Disorders of Sex Development (DSD) Flashcards
What are Intersex Disorders?
A partial or complete variance of genotype from sexual phenotype
What are Ambiguous genitalia?
When external phenotype is sufficiently abnormal to cause uncertainty with regards to gender
What are Disorders of sex development (DSD)?
Defines congenital conditions involving atypical chromosomal, gonadal or anatomical sex.
What is Gender identity disorder (GID)?
Unhappiness with assigned sex.
Describe the Embryology of Sexual Development?
- Development of bipotential gonad
- 6 - 8weeks: Formation of the urogenital ridge, double system (Wolffian and Mullerian)
- 8weeks: Mid-line genital tubercle
- 9weeks: Testicular differentiation and testosterone production
- 11weeks: Ovarian differentiation
Describe Internal Genital Development?
If there is no Y chromosome, there is absence of testis determining genes so no AMH. The default mechanism to female
- Mullerian system forms Fallopian tubes, uterus, upper 1/3 of vagina. In presence of testis, there is involution of Mullerian structures.
- Wolffian ducts form epididymis, vas deferens, seminal vesicles and ejaculatory ducts
What embryological structures that form parts of the external genital?
- Genital tubercle: Formed at clitoris or glans penis
- Genital fold: Labia minora or corpus spongiosum
- Genital swelling: Separate to form labia majora or fuse to form scrotum and ventral penis
What is the Genetic pathophysiology of human sex determination?
- Gene transcription occurs through cellular signalling pathways (WNT4–RSPO1 in ovary determination, Map- kinase in testis determination).
- In 46, XY individuals, Map- kinase signalling through MAP3K1 may alter chromatin and histone conformation, activates GATA4 binds directly to SRY promoter which turns on SOX9, initiating testis gene expression
What are clinical presentation of pathologies associated with disorders of sexual development?
- At birth: Ambiguous genitalia
- In childhood: Virilisation of female
- In adolescence: Virilisation of female, Lack of virilisation in male, Pubertal delay and primary amenorrhoea in female
- In Adulthood: Primary amenorrhoea in female - Infertility in male and female
What are the responsibilities of Health care professional for neonates?
- Gender assignment & decision as to sex of rearing as soon as possible through involving MDT and investigations
- To promote attachment & acceptance
- To define condition & avoid illness (CAH)
What are causes of Virilised Girls/Undervirilised boys?
Virilised Female
- Fetal Androgens - CAH
- Maternal Androgens – Ovarian & Adrenal Tumours
Undervirilised Male
- Abnormal Testis Determination – Partial (XY) & Mixed (X/XY) gonadal dysgenesis
Androgen Biosynthetic defects
- LH receptor-inactivation mutations
- 17βOH-dehydrogenase deficiency
- 5α-reductase deficiency
Resistance to Androgen
- Androgen insensitivity
True Hermaphroditism (Karyotype XX, XY, XX/XY)
- Presence of testicular and overian tissue
What is the Clinical Examination of Virilised Girl/Undervirilised boy?
Clinical Examination
- Presence of palpable gonads-likely to be tested
Initial investigation
- Karyotype
What is the Prader Scale of Virilisation?
Apparently females but
- Clitoromegaly
- Posterior Labial Fusion
- Labial/Inguinal Mass
Apparently male BUT
- Non-Palpable Testes
- Perineal Hypospadias
- Micropenis
What are features examined in a Genital Examination?
- Gonads: absent, scrotal, inguinal, abdominal
- Phallic structure: length, width
- Chordee
- Urethral meatus position
- Labioscrotal fusion / scrotum: bifid, shawl, underdeveloped
- Vaginal opening
What causes ambiguous genitalia in gonadal dysgenesis?
Karyotypes include 46,XY, 46,XY/45Xothers
- Complete - Pure streak gonads
- Partial gonads - usually asymmetric. Streak + dysplastic testis (or ovotestis)
Testis can produce testosterone but little AMH. External and internal phenotype dependant on testicular dysgenesis
What are features of congenital adrenal hyperplasia?
- 21-Hydroxylase deficiency is the most common cause of CAH
- Presentation - neonatal period till early adolescence
- Salt wasting only in early onset cases with severe androgenisation
- Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition, resulting in glucocorticoid and mineralocorticoid deficiency and androgen excess, with >90% of cases caused by mutations in CYP21.
- The condition is associated with considerable morbidity and mortality (male neonates).
What are functional tests used in the assessement of an infant with DSD?
