Disorders of Sexual Differentiation (DSD)

Disorders of Sexual Differentiation (DSD)

• A congenital condition where chromosomal, gonadal, or anatomical sex development is atypical
• DSD live birth rates can range from 1/4000 to as high as 1/770
• Can cause genital variations and congenital malformation

Fertilization and Sex Development

• Genetic sex is determined at fertilization
• Gonadal sex (testis/ovary) develops based on genetic sex
• Phenotypic sex (internal/external genitalia) progresses from gonadal sex
• Hormones and the social environment influence psychologic sex and gender identity

Intrauterine Sexual Differentiation

• Until about 42 days of gestation, embryonic gonads of both sexes are indistinguishable, existing as a primitive gonadal structure
• Subsequent differentiation into testes or ovaries hinges on having the testes-determining gene, SRY, on the Y chromosome

Gonadal Development Factors

• SF1, SRY, SOX9, AMH, GATA4, WT1, FGF9 (FGFR2), and DAX1 all contribute
• WT1
• EMX2
• LIM1
• SF1
• CBX2
• GATA4 NANOG
• CXCL12
• CXCR4 are also important factors

Gonadal Differentiation Timing and the Role of SRY

• Before 42 days of gestation there is a primitive gonadal structure
• The sex-determining Region of Y (SRY) on the Y chromosome determines the subsequent differentiation of gonads into testes or ovaries
• Testis development occurs around 43-50 days
• Leydig cell development occurs around 60 days
• External genitalia development around 65-77 days
• Ovary development occurs around 77-84 days
• Absence of SRY results in the primitive gonad differentiating into an ovary within 77-84 days

Internal Duct Development

• Development relies on the presence of functional fetal testes
• Before 7 weeks there is no internal duct differentiation, and a primordial structure has both Mullerian and Wolffian ducts
• The development of internal genital ducts depends on the presence/absence of functional fetal testes between 7-12 weeks

Anti-Mullerian Hormone (AMH)

• Secreted by Sertoli cells and causes Mullerian duct regression (ipsilaterally)

Role of Testosterone in Development

• Secreted by Leydig cells and responsible for further Wolffian duct development
• Results in the Vas deference, epididymis, seminal vesicles, and ejaculatory duct
• Absence of AMH means Mullerian duct develops further to Uterus, Fallopian tubes, cervix, and upper part of the vagina
• Absence of tesosterone results in regression of Wollfian ducts

Steroidogenesis

• Leydig cells in the testes produce testosterone
• Sertoli cells make Anti-Müllerian Hormone
• If SRY is not there, there are suppressed female structures

Female vs Male Structures

• Supporting Cells in Females are Granulosa while Male are Sertoli and both originate from Coelemic Epithelium
• Stromal Cells: Theca in females, Leydig in males and both originate from Mesenchyme
• Primordial Germ Cells: Oocyte in females, Spermatogonia in males originate from Allantois

External Genitalia Differentiation

• Depends on DHT binding to androgen receptors
• Causes fallic enlargement, zipping-up of genital groove into penile urethra, zipping-up of labioscrotal swelling into scrotum, and prostate growth

Placental Hormones and External Genitalia Differentiation

• Placental hCG stimulates fetal Leydig cells, producing testosterone before fetal LH kicks in
• Testosterone is converted to Dihidrotestosteron and causes Androgen receptor activation
• Results in Fallus growth, Fusion of Penil urethra and Labioscrotal swelling to form scrotum as well as prostate growth

External Genitalia Structures

• The genital tubercle becomes the glans penis in males and the and clitoris in females at 14 and 20 weeks repsectively
• The urethral fold becomes the penile shaft in males and the labia minor in females at 14 and 20 weeks repsectively
• The genitourethral sulcus becomes the penil urethra in males and the vagina (lower 2/3) in females at 14 and 20 weeks repsectively
• The labioscrotal fold becomes the scrotum in males and the labia major in females at 14 and 20 weeks repsectively
• The urogenital sinus becomes the bladder/prostatic urethra in males and the bladder in females at 14 and 20 weeks repsectively

Clinical Presentations of DSD and Etiology

• Disorders of gonadal development results in Gonadal dysgenesis, Ovotesticular DSD, Testicular DSD and can lead to abnormal gand development
• Androgen excess can be fetal (3β-hydroxysteroid dehydrogenase 2, 21-hydroxylase, P450 oxidoreductase, 11b-hydroxylase, Glucocorticoid receptor mutations), Fetoplacental (Aromatase deficiency, Oxidoreductase POR deficiency) or Maternal (Maternal virilizing tumours )
• Syndromic associations (e.g. cloacal anomalies) is possible
• Müllerian agenesis/hypoplasia, Uterine abnormalities, Vaginal atresis and Labial adhesions all contribute

