Disorder of sexual development

Disorder of sexual development

1. Dr.Azad A Haleem AL.Mezori MRCPCH,DCH, FIBMS Assistant Professor University Of Duhok College of Medicine Pediatrics Department [email protected] Disorder of sexual development

2. G enetic sex - chromosomes A natomical sex - internal and external genitalia S exual identity - one's identity as male or female. Introduction

3. Definition Disorder of sexual development (DSD) : a congenital discrepancy between genetic ( chromosomal ), gonadal and phenotypic sex ( external genitalia ). The term DSD has replaced earlier used derogatory terms like ambiguous genitala and intersex .

4. Pointers DSD include: atypical genitalia, peno -scrotal bypospadias , bilateral inguinal masses in girls (extreme undervirilization in a boy), cryptorchidism in boys (extreme virlization in girls) & primary amenorrhea. DSD evaluation is not required in isolated micropenis , penile hypospadias or prominent clitoris.

5. Epidemiology Based on these criteria 1 in 3000-4000 neonates have DSD. The incidence of DSD in Saudi Arabia has been estimated at 1:2,500 live births; whilst in Egypt , it has been estimated at 1:3,000 live births.

6. PATHOPHYSIOLOGY Sexual development entails development of internal and external genital organs guided by genetic sex. This involves development of gonads , production of hormones and their action and development of gender identity. Gender determination happens at conception with XX karyotype predicting female and XY karyotype male development.

7. XX XY Mesoderm ( urogenital ridge) Bi-potential gonad 4-6 weeks WTI and NRSAI genes SRY NRSA1 gene FOXL2 and DAX1 SOX9 6 weeks ( 5ARDII ) 12 weeks Genetic sex Gonadal sex Phenotypic sex genital tubercle and urogenital sinuses mullerian and wolfian duct Renal adrenal 7 weeks Estrogen 12 weeks Estrogen

8. Adrenal glands Normally, the adrenal glands are responsible for producing three different hormones: 1. corticosteroids , 2. mineralocorticoids (regulate salt and water) and 3. androgens , which are male sex hormones.

9. Placental aromatase protects female fetus and pregnant mother from androgenic effect of DHEAS produced by fetal adrenals. Fetus is protected from maternal androgens by the placental 17 beta hydroxysteroid dehydrogenase II (17BSD II) enzyme that converts testosterone to androstenidione . Placenta

10. Pathophysiology A. Female infants Virilization: They have a 46,XX karyotype, are SRY-negative, and have exclusively ovarian tissue. B. Inadequate virilization of male infants: This problem is caused by inadequate androgen production or incomplete end organ response to androgen. C. Disorders of gonadal differentiation True hermaphroditism. The presence of both a testis and an ovary (or ovotestes) in the same individual D. Chromosome abnormalities, syndromes, and associations.

11. ETIOLOGY Disorders of sexual development are caused by abnormal gonadal differentiation, development or function. Karyotype based classification helps in understanding the etiology of DSD and planning work-up and manager.

12. XX DSD is the commonest form of DSD. This is placental, ovarian or adrenal androgen excess. XX DSD

13. Adrenal etiology: 21 hydroxylase deficiency (21OHD), 11 hydroxylase deficiency (11OHD), 3BHSD. Aromatase deficiency and P450 oxidoreductase ( POR) deficiency are associated with maternal virlization in pregnancy. Maternal causes: Transplacental passage of androgens before 12 weeks of gestation due to luteoma of pregnancy, androgen producing tumor and androgen exposure in the mother causes genital ambiguity. Gonadal dysgenesis: XX maleness is caused by SRY gene insertion in 90% cases. The men have normal sexual development and puberty but small testis and azoospermia. SOX3, SOX9 and SOX10 over expression also causes XX maleness.

14. XY DSD XY DSD represents a wide range of disorders of testicular development, androgen production and action . Disorders of gonadal development have variable presentation with or without palpable gonads and mullerian structures. Steroidogenic defects have palpable gonads without mullerian structures reflecting normal AMH secretion. Despite significant advances in understanding the pathophysiology a large number of these cases remain unclassified.

