11/3- Disorders of Sexual Development

Question 1

What are the 3 major components of sexual development?

Answer 1

• Differentiation of the gonad (sex determination)
• Differentiation of internal genital organs
• Differentiation of external genital organs

Question 2

What are the main steps of sexual differentiation?

Answer 2

• Chromosomal sex
• Gonadal sex
• Phenotypic sex
• Psychosocial sex

Question 3

What is the main gene responsible for determining sex?

Answer 3

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

Question 4

What happens if SRY gene gets translocated onto X chromosome?

Answer 4

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”

Question 5

What is NROB1?

Answer 5

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

Question 6

What are disorders of sexual development that result from chromosomal abnormalities?

Answer 6

• Turner syndrome
• Klinefelter syndrom
• Other aneuploidy

Question 7

What are disorders of sexual development that result from single gene disorders?

Answer 7

• 21-hydroxylase deficiency (CAH)
• Androgen receptor (Xp)
• 5a-reductase deficiency
• SRY sex-determining region (Yp)
• DHRC7 Smith-Lemli-Opitz

Question 8

What are the 5 main presentations of Turner’s syndrome?

Answer 8

1. Spontaneous abortion; die in utero
2. Presents as newborn baby girl who looks normal, but much skin and puffiness in back and puffy fee
3. Presents as young child with short stature
4. Presents as primary amenorrhea
5. Presents as adult woman with infertility

Question 9

How to diagnose Turner Syndrome?

• Evaluate what other organ systems?

Answer 9

• G-banded chromosome analysis
• FISH for Y centromere/SRY
• If diagnosis considered, obtain Echo and renal ultrasound while genetic results are pending

Question 10

What is NIPS?

Answer 10

Screening test for Turner’s syndrome (not diagnosis!)

Question 11

What are complications of Turner syndrome?

Answer 11

• Cardiovascular: Coarct, Conduction, HTN, AoD
• Renal/GU Anomalies: Horseshoe kidney
• Endocrine: Thyroid, Growth, Sexual, Diabetes
• Orthopedic: Scoliosis, Hip dysplasia
• Ophthalmic/Audiologic
• Cognitive/Behavioral

Question 12

What is Klinefelter syndrome?

• Prevalence
• Diagnosed when
• Features

Answer 12

• 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

Question 13

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

Answer 13

Yup

Question 14

What falls under “ambiguous” genitalia that is apparently male?

Answer 14

• Bilateral nonpalpable testes at term
• Hypospadias associated with separation of scrotal sacs
• Undescended testis with hypospadias

Question 15

What falls under “ambuiguous” genitalia that is apparently female?

Answer 15

• Clitoral hypertrophy
• Forshortened vulva with single orifice
• Inguinal hernia containing gonad

Question 16

What is the DDx if infant has ovary but external male genitalia?

Answer 16

• Congenital adrenal hyperplasia!! (masculinization of 46XX individual)
• Placental aromatase deficiency
• Maternal source of virilization

Question 17

What is the DDx if infant has testis but external male genitalia is underdeveloped or feminine?

Answer 17

• Leydig cell hypoplasia
• Testosterone biosynthesis defect
• 5a reductase deficiency
• Androgen insensitivity

Question 18

What is the DDx for dysgenetic gonads (ovo-testes)?

Answer 18

• Gonadal dysgenesis
• Denys-Drash and Frasier syndromes
• Smith-Lemli-Opitz syndrome
• Campomelic dysplasia

Question 19

What to think if patient presents with:

• Ambiguous genitalia
• Ovaries and mullerian structures present
• 46,XX karyotype

Answer 19

Congenital adrenal hyperplasia

Question 20

What is Congenital adrenal hyperplasia?

• Causes what
• Mechanism/genetics
• Inheritance pattern

Answer 20

• 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)

Question 21

What are clinical features of Congenital Adrenal Hyperplasia?

• Males vs. females

Answer 21

Males appear normal at birth

• Advance bone age, precocious puberty
• Hyperpigmentation of genital skin

Females have virilization

• Noted at birth (ambiguous genitalia)
• Noted later as hirsuitism, clitoromegaly
• Hyperpigmentation of genital skin

Acute adrenal crisis

• Life-threatening salt wasting
• Hyponatremia, hyperkalemia

Failure to thrive

• Vomiting, fever, weight loss

Question 22

What is seen here?

Answer 22

Ambiguous genitalia in CAH 21 OH (Congenital Adrenal Hyperplasia)

Question 23

How is diagnosis made of CAH (21-OHase deficiency)?

Answer 23

• 17-hydroxyprogesterone levels
• Newborn screen
• Amniotic fluid (~16th week)
• Androstenedione
• Serum electrolytes (salt losing in 75%)
• DNA diagnosis
• —- CYP21 gene mutations

Question 24

What is treatment for CAH (21-OHase deficiency)?

Answer 24

Prenatal (dexamethasone) and postnatal treatment

Question 25

What to think when female pt presents with: - Inguinal mass - Primary amenorrhea - Testes present - Mullerian structures absent - 46XY karyotype

Answer 25

Complete androgen insensitivity

Question 26

What cells are responsible for testosterone? MIF?

