Disorders of Sex Development Flashcards
Effect of Leydig cell dysfunction
Underproduction of testosterone
Describe the phenotype of males with no LH (eg. male with anencephaly and other forms of congenital hypopituitarism)
- Leydig cells all but disappear
- Internal and external genitalia do not develop fully
Effect of Sertoli cell dysfunction
Underproduction of AMH -> lack of mullerian duct regression
Describe complete Swyer Syndrome
What organ is missing? What happens as a result? What needs to be done?
46XY gonadal dysgenesis
No testes (leydig cells) -> no testosterone -> female external genitalia
No testes (no Sertoli cells) -> no AMH -> intact Mullerian structures, streak gonads
Delayed puberty - primary amenorrhea but normal pubic hair
Gonadectomy at time of diagnosis – gonadoblastoma (20-30% if gonads left in situ)
What is the risk of gonadoblastoma in a patient with gonadal dysgenesis and a Y chromosome?
20-30%
What is the most common tumor in gonadal dysgeneiss?
Bilateral gonadoblastoma
What are cellular types found in gonadoblastomas?
Granulosa, theca, germ cells
Describe incomplete XY gonadal dysgenesis
Wide range of testicular function
Leads to wide range of phenotypes (some testicular tissue +/- streak)
What are some malignancies that can be found in gonadoblastomas?
Dysgerminoma, embryonal carcinoma seen (can be found WITHIN gonadoblastoma)
What is NR5A1?
Encodes steroidogenic factor 1 (SF-1)
Describe implications of mutation in NR5A1
- Homozygous loss-of-function mutations in NR5A1 are rare and result in gonadal dysgenesis and adrenocortical insufficiency
- Heterozygous loss-of-function mutations in NR5A1 account for approximately 10-15% of cases of testicular dysgenesis and are usually not associated with adrenal insufficiency
What is SRY?
Sex-determining region on the Y chromosome
Describe presentation of loss of SRY function
Loss of SRY function can result in complete or partial testicular dysgenesis, XY ovarian DSD, or XY ovotesticular DSD
Describe mutations in WT-1 and associated diseases (2)
WT-1 mutations are associated with a variety of conditions, some include partial or complete gonadal dysgenesis
- Denys-Drash syndrome is associated with renal failure and high risk for Wilms tumor.
- Frasier syndrome is associated with nephrotic syndrome, usually due to focal segmental glomerulosclerosis, and high risk for gonadoblastoma (~50%).
What is WT-1? What does it do? What is it involved in?
Wilms’ tumor suppressor
Transcription factor containing zinc finger motif that can activate the promoter of human SRY
Involved in both renal development and gonadal development (some mullerian duct regression)
Name the loss-of-function mutations and inheritance patterns of genes essential for testicular development that can lead to XY dysgenesis (9 genes)
Rare causes of XY gonadal dysgenesis are inherited in an autosomal recessive manner
-Mutations in: MAP3K1, CBX2, DHH, DMRT1, FGF9, FOG, GATA4, SOX9, and ZFPM2
Describe effect of gain-of-function mutations in NR0B1
Duplications of NR0B1 (DAX1) can cause gonadal dysgenesis (inhibiting activity of NR5A1/SF1)
What is NR0B1?
- Encodes protein for DAX1
- Does not appear to have a direct role in normal human gonadal development
- Loss-of-function mutations in NR0B1 do not have a gonadal phenotype, although they do cause adrenal insufficiency (males) and hypogonadotropic hypogonadism (delayed puberty – females)
Loss of function of what genes leads to XY ovarian DSD
SRY, CBX2, NR5A1
Describe the presentation of XY ovarian DSD
- XY individual develops ovaries
- Rare
- Cells only have one X chromosome; ovarian function similar to Turner’s
What causes testicular dysfunction without atypical genitalia?
Persistent Mullerian duct syndrome
Mutations in AMH gene or AMH-R
Normal external male genitalia; variable testicular descent
Describe Leydig cell hypoplasia (LH/HCG receptor defects)
- XY with mutation in this gene will have female external genitalia but lack uterus and fallopian tubes
- Epididymis and vas deferens may be present
- Lab findings: Low testosterone despite elevated LH levels; unresponsive to exogenous HCG
What encodes LH/HCG receptor and where is it located?