15. Disorders of testicular development: These disorders are caused by defects in genes involved in the development of the bi-potential gonad (WT1 and NR5A1), testis (SRY and SOX9) and ovary (DAX1 over expression). Testicular regression due to fetal vascular insult results in anorchia. Mullerian structures are absent as testicular regression usually occurs after 6 weeks of gestation. These children present with small phallic size and no palpable gonads.

16. Disorders of testosterone production: These disorders are characterized by low testosterone and high gonadotropin levels. Mullerian structures are absent as AMH production is normal. Combined adreno-testicular defect: can present with salt wasting (SLO, StAR , SCC, POR and 3BHSD deficiency) or mineralocorticoid excess (17 hydroxylase deficiency). Isolated testicular steroidogenic defect due to 17BHSD III deficiency is associated with high androstenedione and low testosterone level. LHCGR (Luteinizing Hormone/Choriogonadotropin Receptor) defect is characterized by low testosterone deficiency, elevated LH and normal FSH levels. The presentation is usually as female external appearance with palpable gonads.

17. Disorders of testosterone action: DHT mediates androgen effect on external genitalia while testosterone maintains wolfian structure. 5ARDII deficiency is associated with low DHT despite high testosterone levels. Wolfian structures are normal due to preserved testosterone effect but external genitalia range from normal female to phenotypic male.

18. Androgen insensitivity syndrome (AIS) is characterized by high DHT and testosterone levels. The phenotype depends on the level on androgen resistance. Complete AIS represents the extreme form of the disease with no testosterone effect. Aromatization of testosterone during puberty results in feminization. Neonatal presentation with palpable gonads is characteristic. Mullerian structures are absent as AMH action is normal.

19. Inefficient AMH action: Decreased production or action of AMH results in persistent mullerian duct syndrome. The condition is associated with undescended testis, inguinal hernia and vas deferens entwined in mullerian structure. The condition is associated with infertility and testicular torsion.

20. SEX CHROMOSOME DSD Ovo-testicular DSD is characterized by the presence of testicular (as confirmed by seminiferous tubules) and ovarian (as confirmed by oocytes) tissue in the same individual. Gonads could be in the form of ovary and testis on different sides or ovo-testis. Genital asymmetry points to the condition. Karyotype is variable from 46 XX to 46 XX/XY and 46 XX/47 XXY.

21. ASSESSMENT DSD represents a medical and social emergency. The initial evaluation of the infant with ambiguous genitalia should include: History physical examination evaluation of the sex chromosomes. assessment of internal anatomy by ultrasound Measurement of adrenal and gonadal steroid secretion. APPROACH

22. HISTORY Virlization in mothers during pregnancy (suggesting aromatase and oxidoreductase deficiency or luteoma of pregnancy) and intake of androgenic agents (progestogens, valproate) should be noted. Family history of sibling death, consanguinity, infertility (in maternal aunts indicative of X linked AIS) and delayed puberty should be enquired. Genital ambiguity at birth is indicative of steroidogenic defects, partial ÁIS or gonadal dysgenesis. Failure to thrive, pigmentation and salt wasting crisis suggests congenital adrenal hyperplasia . Girls with primary amenorrhea and inguinal masses most likely have complete AIS or 17BHSD deficiency.

23. EXAMINATION Careful examination would help exclude normal variants like clitoromegaly due to lack of suprapubic fat, apparent micropenis due to buried penis, penile hypospadias and labial adhesion. Further examination should include identification of gonads, extent of labio-scrotal fusion, genital symmetry, number of urogenital openings and phallic size. Round, smooth gonads palpable below the inguinal ring are usually testis.

24. Ovo-testis is an irregular structure higher up around the inguinal canal. Rarely globular swelling around the inguinal region may represent prolapsed fallopian tube . Careful palpation of the inguinal canal in squatting position may be required to localize gonads. Mullerian structures can be identified using per rectal examination or pelvic ultrasound .

