Disorders Of Sexual Development Flashcards
At week 5, medioventral border of urogenital ridge thickens to become __
Gonadal ridge
At week 6, primordial germ cells are incorporated into __
Primary sex cords
When is sex indistinguishable in the fetus?
before week 6
When does development begin in male vs female?
Male: testis organization begins in weeks 6 and 7
Female: begins week 12
External genitalia of both sexes identical up to about week 8
What does DHT do for male development?
Stimulates growth of genital tubercle and induces fusion of urethral folds and labioscrotal swellings
Inhibits growth of vesicovaginal septum preventing development of vagina
Describe the SRY gene
One exon
GC-rich in 5’ region
2 zinc-finger rich recognition sites for Sp1
Has HMG motif (conserved protein sequence that participates in transcription, replication, recombination, and repair. Induces conformational change for other factors to bind and direct transportation)
What happens if there are HMG octamer mutations in SRY gene?
No binding to DNA
No male differentiation
46 XY female
Describe steroidogenic factor 1
Required for SRY expression
Gonads and adrenal development require SF1
Required for sexual determination, sexual differentiation, steroidogenesis, and lipid metabolism
What is required for SRY expression, gonad and adrenal development, sexual determination, sexual differentiation, steroidogenesis, and lipid metabolism?
Steroidogenic factor 1
What upregulates SOX9 expression?
SRY expression in Sertoli cells
What does SRY expression in Sertoli cells upregulate?
SOX9
What does a mutation in SOX9 lead to?
Camptomelia dysplasia
Camptomelia dysplasia results from a mutation in what gene?
SOX9
Describe the clinical manifestations of campomelia dysplasia
Bowing of long bones Shortened long bones Skeletal dysplasia (hypoplastic scapulae, narrowed iliac bones, chest hypoplasia with respiratory distress)
What disorder is characterized by bowing of long bones, shortened long bones, hypoplastic scapulae, narrowed iliac bones, chest hypoplasia with respiratory distress?
Campomelia dysplasia
Describe mechanism behind campomelia dysplasia
Associated with sex reversal due to gonadal dysgenesis in 46 XY
No SOX9 -> Mullerian ducts do not degenerate so ovary develpment occurs
AMH diffuses from Sertoli cells to paired Mullerian duct primordia
AMH attaches to receptors (serine-threonine protein kinases - single transmembrane domain)
Apoptosis occurs
What is associated with sex reversal due to gonadal dysgenesis in and persistence of Mullerian ducts in 46 XY?
Campomelia dysplasia
Describe DAX1 gene (dosage sensitive sex reversal - adrenal sensitive sex reversal on X chromosome)
DAX1 is normally down-regulated by SRY in developing testes but not in ovary
DAX1 blocks AMH upregulation
What does mutation or deletion of DAX1 result in?
Congenital adrenal hypoplasia and hypogonadotropic hypogonadism
Duplication in males -> 46 XY females
Duplication in females -> no effect
What mutations can cause sex reversal?
SRY mutations: 46 XY females; 46 XX males with SRY translocated to X
SOX9 mutations
DAX1 duplication
Describe hypospadias
Abnormality of anterior urethral development in which urethral opening is ectopically located on ventrum of penis proximal to tip of glans penis.
May have associated ventral shortening and curvature (chordee)
What is the Smith-Lemli-Opitz syndrome?
Congenital multiple anomaly syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of enzyme 7-dehydrocholesterol (7-DHC) reductase
What is the congenital multiple anomaly syndrome caused by deficiency in 7-dehydrochlesterol (7-DHC) reductase?
Smith-Lemli-Opitz syndrome
Describe the characteristics and malformations of Smith-Lemli-Opitz syndrome
Prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation
Distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of toes
What syndrome is characterized by prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, cleft palate, cardiac defects, underdeveloped external male genitalia, postaxial polydactyly, and 2-3 syndactyly of toes? What is the defect?
Smith-Lemli-Opitz syndrome
7-dehydrocholesterol reductase
What are causes of testosterone synthesis defects?
Impaired Leydig cell differentiation
Enzyme defects in testosterone synthesis
Defects in adrenal and testicular steroidogenesis
STAR deficiency
P450scc deficiency
3beta hydroxysteroid dehydrogenase deficiency
17alpha hydroxylase deficiency
17beta hydroxysteroid dehydrogenase deficiency
What is a cause of testosterone metabolism defects?
5alpha reductase deficiency
Describe androgen insensitivity syndrome (defect in androgen action)
XY sex chromosomes Female body shape Enlarged breasts with juvenile nipples Absent or scanty axillary or pubic hair Female external genitalia with small labia Blind-ending vagina Absent or rudimentary internal genitalia Cryptorchisdism Normal male testosterone levels Testes produce androgens and estrogen Eleveated FSH, LH, hCG No male pattern baldness
What syndrome is characterized by XY, normal male testosterone levels, elevated FSH, LH, hCG, female body shape, enlarged breasts with juvenile nipples, absent or scanty axillary or pubic hair, female external genitalia with small labia, blind-ending vagina, cryptorchidism?