LHCGR gene on chromosome 2p21
Describe Smith-Lemli-Opitz syndrome
- Defect in enzyme that catalyzes last step in cholesterol synthesis, sterol delta-7-reductase (DHCR7 gene)
- Presentation: Developmental delays, microcephaly, cleft palate, syndactyly, varying degrees of virilization
What causes 17-beta-hydroxysteroid dehydrogenase type 3 deficiency?
Caused by at least 15 different mutations in the HSD17B3 gene, which encodes an enzyme required for conversion of androstenedione to testosterone
Describe presentation and lab findings in 17-beta-hydroxysteroid dehydrogenase type 3 deficiency
- Virilization at puberty due to extra-testicular (peripheral) conversion of androsentedione to testosterone
- Serum testosterone concentrations are often in the lower normal range, whereas serum concentrations of androstenedione, the intermediate before the enzymatic block, are elevated several-fold
- Ratio of testosterone to androstenedione is usually < 0.8, which distinguishes this disorder from other forms of undervirilization
What causes 5-alpha-reductase type 2 deficiency?
Inheritance pattern?
Chromosome location?
Mutations in SRD5A2
Autosomal recessive
Chromosome 2
5-alpha-reductase type 2 deficiency presentation in 46XY
- XY individuals with bilateral testes and normal testosterone formation have impaired external virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone
- External Genitalia: Female (underdevelopment of phallus, urethra, prostate)
- Internal genitalia: Male (testosterone present, AMH present)
- Virilization at puberty – increased testosterone or some DHT made (type I enzyme intact)
What is androgen insensitivity?
X-linked defect in androgen receptor function
How does androgen insensitivity present in males and females?
- Males: Blind ending vagina, undervirilization, gynecomastia, infertility secondary to oligo/azoospermia
- Females: Ambiguous genitalia, inguinal hernias/labial masses, primary amenorrhea, normal pubertal development (but diminished pubic hair), virilization at adolescence (clitromegaly)
What is the only clinical instance where gonadectomy can be delayed due to decreased risk of tumor formation?
Complete AIS, carries risk of 5-10% of tumor formation
When should gonadectomy be considered for patients with incomplete AIS?
Earlier surgery than complete AIS is indicated to prevent the virilization at puberty
How does androgen insensitivity affect mullerian structures in 46XY?
Mullerian (paramesonephric) ducts absent as testes (sertoli cells) make AMH normally
How does androgen insensitivity affect Wolffian structures?
Wolffian (mesonephric) ducts absent – testosterone cannot act on ducts secondary to absence of AR
How does Lipoid CAH present?
- Caused by deficiency of steroidogenic acute regulatory (StAR) protein
- Severe adrenal insufficiency very soon after birth, presenting with vomiting, diarrhea, volume depletion, hyponatremia, and hyperkalemia, often with hyperpigmentation
- XY individuals have phenotypically female external genitalia
What causes P450 side-chain-cleavage (SCC) enzyme deficiency?
Mutations in CYP11A1
P450 side-chain-cleavage (SCC) enzyme deficiency presentation
Similar to lipoid CAH
- Characterized by adrenal insufficiency and hyperpigmentation presenting in infancy or childhood,
- Phenotypically female external genitalia in XY individuals
17-alpha-hydroxylase deficiency genetics
Autosomal recessive mutations in CYP17A1 (chromosome 10); encodes protein with both 17-alpha-hydroxylase and 17,20-lyase activities
17-alpha-hydroxylase deficiency presentation
-Characterized by severe undervirilization in XY; may result in typical female external genitalia.
-Most affected individuals have hypertension and HYPOkalemia because of overproduction of mineralocorticoids (no salt wasting)
-Symptomatic adrenal insufficiency is rare
-Mutations in CYP17A1 that affect only 17,20-lyase activity are rare and produce undervirilization without cortisol deficiency (sexual infantilism; Tanner I/11)
Presentation: most are hypertensive (increase mineralocorticoids)
17-alpha-hydroxylase deficiency anatomic/reproductive presentation in males and females
Males – phenotypically female (no androgen) with blind vagina, neither mullerian or wolffian structures, intra abdominal testes
Females – normal Mullerian structures, primary amenorrhea, hypergonadotrophic hypogonadism
What forms of CAH lead to XY DSD?
- 3-beta hydroxysteroid dehydrogenase type 2 deficiency
- 17-alpha-hydroxylase deficiency
- P450 oxidoreductase (POR) deficiency
- Lipoid CAH
- P450 side-chain-cleavage (SCC) enzyme deficiency
What is the inheritance pattern for all androgen insensitivity disorders?
