Ambiguous Genitalia

1
Ambiguous Genitalia Neonatal Presentation

2

• Baby H
• Born 11/08/2003
• Mother -
• Somalian origin
• P4 G4 others healthy, normal
• Booked, Rh negative, Syphilis negative, HIV
  negative
• Term, appropriate for gestational age, weight
  3322g
• Apgars 8, 8, 9
• Sent to nursery unsure of sex
• On examination
• Not dysmorphic
• Blood pressure 57/28 mmHg
• Dextrostix normal
• Cardiac examination 3/6 ejection systolic
  murmur, left sternal border
• Genitalia labioscrotal folds (unfused),
  palpable gonads, 1cm phallus, perineoscrotal
  hypospadias
• Management and Progress
• Stayed 1 week
• Dextrostix normal, BP stable
• Fed well

3
(No Transcript)
4

• Day 3 no urine output, distended bladder,
  required catheterisation - catheter fed into
  perineal opening
• Passed urine normally after catheter removed
• Cardiac consult small PDA, small PFO, apical
  VSD
• Pelvic ultrasound no uterus, normal bladder,
  kidneys
• Blood results
• WCC 14,27 Hb 16,5 Plts 159
• UE 139 / 3,9 / 104 / 14 / 5,0 / 92
• Hormone levels to be discussed later
• To be followed up at endocrine clinic

5
Ambiguous Genitalia

• Manifestation of Intersex Disorders
• Characterised by abnormal differentiation,
  development of external, (sometimes) internal
  sexual structures
• Normal sexual differentiation
• Phenotypic sex - genetic/chromosomal sex, follows
  logical sequence of events
• Chromosomal sex established at fertilisation
  determines gonadal sex
• Gonads determine differentiation/regression of
  internal ducts (Wolffian/Müllerian)
• At 6 - 7 weeks gestation
• Y chromosome gt undifferentiated gonad gt testis
• Absence of Y chromosome gt ovary
• Process dictated by Testisdetermining factor
  (TDF), product of Sexdetermining region on Y
  chromosome (short arm)
• Absence of TDF ovaries develop
• Also autosomal determinants of sexual
  differentiation
• Still unexplained true hermaphrodites (XX), XX
  males no Y chromosome
• General rule Y chromosome necessary for
  presence of testes

6
(No Transcript)
7

• Gonads develop from blastemal mass, primordial
  germ cells
• Leydig cells testosterone under influence of
  HCG (placental) and
• LH (pituitary)
• Week 4
• Wolffian ducts develop, open into cloaca
• Müllerian ducts develop later
• Both complete by week 8
• Testosterone binds to testosteronebinding
  androgen receptors, development of epididymis,
  vas deferens, seminal vesicles
• External genitalia respond to Dihydrotestosterone
  requires conversion of testosterone by 5 alpha
  reductase
• Anti-Müllerian Hormone (Sertoli cells) local
  (paracrine) effects
• Role in descent of testis
• halts spermatogenesis at meiosis, continued
  later at puberty
• Regression of Müllerian ducts (9 11 weeks)
• Without AMH, Wolffian ducts disappear, fallopian
  tubes, uterus, upper 1/3
  vagina develop
• This occurs with/without ovaries not affected by
  androgens

8

• External Genitalia from genital tubercle,
  urogenital groove, paired urethral folds,
  labioscrotal swellings, urogenital sinus (see
  picture)
• Male
• development dependent on 5 alpha
  dihydrotestosterone
• AMH testes into inguinal region,
• testosterone Wolffian duct derivatives, testes,
  into scrotum
• Female
• Urogenital sinus forms lower 2/3 of vagina
• Role of Pituitary and Placenta
• Major stimulus to Leydig cells initially
  placental HCG
• After critical period of sexual differentiation,
  pituitary gonadotrophins responsible for growth
  of penis
• Fetal LH, placental HCG necessary for normal
  growth of penis, scrotum, descent of testes
• Hypopituitarism (congenital gonadotrophin
  deficiency) micropenis, bilateral
  cryptorchidism
• Females placenta major source of oestrogen

9
(No Transcript)
10
Abnormal Sexual Development

• Intersex disorders divided into 3 groups
• Virilised females
• Undervirilised males
• Disorders of gonadal differentiation
• 1) Virilised Females
• 46 XX, normal ovaries, internal genitalia
• Varying degrees virilisation depends on time,
  amount of androgen exposure
• Early retention of urogenital sinus,
  labioscrotal fusion
• Later clitoral hypertrophy
• Müllerian duct differentiation normal
• CAUSES
• Fetal androgens - Congenital Adrenal Hyperplasia
  (CAH)
• Maternal androgens anabolic steroids, Danazol,
  ovarian / adrenal tumours
• Syndromes Zellweger, Beckwith-Wiedemann
• Idiopathic

11
Congenital Adrenal Hyperplasia (CAH)

• Constitutes 60 of all intersex cases in
  literature (however in South Africa true
  hermaphroditism is dominant)
• Possible medical emergency
• Results from block in steroid synthesis pathway
  excess of precursors, deficiency of end-product
• Decreased negative feedback increased ACTH
  adrenal hyperplasia, pigmentation
• Manifestations depend on level of block
• (see diagram)
• 90 of cases 21 Hydroxylase deficiency
• Salt-wasting, hyperkalaemia, hypotension,
  vascular collapse
• Autosomal recessive

