DSD Flashcards Preview

Postnatal > DSD > Flashcards

Flashcards in DSD Deck (55):

Briefly describe the process of of sex determination in the first 7 weeks

Mammalian primary sex determination has no default state. The formation of ovaries or testes is and active, gene directed process controlled by: SRY and SOX9 (male) and RSPO1/WNT/B-catenin (females).

1) at 4wks the urogentical ridge and gonads have developed from the intermediate mesoderm.
2) at 6-7wks there is a bi-potential gonad and 2 sets of ducts. the germ cells migrate into the gonad.
3) at 7wks the bi=potential gonads begin to develop into ovaries or testes.


what genes are expressed in bi-potential gonads.



which genes are responsible for the conversion of the genital ridge into the bi-potential gonad

LHX9, SF1, WT1


Whats the gene pathway of female development

Pathway is initiated by WNT4 and NR0BI (DAX1).

In the absence of SRY: RSP01 is up regulated. This then up regulates WNT4 which actiavtes the B-catenin pathway that inhibits the SOX9/male development pathway.
WNT4 also activates NR0B1 and FOXL2 which activates the ovary specific pathway.


Briefly describe the female development pathway

The mesenchyme of the ovary differentiates into thecal cells, and the surface epithilium produce cortical sex cords that surround the germ cells and become the granulosa cells.

The thecal and granulosa cells (will become follicles) secrete estrogen which induces the differentiation of the mullerian ducts into female genitalia (uterus, cervix, oviduct, upper vagina).

The absence of testosterone causes the wolffian ducts to degenerate.


Whats the gene pathway of male development

Pathway is initiated by SRY and SOX9.

SRY inhibits NR0B1 & WNT4 which inhibits the female pathway.

SRY activates SOX9, that actiavtes FGFR9 & PGD2 (which in turn activate SOX9 in a +ve feedback loop).
FGFR9 & PGD2 initiate the testis specific pathway and sertoli cell formation. They also inhibit RSP0I

SRY & SF1 are transcription factors. The are required together in the sertoli cells to tincrease the levels of transcribed amh.


Briefly describe the male development pathway

The sex cords continue to proliferate through week 8 and become the testis cords which will develop into the seminiferous tubules at puberty. The cells of the seminiferous tubule are the sertoli cells. These cells secrete AMH.

The wolffian ducts differentiate into the epididymis and the Vas Deferens.

the interstitial mesenchyme cells of the testes differentiate into the leydig cells and secret testosterone.


Name the 2 major hormones produced by the testes and their roles

AMH: Anti-Mullerian Hormone (causes mullerian ducts to regress).

Testosterone (differentiation of the wolffian ducts into the internal male genitalia).


What is testosterone converted to and whats its role

In the urogential region.

Testosterone is converted to DHT (dihydrotestosterone) by 5a-reductase-2.

Causes the morphogenesis of the penis and the prostate gland and the secondary sexual characteristics.


In very simple terms explain secondary sexual determination

Its the development of the phenotypic sex by response to hormones secreted by the ovaries.

In the presence of no/little secreted hormones the fetus will show a female phenotype due to the estrogen from the mother & placenta.

The male phenotype requires DHT.


Whats the phenotype of a male with 5a reductase 2 deficiency

Male internal genitalia (wolffian ducts differentiation controlled by testosterone).

External phenotype: blind vagina, enlarged clitoris, appear female.

At puberty the increase in testosterone causes and enlarged penis, scrotum descends and person looks male.


What is the role of estrogen

required for the complete development of both wolffian and mullerian structures.

In female: needed for mullerian differentiation.

In males: needed for fertility (regulates the absorption of water by the Vas Efferens).


For neonates with ambiguous genitalia what should be considered by the MDT

Surgery options.
Hormonal Therapies available.
Prospects of gonadal cancer.
Future fertility

parents should be fully informed and involved in the decision making process.


What is the 1st line testing for neonates with ambiguous genitalia

Pelvic ultrasound/MRI.
Levels of:
serum electrolytes.
urinary steriods.

some babies with DSD have adrenal insufficiencies that cause critical conditions: hyopglycaemia, electrolyte disorders.


screening for what deficiency is screened for in the newborn screening programm that associated with XX DSD

21-hydroxylase deficiency (most common cause of CAH).


what are some common referrals for adolescent DSDs

Inguinal hernia/tumour.
Delayed/incomplete puberty.
Primary amenorrhea/ virilisation of girls.
Breast developemtn in boys.


What is the testing for adolescents ?DSD

Pelvic ultrasound/MRI.

Levels of: 17-hydroxyprogesterone. testosterone. estrogen. serum electrolytes. gonadotrophins. urinary steriods. DHT (in boys). sex hormone binding globulin.


what did the 5th world congress on family law and childrens rights (2001) say were the 6 principles of ethical management of DSD

1) minimise physical risk to child. 2) minimise psychosocial risk to child. 3) preserving the potential for family. 4) preserving/promoting the capacity to have satisfying sexual relationships. 5) leaving fertility options open for the future. 6) respecting the parents wishes and beliefs.


