11/3- Disorders of Sexual Development Flashcards
What are the 3 major components of sexual development?
- Differentiation of the gonad (sex determination)
- Differentiation of internal genital organs
- Differentiation of external genital organs
What are the main steps of sexual differentiation?
- Chromosomal sex
- Gonadal sex
- Phenotypic sex
- Psychosocial sex
What is the main gene responsible for determining sex?
SRY: testes determining factor
- Sex-determining region on the Y chromosome
- DNA-transcription factors
- Centromeric to the pseudoautosomal region on Y
- Expressed in embryonic development
- Initiates development of the testis
- Mutations in SRY can cause female phenotype
- Can get displaced during male meiosis
What happens if SRY gene gets translocated onto X chromosome?
Can have XX genotype with male phenotype or (if this translocation is not inherited), an XY genotype with female phenotype
- Due to crossover at “pseudoautosomal region”
What is NROB1?
NROB1 (DAX): dosage sensitive sex reversal on X
- Expressed in embryonic development
- Necessary for initiation of ovarian development
- 46,XY, duplication DAX1: male to female sex reversal
- 46,XY, deletion DAX1: normal testicular development
- 46,XY, mutation of DAX1: abnormal spermatogenesis
- Congenital Adrenal HYPOplasia, with hypogonadotropic hypogonadism
What are disorders of sexual development that result from chromosomal abnormalities?
- Turner syndrome
- Klinefelter syndrom
- Other aneuploidy
What are disorders of sexual development that result from single gene disorders?
- 21-hydroxylase deficiency (CAH)
- Androgen receptor (Xp)
- 5a-reductase deficiency
- SRY sex-determining region (Yp)
- DHRC7 Smith-Lemli-Opitz
What are the 5 main presentations of Turner’s syndrome?
- Spontaneous abortion; die in utero
- Presents as newborn baby girl who looks normal, but much skin and puffiness in back and puffy fee
- Presents as young child with short stature
- Presents as primary amenorrhea
- Presents as adult woman with infertility
How to diagnose Turner Syndrome?
- Evaluate what other organ systems?
- G-banded chromosome analysis
- FISH for Y centromere/SRY
- If diagnosis considered, obtain Echo and renal ultrasound while genetic results are pending
What is NIPS?
Screening test for Turner’s syndrome (not diagnosis!)
What are complications of Turner syndrome?
- Cardiovascular: Coarct, Conduction, HTN, AoD
- Renal/GU Anomalies: Horseshoe kidney
- Endocrine: Thyroid, Growth, Sexual, Diabetes
- Orthopedic: Scoliosis, Hip dysplasia
- Ophthalmic/Audiologic
- Cognitive/Behavioral
What is Klinefelter syndrome?
- Prevalence
- Diagnosed when
- Features
- 1/500-1000 males
- Most frequent aneuploidy of sex chromosomes
- Unlike Turner, typically diagnosed ~puberty (unless detected on prenatal testing)
- Tall stature, reduced facial/body hair
- Gynecomastia, hypogonadism, infertility
- Cognitive / Behavioural
Key point: While Turner and Klinefelterare disorders involving the sex chromosomes, there is usually NOTa question of gender or poorly differentiated external genitalia at the time of birth with these conditions
Yup
What falls under “ambiguous” genitalia that is apparently male?
- Bilateral nonpalpable testes at term
- Hypospadias associated with separation of scrotal sacs
- Undescended testis with hypospadias
What falls under “ambuiguous” genitalia that is apparently female?
- Clitoral hypertrophy
- Forshortened vulva with single orifice
- Inguinal hernia containing gonad
What is the DDx if infant has ovary but external male genitalia?
- Congenital adrenal hyperplasia!! (masculinization of 46XX individual)
- Placental aromatase deficiency
- Maternal source of virilization
What is the DDx if infant has testis but external male genitalia is underdeveloped or feminine?
- Leydig cell hypoplasia
- Testosterone biosynthesis defect
- 5a reductase deficiency
- Androgen insensitivity
What is Congenital adrenal hyperplasia?
- Causes what
- Mechanism/genetics
- Inheritance pattern
- Most common cause of ambiguous genitalia
- Enzyme defects in steroidogenic pathway leading to biosynthesis of cortisol
- Most commonly 21-hydroxylase deficiency (CYP21)
- Decrease in cortisol -> increase in ACTH
- Deficiency in glucocorticoids (cortisol) and/or mineralocorticoids (aldosterone)
- Accumulation of androgenic hormone intermediates; elevated 17-hydroxyprogesterone in blood (detected in Texas Newborn Screen*)
- Autosomal recessive
*Newborn screen is more important for male; while female may present at birth with ambiguous genitalia, male not present until salt-wasting (hypo-Na, hyper-K)
What is seen here?
Ambiguous genitalia in CAH 21 OH (Congenital Adrenal Hyperplasia)
What is seen in gonadal dysgenesis due to A93-73?
What is the cause?
- Preterm infant
- Multiple anomalies: growth, craniofacial, CNS, limb
- Ambiguous genitalia due to lack of testosterone (absent Leydig cells)
- Persistence of Mullerian structures (due to dysgenic gonads- abnormal sertoli cells)
Caused by testis with absent Leydig cells
What is seen here?
Testis with absent Leydig cells (A93-73)