X linked recessive
Describe external genitalia for complete vs incomplete AIS?
Complete AIS- female
Incomplete AIS- female with cliteromegaly
Describe Wolffian structures for complete vs incomplete AIS?
Complete AIS- absent
Incomplete AIS- underdeveloped
Define totipotency
Ability of single cell to divide/produce all the differentiated cells in an organism (until 16-cell stage)
Define pluripotent
Stem cells that have the potential to differentiate into the three germ cell layers (endoderm, mesoderm, ectoderm). Can give rise to any fetal/adult cell type but alone can’t develop into fetal/adult organism.
Define multipotent
Progenitor cells that have the potential to give rise to cells from multiple but a limited number of lineages (ex. mesechymal stem cells - differentiate into osteoblasts, chondrocytes and adipocytes)
Define unipotent
Capacity to differentiate into only one cell type (ex. hepatocytes, skin) aka precursor cells
4 genes important in ovarian development
- RSPO1 (respondin 1)
- WNT4 (wingless family of genes)
- DAX-1 (dosage sensitive adrenal hypoplasia)
- FOX-L2 (Forkhead box L2)
What happens with sex chromosomes during meiosis?
In males, X and Y align and can recombine during meiosis (Y has pseudo-autosomal region)
Where are genes involved in testis formation and development located?
Y chromosome
What cells secrete FGF-9 and what does it do?
Sertoli cells
Reinforces SOX9
What cells secrete PGD2 and what does it do?
Sertoli cells
Play a role in testis determination
What is SRY and where is it?
Sex-determining region Y chromosome
Distal p-arm of Y (adjacent to psuedoautosomal region)
What does SF-1 do?
for testicular development
Steroidogenic factor 1, a nuclear “orphan receptor”
transcription factor essential for development of gonads and the adrenal cortex, that also activates SRY by binding to it’s promoter
What does WT-1 do?
for testicular development
Transcription factor that can activate promoter of SRY
What does GATA-4 do?
for testicular development
Transcription factor w/ zinc finger motif that can activate promoter of SRY
What are SRY HMG box protein family involved in?
Downstream events of sexual differentiation
What is the most likely SRY target gene?
SOX9
What can virtually all male-female sex reversal be explained by?
Failure to generate sufficient levels of SOX-9 to promote the positive feedback loops
Causes of XX DSD (3)
Adrenal overproduction of androgens
Gonadal overproduction of androgens
Gestational hyperandrogenism
Genetics of classic CAH (mutation, inheritance, chromosome)
- Mutation in CYP21A2 gene that encodes 21-hydroxylase (P450c21)
- Autosomal recessive, chromosome 6
Most frequent enzymatic defect to cause ambiguous genitalia
Classic CAH (95% of CAH)
Diagnosis of classic CAH
Elevated 17-OHP (may have false positive in luteal phase), low DOC and 11-deoxycortisol, low aldosterone, low cortisol -> adrenal crisis
Androstenedione and DHEA in classic CAH
Overproduced
Electrolytes in classic CAH and physiologic result
Salt-wasting: hypoNa, hyperK -> hypotension
Most common cause of endocrine death
Classic CAH
Genetics of most non-classical CAH patients
Compound heterozygotes
Second most common cause of CAH in the US
11-beta hydroxylase deficiency
Genetics of 11-beta hydroxylase deficiency (mutation, inheritance, chromosome)
- Mutation in CYP11B1 gene encoding 11-beta hydroxylase (P45011b)
- Autosomal recessive, chromosome 8
Labs in 11-beta hydroxylase deficiency
Significant elevation in 11-deoxycortisol and mild elevation in 17-OHP
Electrolytes in 11-beta hydroxylase deficiency and physiologic result
Hypernatremia, hypokalemia (mineralocorticoid effects of elevated 11-deoxycortisol) -> hypertension
3rd most common enzymatic deficiency in CAH
3-beta hydroxysteroid dehydrogenase type 2 deficiency
Inheritance of 3-beta hydroxysteroid dehydrogenase type 2 deficiency
Autosomal recessive
Presentation of 3-beta hydroxysteroid dehydrogenase type 2 deficiency
Cortisol + aldosterone deficiency (XX->mild virilization; XY->undervirilization)
• Elevated 17-hydroxypregnenolone and elevated 17-OHpregnenolone/cortisol ratio
• Another isoform of 3-beta-HSD that is encoded by a different gene (HSD3B1) and expressed in the liver, converts 17-hydroxypregnenolone to 17-OHP and DHEA to androstenedione (weak androgen)
P450 oxidoreductase deficiency mutation
Mutations in POR gene -> combined CYP21A2 and CYP17A1 deficiency
Labs in P450 oxidoreductase (POR) deficiency
Mild 17-OHP elevation; variable glucocorticoid deficiency; risk of salt-wasting and adrenal crisis
Sexual differentiation phenotypes in POR deficiency
XX->mild virilization; XY->undervirilization; similar to 3B-HSD deficiency
Glucocorticoid resistance genetics
Mutations in the NR3C1 gene that encodes the glucocorticoid receptor
Glucocorticoid resistance pathophysiology
Impaired response to cortisol results in loss of negative feedback and high levels of ACTH –> overproduction of mineralocorticoids (HTN, hypoK, alkalosis) and androgens (ambiguous genitalia, hyperandrogenism later in life in females)
Glucocorticoid resistance phenotype
Can cause features similar to those of virilizing forms of CAH, though cortisol synthesis is not disrupted
What is XX testicular DSD and how does it present?