What are DSD disorders of Sexual Development

Congenital disorders where the chromosomal/ gonadal/ anatomical sex is atypical.

newborns: ambiguous genitalia. Adolescents: atypical secondary sexual development.

Genetic diagnosis accounts for about 20% cases.


List the 3 general classes of DSD

1) sex chromosome DSD.
2) 46, XY DSD (disorders of testicular development or androgen synthesis).
3) 46, XX DSD (disorders of ovarian development or fetal androgen excess)


list two 2 DSD types of complete sex reversal

46, XX testicular DSD.

46 XY complete Gonadal Dysgenesis (CGD)


list the 2 types of mild DSD phenotype

46 XY DSD (XY feminisation)

46 XX DSD (XX virilisation)


Whats the DSD term for previously hermaphrodite

ovotesticular DSD (46,XX , 46,XX/46,XY , 46,XY)


discuss 46 XY complete Gonadal Dysgenesis (CGD)

Swyer Syndrome 1/20-30,000) (Raised as females)

Normal female external genitalia.
Normal-tall stature.
Internal mullerian structures present (due to no AMH production).
Streak gonads.
No sperm production.
lack secondary characterisitcs.

Gonadoblastoma: common- often streak gonads: removed.


Discuss 46 XY DSD (partial gonadal dysgenesis/ feminisation)

Ambiguous genitalia (wide spectrum of incomplete masculinisation: mild to severe- can have partial testicular diff).
Mild-severe penoscrotal hypospadias with or without chordee.
Dysgenetic testes (defective embryonic development of gonads).
Reduced-no sperm production.
Mullerian structures range from absent to fully developed uterus & Fallopian tubes.
Sub-normal levels of T & DHT.

Risk of Gonadoblastoma: common- often gonads: removed.


Discuss 46 XY DSD (partial gonadal dysgenesis/ feminisation) and Fertility

Women with XY DSD/CGD and mullerian structure MIGHt get pregnant through Zygote donation.

Males with XY DSD: possible to donate gametes through ICSI.


what genes are seen to be involved in XY DSD

SRY (del/LoF mut): 1% DSD/ 15% CGD.
NR5AI (SF1) (mut): 13% DSD.
DHH (mut): 20% DSD/ 50% CGD.
NR0B1 (DAX1) (duplication): low penetrance.
WNT4 (duplication): low penetrance.


whats the genetic testing strategy for XY DSD/ CGD

Karyotype first: if XY FISH for SRY del: if deleted: diagnosis.
If SRY present: sequence SRY, NR5AI, DHH.
If all normal: look for NR0B1 & WNT4 duplications (aCGH/FISH)


What are the features of testicular regression syndrome

46,XY. developmental anomaly:

Testicular tissue begins to develop, but then regresses.
Absence of 1 or both testes at birth.
Ambiguous genitalia or sever micropenis.
Dysgenetic testes- disorganised seminiferous tubules.
Primitive sex cords devoid of germ cells.


briefly describe what Androgen Insensitivity Syndrome is, including gene and the 3 types.

Caused by LoF mutations of the AR gene at Xq12.
Can be seen as germline or somatic mosaicism.

CAIS: complete AIS: typical female external genitalia.

PAIS: Partieal AIS: predominantly female/ predominanlty male/ ambiguous genitalia.

MAIS: Mild AIS: typical male external genitalia.


what are the general features of AIS

'Evidence of feminisation of external genitalia at birth.'
'Abnormal secondary sexual development at puberty.'

Undermasculinisation of external genitalia.
Impaired spermatogenesis with normal testes.
Absent/ rudimentary mullerian structures.
Evidence of Normal or increased synthesis of T and DHT.
Normal or increased Luteinising hormone levels.


discuss CAIS

95% have AR mutations.

Absolute absence of androgen action.
Prepubertal inguinal hernia.
At puberty: incomplete breast developement. Primary amenorrhea with abesnt/sparse public hair.

Gonadodectomy. Hormone therapy.Vaginal dilation.


Discuss MAIS


develop gynaecomastia; have sparse/absent public hair; have a small penis


List some disorders of androgen action

defects in androgen biosynthesis.

testosterone secretion defect (impaired leydig cells).
5a reductase defficiency.
enzymatic defect in T synthesis.
cholesterol synthesis defect (Smith Lemli Optiz).


Name some disorders characterised by XY DSD/CGD

Campomelic dysplasia (AD SOX9 mut 17q24: sekeltal malformations).