Answer 26

- Leydig cells: **testosterone** - Sertoli cells: **MIF** (Mullerian inhibitory factor)

Question 27

Describe androgen insensitivity - Inheritance pattern - Genetic cause - Features

Answer 27

Androgen Receptor (AR) - Xp: X-linked recessive - Normally binds testosterone and DHT Mutations AR cause androgen insensitivity _Various mutations–various phenotypes_ - Complete testicular feminization - Incomplete testicular feminization - Infertile male syndrome - Undervirilized fertile male syndrome

Question 28

More on androgen insensitivity - Karyotype - Phenotype - Urogenital features - Endocrine findings

Answer 28

- Karyotype = 46XY _Phenotype:_ - Female, underdeveloped labia - Breast development - Paucity of axillary/pubic hair _Urogenital features:_ - Blind ending vagina - No Müllerian or Wolffian derivatives - Testes may be intraabdominal _Endocrine findings:_ - Testosterone: normal to high male - Estrogen: higher than normal men - Gonadotropin: elevated LH

Question 29

What to think when patient present with: - Ambiguous genitalia - Testes present - No Mullerian derivatives - 46,XY karyotype

Answer 29

Partial androgen insensitivity or 5a reductase deficiency

Question 30

What to think when patient presents with: - Infertility and/or undervirilization - +/- hypospadius - +/- cryptochism - 46XY karyotype (NOT 46XXY)

Answer 30

Partial androgen insensitivity

Question 31

What to think when patient presents with: - Ambiguous genitalia - Testes present - Virilization at puberty - 46,XY karyotype

Answer 31

5a reductase deficiency

Question 32

What is 5a reductase responsible for?

Answer 32

Converts testosterone to dihydrotestosterone - Testosterone secretion is normal

Question 33

What is seen in 5a reductase deficiency?

Answer 33

Ambiguous genitalia in XY individuals - Testes in inguinal or labial areas - Wollfian derivatives end or empty to vagina - No Müllerian derivatives - Variable virilization at expected puberty Biochemically affected females are normal

Question 34

What is the major issue for individuals with 5-ARD?

Answer 34

Gender assignment - Almost all children with 5-ARD are assigned a female gender at birth - In the US, surgical feminizing genitoplasty is performed during infancy (controversial) - Most males virilize adequately for normal sexual function without replacement - In many cultures in which early surgery is not performed, some individuals with 5-ARD adopt male gender identity and a male gender role at puberty

Question 35

What to think when patient presents with: - Ambiguous genitalia - Dysmorphic features +/- organ involvement - 46XX or 46XY or other karyotype

Answer 35

Gonadal dysgenesis

Question 36

What syndromes/conditions fall under gonadal dysgenesis?

Answer 36

- 45,X/46,XY - Denys-Drash and Frasier syndrome - Smith-Lemli-Opitz syndrome - Campomelic dysplasia - Chromosomal abnormalities

Question 37

What are features of gonadal dysgenesis?

Answer 37

- Incomplete differentiation of the bipotential gonad - Insufficient secretion of testosterone and/or MIF - Variable degree of external ambiguity - ~75% 46,XY GD have Müllerian structures

Question 38

What is seen in gonadal dysgenesis due to A93-73? What is the cause?

Answer 38

- 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

Question 39

What is seen here?

Answer 39

Testis with absent Leydig cells (A93-73)

Question 40

What should be considered if there are multiple congenital anomalies and the chromosomes and/or CMA (aCGH) are normal?

Answer 40

Single Gene Disorders causing Gonadal Dysgenesis - Smith-Lemli-Opitz: DHCR7 - Camptomelic Dysplasia: SOX9 - Denys-Drash: WT1

Question 41

What is seen in Smith-Lemli-Opitz? - Cause - Inheritance pattern

Answer 41

- Multiple congenital anomalies - Genital anomalies in males - Defect in cholesterol biosynthesis * Elevated 7-dehydrocholesterol (plasma sterol analysis) - Autosomal recessive

Question 42

More details for Smith Lemli Optiz syndrome - Multiple congenital anomalies - Neurological deficits - Defect in cholesterol biosynthesis - Fetal demise

Answer 42

**Multiple congenital anomalies** - microcephaly,holoprosencephaly - cleft palate - congenital heart defect - genito-urinary anomalies - ambiguous genitalia - syndactyly **Neurological deficits** - developmental delay - seizures **Defect in cholesterol biosynthesis** - biochemical dx - d-7-dehydrocholesterol reductase - NOT a chromosomal abnormality **Fetal demise** - IUGR and microcephaly - Dysmorphic features - Cleft palate - Short limbs - Congenital heart defect - Sex reversal: * 46,XY * female genitalia - Family history: * 2 previous SABs

Question 43

Summary of Methods of Evaluation

Answer 43

**History/Physical** - maternal androgen exposure; family history - determine if gonads are palpable - degree of masculinization (Prader) **Determine chromosomal sex/abberations** - G-bands; FISH XY; FISH SRY **Diagnostic imaging** - pelvic/renal ultrasound - urogenital sinogram - brain, cardiac, skeletal … **Biochemical analysis** - 17 OH progesterone; 11 DOC; Androstenedione testosterone; DHT (pre and post hCG stim) - biopsy: peroneal skin; gonadal