1. DSD (disorders of sex development)
M. Šnajderová
Pediatrická klinika, 2. LF UK a FN Motol, Praha
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2. Sex development Genes related to gonadal development
Gonadal differentiation
Internal and external genitalia
Phenotype and pubertal development
Sexual identity

3. Disorders of sex development (DSD)

4. Male development Y chromosome (SRY) Genes Hormones(T, DHT, AMH)
Androgen sensitivity
T testosterone DHT dihydrotestosterone
AMH Antimüllerian hormon

5. DSD: „disorders of sex development“
Prevalence
Genital anomalies
1: births
(Thyen, U. et al.,Horm.Res., 2006)
DSD: „disorders of sex development“
congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical

6. DSD Most cases recognised in neonatal period Later presentation:
Previously unrecognised genital ambiguity
Inguinal hernia with gonads in „girl“
Delayed or incomplete puberty
Virilisation in girls
Primary amenorrhea
Breast development in boy
Occassionally cyclical haematuria in a boy

7. Revised nomenclature (DSD) LWPES and ESPE 20061
Previous
Proposed
Intersex
Male pseudohermaphroditism
Undervirilisation of XY male
Undermasculinisation of XY male
DSD (disorders of sex development)
46, XY DSD

8. Revised nomenclature 2 Previous Proposed Female pseudohermaphrodite
Overvirilisation of XX female
Overmasculinisation of 46 XX female
True hermaphrodite
XX male nebo XX sex reversal
XY sex reversal
46, XX DSD
Ovotesticular DSD
46, XX testicular DSD
46, XY complete gonadal dysgenesis

9. DSD
Life threatening
If not
Urgent
Time for diagnostics

10. Approach to the problem 1
History (family history of ambiguous genitalia, maternal health including virilisation), drugs during pregnancy, previous stilbirths or neonatal deaths
Examination (dysmorphic features of midline defects, hydration, blood pressure)

11. Approach to the problem 2
Genitalia
Palpable gonads? (if yes: likely to be testes – normal or dysgenetic or ovotestes)
Degree of virilization (Prader)
Measure the length of the phallus stretched length from pubic tubercle to tip of penis). (Normal: about 3 cm, micropenis 2-2.5 cm (ethnic origin)
Position of the urethral opening, vaginal opening, urogenital sinus?

12. Approach to the problem 3
Appearance of labioscrotal folds, rugosity
Note the pigmentation of genital skin (excessive ACTH and opiomelanocortin in CAH)
Determine the baby´s gestation (preterm girls: clitoris and labia minora are relatively prominent, in boys usually testes undescended until 34 weeks)

13. Investigations 1 FISH or PCR for Y and X chromosomes Blood karyotype
Blood electrolytes
Blood sugar
If male/mosaic karyotype is confirmed: investigation directed at determining anatomy of internal genitalia and establishing whether testes are capable of producing androgens

14. Investigations 2 T and hCG test LH, FSH and GnRH test
ACTH test (17-OHP,DHEAS, A-dion, T, DOC…)
Determining of internal anatomy (Prader stages I-V)
Ultrasound scan (anatomy of urogenital sinus/vagina/uterus/renal anomalies)
Urogenital sinogram

15. Investigations 3
Cystography, laparoscopy with or without biopsies of gonads and skin
MRI scan of the pelvis

16. BIOSYNTHETIC DEFECT Testosterone biosynthetis defect
StAR defect, Smith-Lemli-Opitz syndrome, 3&-HSD deficiency, 17α-OHD
Karyotype 46 XY
↓basal and ↓ hCG stimulated T
↑ T precursors (A-dion, DHEAS) on hCG test
in lipoid CAH: adrenal failure confirmed on ACTH test, electrolytes and urinary steroids

17. BIOSYNTHETIC DEFECT 5α – reductase deficiency Karyotype 46 XY
= / ↑ basal and peak T on hCG test
↑ T/DHT ratio
Screening for mutations in the 5α – reductase type II gene (5RD5A2) in blood