25. Identification of gonads and mullerian structures allows preliminary classification of DSD. Mullerian structures without palpable gonads indicates androgen excess in a girl while palpable gonad without mullerian structures should raise the possibility of androgen deficiency in a boy . Presence of both gonads and mullerian structures suggests gonadal dysgenesis or inefficient AMH action. Absent mullerian structures and gonads could be due to abdominal gonads or testicular regression syndrome.

26. Extent of labio-scrotal fusion is assessed using prader staging where stage I indicates normal female development and stage V normal male appearance. Prader Staging was developed for virlizing CAH and External Masculization score is more appropriate for XY DSD.

27. Penile length less than 2 cm and clitoral size more than 1 cm are considered abnormal. The extent of labio-scrotal fusion is assessed using anogenital ratio (ratio of distance between anus and anterior forchette to that between anus and posterior forchette ). Levels greater than 0.5 suggests virlization . The site and number of uro -genital openings are important for surgical management. Genital asymmetry points to ovo testicular DSD or mixed gonadal dysgenesis.

28. DIAGNOSTIC WORK-UP Diagnostic work-up is aimed at classification of DSD and involves ascertainment of genital sex and work-up to pinpoint the cause .

29. Initial assessment: Initial assessment depends on the time of presentation and likely clinical diagnosis. Evaluation of the sex chromosomes( Karyotype) Assessment of internal anatomy by pelvic ultrasound. Serum electrolytes. MRI abdomen and pelvis may be required in older children. Measurement of adrenal and gonadal steroid secretion. Testosterone level. Gonadal biopsy may be considered.

30. MANAGEMENT Management of DSD includes treatment of life threatening conditions, parental education, decision about gender of rearing and initiation of specific treatment. Multi-disciplinary team including : Paediatric Endocrinologist, Paediatric Surgeon, Geneticist and social worker is required.

31. IMMEDIATE MANAGEMENT: Serum electrolytes and blood glucose should be monitored and steroid replacement initiated in children with congenital adrenal hyperplasia.

32. COUNSELLING: Parental counselling should include detailed information about sexual development, the possible etiology in the child, probable gender of rearing, long term implications including fertility issues and need for medical and surgical management. The counselling should be done in a phased manner. Gender specific terms (he, she), neutral titles (it) and layman language should be avoided.

33. SPECIFIC MANAGEMENT: Specific management includes Steroid replacement in congenital adrenal hyperplasia, Testosterone in children with biosynthetic defects and topical DHT cream in 5ARDII. Gonadectomy and estrogen replacement is indicated in complete AIS.

34. GENDER OF REARING: Decision regarding gender of rearing should be taken only after extensive evaluation. This is important given the significant psychosocial impact of hormonal milieu. Key considerations include sexual and reproductive prospects and feasibility of reconstruction. Most children with XX DSD have a prospect of fertility and should be reared as females. Children with simple virilising form of CAH often present at a late stage with male gender identity and appearance. Male gender of rearing with hysterectomy may be considered in this setting. Male gender of rearing is recommended in most individuals with XY DSD with the exception of complete AIS where female gender is desirable. 

35. Surgical management: Clitoroplasty for XX DSD is done before one year of age. Early vaginoplasty has a risk of vaginal stenosis mandating resurgery . Vaginoplasty should therefore be done after puberty with regular dilatations subsequently. Severely virilised individuals with XX DSD wanting male gender of identity should undergo hysterectomy and oophorectomy, Multi-step correction for hypospadias and chordee is requirec in XY DSD. Prosthetic testis may be considered in boys with anorchia.

36. Consideration for gonadectomy: An important cause of concern in a child with gonadal dysgenesis is the risk for development of gonadal neoplasm ( Gonadoblastoma ); XY dysgenesis with abdominal testis. The risk is very low for complete AIS and gonadal biopsy after puberty could be sufficient.

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