ATRX a-thalassemia X-linked (genital anomalies from hypospadias to ambiguous genitalia with undescended testes. Dev del, microcephaly, hypertelorism, MR)

WT1: 11p13 Wilms tumour related disdorders


Discuss WT1 related disorders int terms of DSD

WAGR (Wilms, Aniridia, Genitourinary abns, MR, obesity)

Denys-Drash (dysgenetic XY DSD with early onset kidney failure 7 wilms tumours in 1st yr of life)

Frasier syndrome (female to ambiguous genitalia, renal failure in 2nd decade of life, streak gonads, increased risk of gonadoblastoma)


describe 46 XX testicular DSD

Normal male (short).
male external genitalia ranging from normal to ambiguous.
2 testes (often maldescended).
absence of mullerian structures.
10-15% have varying degrees of hypospadias

if left untreated: suffer testosterone deficiency.


when is 46 XX testicular DSD detected

85%: after puberty: normal pubic hair and penis size; small testes, gynaecomastia, azoospermia.

15%: at birth: ambiguous genitalia


What tests are carried out for ? 46XX DSD

endocrine testing (hypogonadotrophic hypogonadism) and cytogenetics.

90% cases: SRY+ (consider recurrence)

10% cases: SRY- for these cases investigate SOX9 and SOX3 status (aCGH)

SOX9: 17q24.3: small duplication of gene or promoter (increased activity).
SOX3: Xq27.1 microdeletion upstream of reading frame or duplication of gene.


whats the treatment for XX DSD

after 14 yrs low dose tesosterone therapy, increasing until adult life.

growth hormone if necc.


describe 46 XX gonadal dysgensis

can be inherited Auto recess.

Female phenotype (no TS stigmata)
Doesn't develop secondary sexual characteristics.
Primary amenorrhea.
Elevated gonadotrophins.
Streak gonads.

Mutations of: FSH receptor gene (FSHR), FMR1, BMP15


Briefly describe XX DSD Congenital Adrenal Hyperplasia

family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by adrenal cortex.

21 hydroxylase deficiency (21 OHD) : most common cause (95%).


Discuss what 21-hydroxylase deficiency form of CAH is

Caused by the excessive adrenal androgen biosynthesis.

Theres 2 forms; the classic form: prenatal onset (severe enzyme deficiency; virilisation)/ non-classic form (mild enzyme deficiency and postnatal onset).


What are the 2 major features of 21-hyroxylase deficiency (21-OHD) form of CAH

Salt wasting (75%) (hence being part of newborn screening programme)

Virilisation (25%) (affects growth, maturation, sex hormone-sensitive areas)


In terms of sex phenotype describe females with Congenital Adrenal hyperplasia

Complete or partial fusion of the lbioscrotal folds.
Phallic urethra.
Mullerian structures develop normally (if correctly treated and menses occur- pregnancy possible)


In terms of sex phenotype describe males with Congenital Adrenal hyperplasia

Normal Genitalia.
MAY develop testicular adrenal rest tumours which can lead to infertility


describe Salt wasting in patients with CAH

Occurs 1-4 weeks.
Failure to Thrive.
Recurrent vomiting.


What treatments can be given to males or females with CAH

Females prenatally: dexamethasone (prevent development of signs of androgen excess)

Salt wasting: mineralocorticoid 9a-fludrohydrocortisone therapy.


Discuss X-linked CAH (in XYs)

mutations of NROB1 (~100% familial).
features: salt wasting (possible ass. with delayed puberty, infertility)

60%: infantile onset: acute primary adrenal insufficiency at ~3wks old.

40% childhood onset:


What are the 3 types of (non-X-linked) CAH

21-hyroxylase deficiency (CYP21A2) (21-OHD) (95%).

11b-hydroxylase deficiency (CYP11B1) (5%)

3b-hydroxysteroid dehydrogenase 2 deficiency (


Name the 3 disorders that can cause non CAH XX DSD

Aromatose deficiency: fetoplacental.

POR Gene defect (P450 oxidoreductase).

Luteoma of pregnancy


what causes Aromatose deficiency: fetoplacental.

Increased prenatal exposure to androgens.
Steriod hormones produced by the placenta aren't converted to estrogen.

Results in virilisation of mother during pregnancy.
Female fetus is exposed to adrenal androgens resulting in ambiguous genitalia/ undetectable estrogens at birth.

lack breast development. primary amenorrhea. Tall, multicystic ovaries


discuss POR Gene defect (P450 oxidoreductase).

Glucorticoid and sex steroid deficiency.

presents neonatally (disordered sexual development, skeletal malformations, Glucorticoid deficiency)


Whats Luteoma of pregnancy

a non-neoplastic hormone dependent tumour-like lesion on ovary.

25% secret androgen: virilise mum and expose fetus to androgen (female fetus will be affected)


Whats ovotesticular DSD

can be 46,XX / 46,XX/46,XY / 46,XY (rare)

Well differentiated ovarian and testicular tissue present (either as separate gonads or ovotestes).
Mullerian and Wolffian derivatives present.
external genitalia ambiguous.