Androgen insensitivity syndrome
What causes persistence of Mullerian ducts syndrome?
Defect in AMH synthesis
Defect in AMH receptor
What causes congenital non-genetic 46 XY DSD?
Maternal intake of endocrine disuptors:
BPA, phthalates, parabens, PBDE, PCB, dioxin, pesticides/herbicides, heavy metals
Describe ovotesticular DSD
Both ovarian and testicular tissue in one or both gonads
Internal and external differentiation is variable (often ambiguous, cryptochidism common, hypospadias common)
Ovotestis is the most common gonad found
Describe 17beta-hydroxysteroid dehydrogenase deficiency
46 XY with female external genitalia
Testes and Wolffian derivatives
At puberty - virilization
Deepening voice, clitoral enlargement, hirsutism, male muscularity, breast development
What disorder is characterized by 46 XY with female external genitalia, testes and Wolffian derivatives, and virilization at puberty (clitoral enlargement, hirsutism, male muscularity, breast development)?
17beta-hydroxysteroid dehydrogenase deficiency
Describe 5alpha reductase deficiency?
Deficient conversion of testosterone to DHT, so deficient DHT binding to androgen receptor
External genitalia appear female at birth
Testes extra-abdominal, usually inguinal
Hypospaid microphallus
Blind vaginal pouch
Normal blood testosterone but elevated T:DHT ratio
What disorder is characterized by deficient conversion of testosterone to DHT, normal blood testosterone but elevated T:DHT ratio, external genitalia that appears female at birth, extra-abdominal testes, hypospadic microphallus, and blind vaginal pouch?
5alpha reductase deficiency
What happens with excess androgen?
Masculinize external genitalia during female development
Prematurely virilize external genitalia of affected male
Virilize woman during pregnancy of affected child
What occurs with virilization in pregnant female?
Acne
Low pitch voice
Clitoral hypertrophy
Child -> ambiguous genitalia
Describe Klinefelter syndrome
47 XXY
Puberty may be delayed
Seminiferous tubules do not enlarge, instead undergo fibrosis and hyalinization -> small, firm testes
Obliterated seminiferous tubules -> azoospermia
Functionally abnormal Leydig cells -> secrete estradiol and increase LH
Testosterone decreased
High E:T ratio responsible for feminization and gynecomastia
FSH also high
Abnormal skeletal proportions: LS>US
Mental retardation
Dissocial behavior
Increased risk for autoimmune disorders (diabetes)
What is characterized by small and firm testes, obliterated seminiferous tubules, abnormal Leydig cells, high LH and FSH, high E:T ratio, gynecomastia, abnormal skeletal proportions, retardation, dissocial behavior, and increased risk for autoimmune disorders?
Klinefelter syndrome
Describe Turner syndrome
45X Normal intelligence Gonadal dysgenesis Short stature Webbed neck Coarctation of aorta High arched palate Shield-like chest with widely spaced nipples Short metatarsals Renal abnormalities Cubitus valgus Edema of hands and feet Micrognathia
What syndrome is characterized by 45X, normal intelligence, gonadal dysgenesis, short stature, webbed neck, coarctation of aorta, high arched palate, shield-like chest with widely spaced nipples, short metatarsals, renal abnormalities, cubitus valgus, edema of hands and feet, and micrognathia?
Turner syndrome
Describe the hormones of Turner syndrome
Lack of ovarian development leads to deficient secretion of sex steroids
Elevated LH/FSH
Decreased estrogen
Describe Noonan syndrome
"Male Turner" syndrome Autosomal dominant Mutations in PTPN11 gene KRAS - more severe form RAF1 - heart problems (hypertrophic cardiomyopathy)
What syndrome is caused by mutations in PTPN11 gene, and KRAS or RAF1?
Noonan syndrome
What are the characteristics of Noonan syndrome?
Delayed puberty Down-slanting or wide-set eyes Hearing loss Low-set or abnormally shaped ears Mild mental retardation Pulmonary stenosis Short stature Sagging eyelids (ptosis) Small penis Undescended testicles Unusual chest shape (sunken chest called pectus excavatum) Webbed and short-appearing neck Fertility problems but fertile
What syndrome has the characteristics of sagging eyelids (ptosis), short stature, webbed and short-appearing nect, pectus excavatum, small penis, undescended testes, delayed puberty, down-slanting eyes, hearing loss, low-set ears, mild mental retardation, pulmonary stenosis?
Noonan syndrome
At week 4, primordial germ cells are recognizable in yolk sac wall, go through mitosis and migrate through ___
Dorsal mesentery of hindgut