18. BIOSYNTHETIC DEFECT
Leydig cell hypoplasia (inactivating mutation of LH receptor)
Karyotype 46 XY
↓ basal and hCG stimulated T
↑ LH level

19. END-ORGAN UNRESPONSIVENESS
PAIS (mutation in the androgen receptor)
Karyotype 46 XY
= / ↑ basal and peak T in hCG test
Normal T:DHT ratio
Abnormality in genital skin fibroblasts or a mutation in the androgen receptor
CAIS
does not present in the neonatal period (normal female phenotype)

20. SYNDROMES Smith-Lemli-Opitz Denys-Drash syndrome
Genital ambiguity, congenital nefropathy and Wilms´tumour
Mutations in the Wilms´tumour suppressor (WT1) gene
Proteinuria and renal impairment and determinind
WT1 mutation

21. Intersex criteria for sex determining
Anatomical defect and function aspects
Psychosocial aspects
Future sexual function and fertility

22. Therapeutic options and strategies
CAH: prenatal diagnostics, recent approaches to the treatment of girls in utero
Hormonally active tumors - oncologist
Gonadal dysgenesis (45X/46XY and other mosaics)
Disorders of biosynthesis and metabolism of androgens
Androgen insensitivity partial complete

23. Hormone replacement (HRT)
defects of steroidogenesis
after removal of the gonads, afunction, gonadal agenesis
induction of puberty
feminization, virilization and maintain the state sexual function
induction of spermatogenesis (when, how?)
induction of ovulation
reproduction

24.  risk (<5%): biopsie and gonadectomy?
Risk of gonadal tumors 1
   risk: gonadectomy ±
+ TSPY (testis-specific proteinY encoded) u GD: (gonadal dysgenesis) : risk 15-40%
PAIS intra-abdominal gonads : risk 50%
Frasier syndrome : risk 60%
 risk (<5%): biopsie and gonadectomy?
ovotestis DSD : risk %
CAIS : risk 0.8-2% 24

25. Risk of gonadal tumors 2 Moderate risk: No risk (?):
Turner syndrome (-Y) : gonadectomy ±, risk 12%
17 beta-HSD : monitoring risk %
GD (gonads in scrotum) : biopsy and irradiaton? risk ?
PAIS (gonads in scrotum) : biopsy and irradiation?
risk 15%
No risk (?):
5aR risk 0 ???
Leydig cells hypoplasia risk 0 ??? 25

26. B C A E D F
Fig. 3. Gonad histology and immunohistochemical analysis.
A Branching seminiferous tubule. B Region settled with germ cells (stained for TSPY, red) neighboring with an area of Sertoli-cell only tubules. C FOXL2-positive (granulosa) cells (orange) within seminiferous tubules settled by Sertoli cells positive for SOX9 (blue). D Multiple calcifications. E Double-staining for OCT3/4 (orange) and TSPY (blue) with double-positive cells attached to the basal lamina (arrows). F Same area with KITLG expression (red).
45,X/46,X,psu dic(Y) Gonadal Dysgenesis: Influence of the Two Cell Lines on the Clinical Phenotype, Including Gonadal Histology
J. Kaprova-Pleskacova, M. Snajderova, J. Stoop, M. Koudova, E. Kocarek, D. Novotna, S.L.S. Drop, B Obermannova, J. Lebl, J.W. Oosterhuis, L.H.J. Looijenga
Sex Dev DOI: /

27. Surgical management Prader III – V virilisation in girls
Preservation of erectile function and innervation of clitoris
Timing of separation of the vagina and urethra not before puberty (beneficial effects of estrogen on tissue)
Vaginoplasty in some cases
DSD with hypospadias: urethral reconstruction, phalloplasty, penile reconstruction

28. CAIS and PAIS raised as female: testes should be removed to prevent malignancy in adulthood (E2-HST)
Mixed gonadal dysgenesis (MGD):
streak gonad to remove (laparo) in males in early childhood
bilateral gonadectomy in females (bilateral streak gonads) and Y chromosome