Conditions in which the gonads develop along testicular rather than the ovarian pathway
Labial/scrotal mass
What is XX ovotesticular DSD?
Both ovarian follicular and testicular tubular tissue are present; diagnosis is made based on histology (formerly true hermaphrodite)
What is the % of patients with each histology in XX ovotesticular DSD?
- 20% bilateral ovotestis
- 50% unilateral ovotestis + unilateral ovary or testis
- 30% ovary + testis
Fertility potential in XX testicular DSD
Infertile: no spermatogenesis due to lack of Y chromosome
Fertility potential in XX ovotesticular DSD
May have some fertility potential if intact ovarian tissue present
Causes of XX testicular or ovotesticular DSD (5)
- Presence of SRY (de la Chapelle syndrome):
- Mutations in NR5A1 (SF1)
- Duplication of SOX9:
- Inappropriate expression of SOX3:
- Loss-of-function mutations in genes that repress testicular pathways (WNT4, RSPO1)
de la Chapelle syndrome
Presence of SRY. Due to translocation of SRY to the X chromosome or an autosome and accounts for roughly one-half of cases of XX testicular DSD
Gain-of-function mutations in NR5A1 (SF1) in XX
Gain-of-function mutations that cause inappropriate activation of testicular pathways in the XX gonad; described in ~10-20% of XX testicular or ovotesticular DSD cases
Duplication of SOX9
SOX9 encodes a transcription factor that functions downstream of SRY and is both necessary and sufficient for testicular development.
Inappropriate expression of SOX3
SOX3 encodes a transcription factor similar to SOX9. SOX3 does not have role in normal gonadal development, but activates testicular pathways when inappropriately expressed
Two loss of function mutations in genes that repress testicular pathways (lead to XX testicular/ovotesticular DSD)
What do they normally inhibit?
WNT-4 and RSPO1
both inhibits SOX9 and FGF9 expression in absence of SRY
Syndrome a/w WNT 4 mutation, inheritance, and phenotype
Associated with the autosomal recessive SERKAL syndrome (sex reversal with dysgenesis of kidneys, adrenals, and lungs)
Syndrome a/w RSPO1 mutation and inheritance
Autosomal recessive cause of palmoplantar hyperkeratosis in combination with testicular or ovotesticular DSD
Genetics of aromatase deficiency
Mutations in CYP19A1
Phenotypes in aromatase deficiency
- Female: Can result in overproduction of testosterone by an otherwise normal ovary -> ambiguous genitalia, hyperandrogenism, hypergonadotrophic hypogonadism, multicystic ovaries
- Males: Normal sexual differentiation/puberty; E2 deficiency -> continued linear growth due to lack of epiphyseal closure (extremely tall) and osteoporosis
Maternal effect when carrying infant with aromatase deficiency
Deficient placental expression of aromatase -> androgens from fetus cross the placenta and also cause maternal virilization
Why is gestational hyperandrogenism so rare?
Because the placenta produces the aromatase enzyme, which converts androgens to estrogens, only very high levels of maternal androgens can overcome placental aromatase to cause virilization of the fetus
Causes of gestational hyperandrogenism (2)
Maternal luteoma or theca lutein cyst
Embryonic layer origin of gonads? and what part?
Intermediate mesoderm - caudal
What is FGF-9
for testicular development
Maintains levels of Sox9 expression required to induce testis differentiation
Ovarian development results from ___ of genes within the testis pathway
active suppression
What is DAX1 (dosage-sensitive sex reversal)?
