAH (↓ androgens) § Testosterone synthesis defects Complete Androgen Insensitivity Syndrome (CAIS) Mutation of androgen receptor in males (XY) located on the X chromosome Inability of cells to respond to androgens, such as testosterone and dihydrotestosterone (DHT) Testes form in utero (SRY gene present) No ovaries No internal or external male genital development o No cellular response to androgens Sertoli cells (testes) present → MIH o Degeneration of mullerian structures o Absent uterus, fallopian tubes XY male with a female appearance Abdominal testes Amenorrhea at puberty (no uterus) At puberty: o Breasts develop (testosterone → estrogen) o Widening of the hips. o No armpit/pubic hair (depends on androgens) Swyer Syndrome 46, XY complete gonadal dysgenesis Absence of both ovarian and testicular tissue Female with 46, XY chromosomes, and no ovaries The phenotype is similar to Turner syndrome (45, X0) due to a lack of X inactivation Streak gonads o Mainly fibrous tissue o Risk of malignancy (often removed surgically) Female external genitalia Müllerian ducts (no Sertoli cells = no MIH) No puberty/menstruation o No functioning ovaries to produce ↑ estrogen o Usually given estrogen supplementation Treatment: estrogen and progestogen promoting the development of female characteristics Hormone replacement therapy can also reduce the likelihood of osteoporosis 5-α Reductase Deficiency Autosomal recessive disorder 46, XY male able to make testosterone, not DHT Normal internal genitalia o Normal epididymis, vas deferens, seminal vesicles o Empty into a blind-ending vagina External genitalia predominately female o Absent external male genitalia o Range of female genitalia seen o Sometimes ambiguous genitalia Masculinization at puberty o Increased testosterone → muscle growth o Some DHT production Typical case o XY male with ambiguous genitalia o Female child with masculinization at puberty o Bilateral undescended testes o Normal or elevated testosterone levels while low DHT levels o Vas deferens, seminal vesicles present o Absence of uterus o Blind vagina o Missing/abnormal male external genitalia XY DSD Gonads Internal Swyer Female 5-α Reductase Testes Male CAIS Testes External Puberty Female Female Masculinization Female No menses 21-α Hydroxylase Deficiency Classic cause of CAH (90% of CAH) Excess production of male hormones in utero Low mineralocorticoid symptoms o Salt loss (volume depletion) o Electrolyte imbalance Hypertension due to excess production of hormone Androgen symptoms o Girls (46XX): ambiguous genitalia o Boys (46XY): precocious puberty (early onset) Congenital Adrenal Hyperplasia Clinical evaluation: ambiguous genitalia in females, salt wasting, hypertension, early puberty, hirsutism Hormone Testing: low cortisol and aldosterone levels and high levels of androgens ACTH (adrenocorticotropic hormone) Stimulation Test: stimulates the adrenal glands to produce cortisol o CAH, the adrenal glands may not respond adequately to ACTH stimulation, resulting in low cortisol levels Newborn Screening: 17-hydroxyprogesterone o Elevated levels of 17-hydroxyprogesterone Genetic testing Imaging: Adrenal gland ultrasound or MRI Gestational Hyperandrogenism Maternal source of androgens in pregnancy Mother develops hirsutism and virilization Leads to virilization of female fetuses Causes: Rare gestational masses o Luteomas most common – ovarian mass o Secrete testosterone and dihydrotestosterone Maternal administration progestins or androgens o Some progestins have androgen activity o Given for threatened abortion Placental Aromatase Deficiency Placenta synthesizes estradiol from testosterone Aromatase deficiency → androgen excess Increased androstenedione and testosterone Maternal/fetal virilization Kallman Syndrome Hypogonadotropic hypogonadism plus anosmia (lack of sense of smell) Caused by GnRH deficiency ↓ LH/FSH KAL1 gene mutation Impaired migration GnRH neurons to hypothalamus Primarily a disease of males (5:1 ratio) Newborn females appear normal Some newborn males: micropenis/cryptorchidism Often discovered at puberty – puberty fails to start Females o Little or no breast development, no axillary hair o 1 ° amenorrhea Males o No facial or body hair o No increase in muscle mass o Failure of the voice to deepen o Infertility Diagnostic Tests Karyotype Abdominal imaging: Abdominal testis, uterus 17-hydroxyprogesterone: Elevated in CAH due to 21-hydroxylase deficiency Testosterone and DHT o Both elevated in CAIS o ↓ DHT in 5α reductase deficiency Luteinizing Hormone Secreted by pituitary Negative feedback by testosterone o LH low when testosterone high o LH high when testosterone low Testosterone Gonadal failure ↓ Exogenous Testosterone ↓ Pituitary failure ↓ LH ↑ ↓ ↓ Testosterone Tumor CAIS ↓ ↑ ↑ ↑ Which of the following is a common example of Disorders of Sexual Development (DSD)? A. Androgen Insensitivity Syndrome (AIS) B. Celiac Disease C. Type 1 Diabetes D. Hypertension A Klinefelter syndrome is a chromosomal disorder characterized by: A. XXY chromosomes B. XY chromosomes C. XX chromosomes D. XXX chromosomes A What is hermaphroditism? A. A disorder of sexual development (DSD) where an individual has both male and female reproductive organs B. A condition where an individual identifies with both male and female genders C. A type of hormonal imbalance affecting sexual characteristics D. A psychological disorder related to gender identity A Individuals with Swyer Syndrome typically have: A. Ambiguous genitalia B. Female external genitalia C. Male external genitalia D. Normal external genitalia B Which of the following is NOT a symptom of Congenital adrenal hyperplasia (CAH) in females? A. Ambiguous genitalia B. Hypertension C. Secondary amenorrhea D. Excessive body hair (hirsutism) C Which of the following symptoms is NOT typically associated with gestational hyperandrogenism in pregnant women? A. Acne B. Hirsutism (excessive hair growth) C. Virilization D. Amenorrhea (absence of menstruation) D Swyer Syndrome, also known as 46, XY complete gonadal dysgenesis, is characterized by: A. Presence of both ovarian and testicular tissue B. Absence of both ovarian and testicular tissue C. Presence of ovarian tissue only D. Presence of testicular tissue only B What does "TORCH" stand for in TORCH infections? A. Tuberculosis, Osteomyelitis, Rheumatoid arthritis, Chronic bronchitis, Hepatitis B. Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, Herpes simplex virus C. Thyroid disorders, Ovarian cancer, Rheumatoid arthritis, Coronary artery disease, Hypertension D. None of the above B Which TORCH infection can cause congenital deafness? A. Rubella B. Cytomegalovirus C. Herpes simplex virus D. Toxoplasmosis B _________ is the classic triad in fetus of congenital toxoplasmosis. A. Hydrocephalus B. Liver toxicity C. Kidney failure D. Pneumonia A What is the typical appearance of primary syphilis symptom in pregnant women? A. Chancre B. Maculopapular rash C. Asymptomatic D. Patchy hair loss A Which of the following is NOT a common symptom of Parvovirus B19 infection? A. Rash on the cheeks (slapped cheek appearance) B. Arthritis C. Anemia D. Watery diarrhea D Which of the following is a symptom of rubella? A. Maculopapular rash B. Cough and runny nose C. Painful swelling of the salivary glands D. Jaundice A Which of the following conditions can cause a Blueberry Muffin Baby appearance? A. Congenital cytomegalovirus B. Congenital rubella syndrome C. Congenital toxoplasmosis D. Congenital syphilis B