46XY DSD Etiology

-Complete or partial gonadal dysgenesis leads to abnormal gonadal development -Vanishing testis syndrome, syndromic associations of male genital development all results -Persistent Müllerian duct syndrome, Isolated hypospadias, Congenital hypogonadotrophic hypogonadism and Cryptorchidism all result

• Gonadal, testicular or hormonal issues, Drugs and/or and Environmental influences

Defects in Testosterone Biosynthesis and Action and their Etiology

Smith Lemli Opitz syndrome, StAR protein Deficiency, Leydig Cell Hypoplasia, 17 hydroxylase, 17 - 20 lyase, 3β hydroxy steroid dehydrogenase,5α reductase are among the defects

Diagnosing DSD

• Families should be congratulated on the birth of their child
• Ensure the family that its child has a sex development problem and will be addressed
• Emphasize that the parents are NOT at fault
• Outline the treatment plan and procedures

Clues to Etiologic Diagnosis of DSD

• Consider drugs during pregnancy, maternal virilization during pregnancy and DSD history in the family, history of death of a sibling Physical Exam is Vital -Check for Palpable gonads and be aware that bilateral palpable gonads can point to 46 XY DSD -Increased pigmentation (CAH), Hypertension, Salt wasting and Dysmorphic features are important to note

Diagnosing and DSD

• If there are 46XX DSD cases, Androgen production from adrenal lead to virilization

• Perform ACTH test

• Also remember that 46XY DSD cases can cause decreased masculinization

Genetic Assignment in Sexual Differentiation Management

For 46XX CAH: Assign as female For 46XY with inadequate penis size: Assign Female For 46XY with adequate penis size that responds to testosterone: Assign Male Gonadal dysgenesis: Assign female Ovo-testicular DSD: Assign based on both anatomy and histology.

Timing of Gender Assignment

• By one year infants know male and female
• At 2-3 yrs the child knows his/her gender
• At 5 years the child perceives gender as a constant character
• After 5 years behavior towards appropriate gender is accelerated

Management and Diagnosis

• Look for Virilization and Inguinal hernia
• Diagnose with 5-α Reductase Deficiency and Androgen Insensitivity

Genetics

• Test Androgen Receptors
• Perform 5-a reductase test
• Check HCG levels and test Test/Androstenedion ratio

Surgical Management

• Gonadectomy: Done at the time of gender assignment
• Correction of chordee: 1-2 months
• Orchiopexy: within 18 months
• Correction of hypospadias: before 6 years of life
• Placement of prosthetic testes: during adolescence

Corrective surgery

• Opening-of labioscrotal fusion at 1-2 months
• Cliteroplasty at 1-8 months
• Partial vaginoplasty within first 6 years
• Extensive vaginoplasty with dilatation: During or after adolescence before marriage

Hormone treatment

• Treat with hormones to help with the lack of gonds
• Females should continue taking Continuous estrogen for the first 6-12 months.
• Cycle estrogen and progesterone
• Boys should take testosterone replacement Administer Testosterone and watch phallic response which is important check for masculinization

Other Medical Aspects

• DSD should result in discussions on gender identity
• This is key for sexual orientation and which gender(s) the person is attracked to
• Ambiguous Genitalia results when DSD is present

DSD Nomenclature

- 46, XY DSD 
-46, XX DSD 
-Ovotesticular DSD
-46, XX testicular disorders 
-46, XX Ovarian disorders 
-DSD related with sex chromosome abnormalities (e.g. 45,X/46,XY)

46,XX DSD-FPH causes and Diagnosis

-With virilization = Congenital adrenal hyperplasia, 46XX male, Androgen-secreting tumors,. Use of medications
 - Without virilization- Pure gonadal dysgenesis with 46,XX karyotype

46,XY DSD - Spectrum of clinical presentation

-Simple hypospadias
-Unilateral cryptorchism 
-Bilateral cryptorchidism with normal penis
 -Moderate - severe hypospadias
 -Sex reversal 
 -Miscellaneous

Phenotypes of DSD

-Hypospadias and one/no palpable gonad
 -Micropenis and perineal hypospadias
-Non palpable Testes
  -Clitoral hypertrophy
  -Vuvla
  - Inguinal hernia

46XX DSD - Female pseudohermaphroditism

-Hormonal causes lead to excess hormones (Androgen excess) -Virilizing can be related to congenital adrenal hyperplasia -Check Adrenal tumors and any Glucocorticoid resistance

Etiology of 46XY DSD-Defects

 -Deletion of genes in the short Am of the Y chromosome(Sex Chromosome)
 -Check XY pure gonadal Dysgenesis

Approaching DSD

- Determine is there any threats/life threatening aspects

Once there is an established sex then base rearing based off of the appropriate aspects

Final Note

-The extent of external and internal reproductive system development, gonadal functionality,and Hormone responsiveness are important