12
(No Transcript)
13

• 2) Under-virilised males
• 46 XY, testes
• Causes
• LH Deficiency
• Leydig cell hypoplasia
• Disorders of testosterone synthesis (testes
  alone/testes and adrenals)
• Abnormalities of peripheral testosterone effects
  (resistance)
• Certain syndromes
• 5 alpha reductase deficiency
• Converts testosterone to dihydotestosterone (DHT)
• Ambiguous genitalia (pseudovaginal perineoscrotal
  hypospadias), testes present (descended),
  internal Wolffian duct development normal
• Extreme virilisation at puberty, testosterone
  responsible for male pubertal development
• No prostatic enlargement/ acne/facial hair (these
  depend on DHT)
• Diagnosis high testosteroneDHT ratio (HCG
  stimulation test not necessary in newborn)

14

• End-organ resistance (testicular feminisation)
• Quantitative/qualitative receptor defects
• X-linked recessive inheritance
• Complete/incomplete
• Complete female genitalia, no Müllerian
  structures, short vagina, breasts, no
  pubic/axillary hair
• Many degrees normal female to various degrees
  of virilisation
• NB increased incidence gonadal malignancy
• Disorders of Gonadal Differentiation
• Ovarian and testicular tissue present
• 1) Pure gonadal dysgenesis
• streak gonads ovarian stroma, no oocytes
• Usually XO or XY or XO mosaics
• Turner syndrome is an example
• 2) Mixed gonadal dysgenesis
• Testis on one side (inguinal area or scrotum),
  streak gonad on other side Müllerian structures
  on that side
• Most XO/XY
• Klinefelter Syndrome

15

• 3) True Hermaphrodite
• Well-developed testicular and ovarian tissue,
  same/opposite gonad
• Bilateral ovotestes (20), 1 testis 1 ovary
  (30), or ovotestis testis or ovary
• Wolffian, Müllerian duct development follows lead
  of ipsilateral gonad
• Ambiguous genitalia
• Hernia containing gonad/Müllerian duct derivative
• 46XX commonest karyotype mosaicism common
• ?Translocation of portion of Y chromosome onto X
  chromosome or autosome to explain testicular
  development in absence of Y chromosome

16
Investigations

• Diagnosis important counsel parents, plan
  management, treat medical emergencies
• History
• Genital ambiguity, infertility, unexplained
  changes at puberty/late onset puberty, previous
  unexplained neonatal death
• Maternal drugs
• Maternal virilisation (?tumour)
• Examination
• Dysmorphic features
• External genitalia
• Size, degree of differentiation of phallus
  (clitoromegaly or hypospadias)
• Position of urethral meatus
• Fused/separate labioscrotal folds
• Scrotal/labioscrotal folds rugose or
  hyperpigmented

17

• Gonads
• ?palpable
• Usually only testicular material descends fully
• Rectal examination
• Cervix, uterus may be easier in neonatal period
• Laboratory Studies
• Chromosomal analysis
• Endocrine screening testosterone, DHT, 17
  hydroxy- progesterone, dehydroepiandrosterone
  (DHEA), LH, FSH, ACTH, plasma renin activity,
  aldosterone (later)
• Urea electrolytes, serum glucose
• Androgen receptor levels (genital skin
  fibroblast culture)
• 5 alpha reductase, type 2 levels
• Stimulation tests
• Stimulate potential testicular tissue with HCG
  highlights altered testosteroneDHT ratio
• ACTH stimulation

18

• Imaging
• Pelvic ultrasound
• Difficult, need full bladder
• Uterus, Mullerian structures, adrenal gland
  enlargement (cribriform appearance)
• Uterus present usually virilised female
• Absent uterus more difficult
• Genitogram
• Ductal anatomy
• Contrast injected into urogenital sinus
• Other
• CT scan, MRI, exploratory laparotomy/
  laparoscopy, gonadal biopsy

19
Management

• Medical
• Supportive in CAH, replacement of hormones
• Surgery
• Timing, type controversial
• Issue of gender assignment often very difficult,
  emotional, requires team approach
• Virilised females feminising genitoplasty
• Undervirilised males correction of hypospadias,
  gender reassignment
• Dysgenetic/non-functional gonads require
  removal, high risk malignant change by 4th decade
• Karyotype not necessarily determinant in gender
  reassignment

20
What have we learned in this case?

• Chromosomes 46XY
• Results (13/08/2003)
• Testosterone 3,8nmol/l (normal)
• LH - lt0,1IU/l (normal)
• 17OH Progesterone 1,3nmol/l (normal)
• Cortisol 319 (normal)
• DHEA(S) 0,9umol/l (low)
• Post HCG Stimulation Test
• Testosterone 6,4 nmol/l
• Assessment
• Undervirilised male, normal testicular tissue
• ? 5 alpha reductase deficiency

21
(No Transcript)