- Urination
- Adrenocortical function – Cortisol levels to Synacthen
- Salt and water balance – Daily Urine Na, plasma U&E, renin
- Gonad anatomy and endocrine function – US, MRI, EUA HCG test; GnRH test
- Sexual function – Urology opinion, EUA phallic response to testosterone
- Reproductive function – gonad biopsies, uterus
What are definitive tests used in the assessement of an infant with 21-OHD in DSD?
- Karyotype – 46XX
- 17OHP and Raised Angrogens
- Synacthen test
- Renin, Na, Urea, K, Testosterone, Androstenedione, DHEA, ACTH
What are features of 3β-HSD?
- Undervirilization in males
- Clitoromegaly in females
- Salt wasting in 75%
- Elevated DHEAS
What are investigations for 3β-HSD?
- Karyotype
- Synacthen test with measurement of cortisol, 11-deoxycortisol Urine steroid profile
- Genetic testing
What are features of 11 β-Hydroxylase?
Severe virilization ±Hypertension
What are investigations for 11 β-Hydroxylase?
- Karyotype
- Synacthen test with measurement of cortisol, 11-deoxycortisol Urine steroid profile
- Genetic testing
How is Salt Wasting CAH managed?
- Hydrocortisone 10-15mg/m2/day, TDS,PO Typical dose in neonates- 1.5-2mg, TDS, PO
- Fludrocortisone 150μg/m2/day in neonates, 50- 100μg/m2/day in older children and adults
- Salt during infancy 5-20mmol/kg/day
How is management of Salt Wasting CAH monitored?
- Regular height measurement
- Adjustment of the dosage based on body size
- 4 mo measurement of 17OHP profile
- 24hr Cortisol profile
What is the surgical management of CAH?
- Correction of anatomy of external genitalia in females
- Examination of all females with CAH with examination under anaesthesia for cystovaginoscopy
- Re-examination during adolescent for further correction and possible vaginal dilatation.
What are features of 17β-HSD & 5α-reductase defects?
- Spectrum- undervirilisation with varying phenotype
- Marked virilisation during puberty
- Most will be infertile
Early gender assignment is essential to avoid disorder of gender identity
What are investigations for 17β-HSD & 5α-reductase defects?
Human chorionic gonadotropin (HCG) stimulation test
- High doses of HCG which acts on the LH receptor of the testes and stimulates testosterone production
What are clinical features of 5 alpha reductase deficiency?
- 46XY, Autosomal recessive
- Genitalia: usually ambiguous with small hypospadic phallus and blind vaginal pouch
- Wolffian ducts normal
- Mullerian ducts absent
- Normal testes
- Partial virilisation at puberty with gynaecomastia
What are the presentations of Complete Androgen Insensitivity syndrome?
Complete androgen insensitivity syndrome
- Complete female phenotype
- Karyotype 46, XY
- X linked
- Bilateral inguinal hernia’s
- Sex of rearing- female with or without gonadal removal
- Genitalia female with blind vaginal pouch
- Wolffian duct derivatives absent or rudimentary, intra abdominal testes
- Mullerian duct derivatives absent or vestigial (AMH production normal)
- Low or undetectable amount of androgen receptor
How is Androgen Insentitivity Syndrome investigated?
- Karyotype
- Ultrasound pelvis
- HCG stimulation test
- Genetic testing
What are the presentations of Partial Androgen Insensitivity Syndrome?
Varying degree of virilization
- 46XY
- X Linked
- External genitalia: ambiguous/ hypoplastic male/ normal male (fertile/ infertile)
- Testes
- Androgen receptor mutations lead to qualitative abnormalities
- Only 20% have detectable mutations
What are the physical features of AIS?
- Female body shape
- Enlarged breast with juvenile nipples Absent or scanty axillary or pubic hair Female external genitalia with small labia Blind-ending vagina
- Absent or rudimentary internal genitalia Cryptorchid (undescended testicles) Normal male blood levels of testosterone
- No male pattern baldness
- Flawless complexion - no hormone-driven acne at puberty
- Long, well-developed legs
- Greater than average height for a female
- Physique often more angular and “athletic” than average female
What are biochemical features of AIS?
- Normal male blood levels of testosterone
- Testes produce androgens and estrogen
- Elevated production of gonadotrophins
What is True Hermaphroditism?
- Gonads contain combination of testicular and ovarian tissues
- Varying degree of virilization
- Karyotype and USS pelvis helps in differential diagnosis
- Karyotype mosaic 46,XX/XY;46,X/46,Y/46,XX;