- Nuclear transcription factor
- Inhibits expression of SF-1 (thus repressed Sry expression)
- Upregulated by the ovary
- Repressed by Sox9
What is FOXL2? (forkhead box L2)
what happens when missing? mutated?
- Transcription factor
- If missing – XX appears male
- Mutations can cause premature ovarian insufficiency
What is Lim1?
What is it involved in?
Wthat does absence lead to?
- Gene involved in early kidney and gonadal development
- Change from intermediate mesoderm to indifferent gonad
- Absence of Limi-1 expression leads to no kidneys/gonads
Two populations of cells within the genital ridges
Coelomic epithelium - lines the exterior of gonads
Mesonephric ridge
What is OCT-4
Transcription factor, allows germ cells to remain multipotent
Factors necessary for primordial germ cell development? (from adrenal)
- Lim1
- SF-1
- WT-1
- BMP-4
- Oct-4
Factors necessary for testicular development? (from adrenal)
- SRY
- Sox9
- WT-1
- GATA4
- SF-1
- FGF9
Factors necessary for ovarian and adrenal cortex development?
- Wnt-4
- RSPO-1
- DAX1
- FOXL2
DAX1 gene loss-of-function mutation causes…
Inheritance?
CAH → Adrenal insufficiency and pubertal failure (boy with no pubertal development)
Sertoli cells are responsive to which hormones?
FSH & Testosterone
(lack LH receptors)
46 XX virilized infant causes (3 main ones, and 3 uncommon ones)
- CAH – most common dx; test 17-OHP & electrolytes
- Gestational hyperandrogenism
- Maternal androgen or synthetic progestins (e.g. luteoma, theca-lutein cysts, and placental aromatase enzyme deficiency
- Uncommon: SRY translocation, SOX9 duplication, and ovotesticular disorders of sex development (previously termed true hermaphroditism)
- Measurement of Müllerian inhibiting substance (MIS) or inhibin B and the testosterone response to administration of hCG
What test to look for SRY or SOX9?
FISH
Gonadal dysgenesis and their phenotype?
46XX gonadal dysgenesis
- No breast development
- Primary amenorrhea
- Sparse pubic hair (adrenals can make some androgens)
- Perrault syndrome – gonadal dysgenesis and deafness
46XY gonadal dysgenesis (Swyer syndrome)
- Female external genitalia with intact Mullerian ducts
- Sparse pubic hair
- No breast development
most common karyotype in Turner’s syndrome?
45 X,0 (60%)
most common chromosomal abnormality in gonadal dysgenesis / primary amenorrhea?
45 X, 0
12 year old during appendectomy, streak gonads, hemiuterus, next step?
Karyotype
Most important test prior doing IVF in Turner’s patient?
ECHO
Turner’s Tx:
When to start Growth Hormone? Estrogen/Progesterone?
- GH begin as soon as height falls below the 5th % (usually between 2 and 5 years)
- Estrogen decreases height velocity; not recommended before age 13 or 14 years. Goal to complete sexual maturation over 2-3 years.
- Add cyclic MPA once menses begin, or after 1-2 years of estrogen tx
46XX true hermaphrodite has what?
Bilateral ovotestes (usually ovary on L, testicle on R)
Most common congenital cause of hypogonadism in males
Kleinfelters Syndrome
Most common Kleinfelters Syndrome genetic profile?
47XXY
(or 48XXXY or mosaic 46XY/47XXY from mitotic nondisjunction)
Kleinfelter’s Syndrome
Hormone profile?
Phenotype?
Tx?
Elevated FSH/LH, Low Testosterone
- Small, firm testes (can do TESE for sperm & ICSI)
- Long arms/legs with short trunk
- Gynceomastia (higher rates male BrCa)
Tx: testosterone
What will a testicular biopsy show on someone with:
Kallmann Syndrome (secondary testicular failure)
Klinefelter’s syndrome
Absence of the vas deferens
Kallmann - Seminiferous tubules containing germ along with Sertoli cell only-tubules; May or may not contain mature spermatids
Klinefelter - Tubular fibrosis, Prominent basement membrane, Leydig cell hyperplasia
CBAVD - reduction in spermatids only (due to increased hydrostatic pressure)
what can Finasteride do to a male fetus? especially if given when?
cause hypospadius
esp. if exposed between 9-14 weeks
