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Disorders of sexual differentiation…A challenging girl

Disorders of sexual differentiation…A challenging girl. Dr.MARWA AL-QUDHAIBY MD,KBIM,FRCP,SF-ENDO. The challenging girl. A18 -year-old girl consulted for investigation of 1°amenorrhea

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Disorders of sexual differentiation…A challenging girl

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  1. Disorders of sexual differentiation…A challenging girl Dr.MARWA AL-QUDHAIBY MD,KBIM,FRCP,SF-ENDO

  2. The challenging girl • A18 -year-old girl consulted for investigation of 1°amenorrhea • P/E:- female , 178 cm, 72 kg, with tanner stage 3-4 breast development and infantile external genitalia with a normal clitoris. - speculum and bimanual examination couldn’t be performed. - Upon abdominal examination ,no masses were palpable. • Labs :high gonadotropins and low level of sex steroids. • Karyotype :46,XY. • U/S: small uterus,unvisualised ovaries or any other masses. • Diagnostic and operative laparoscopy : • streak ovaries -> bilateral gonadectomy-> Histological examination -> streak ovaries without neoplasia. • Diagnosis: PURE GONADAL DYSGENESIS • Postoperatively : HRT treatment

  3. The Kuwaiti DSD Committee • To enhance the quality of life of DSD and their parents by effectively utilizing all the resources in an integrated care model based on Multi-Desiplinary Team(MDT). • Established 2003 • The national DSD registry –MOH • Revision of guidelines and protocols 2006,2008 and 2013

  4. Staisitics of Kuwait DSD committeetotal number 2003-2013 is 108 cases1

  5. Agenda • Introduction: • Definition • Nomenclature • Classification of DSD • Epidemiololgy • Embryology of normal sex differentiation process • Clinical features of DSD • Management: • MDT • Gender assignment • Malignancy risk assessment • Psychological back-up and support group

  6. Definition and general management • Any problem in which the genitalia are atypical in relation to the chromosomes or gonads 2 . • The Chicago Consensus conference in 2005 3: • Abnormal sex chromosome DSD • Normal sex chromosome DSD

  7. 331 min

  8. Epidemiology • Genital anomalies :1 in 300 births. 2 • complex anomalies :1 in 5000 births. 4 • A study of 266 patients with primary amenorrhea showed that 3.4% were XY females . 5 • Congenital adrenal hyperplasia (CAH) and mixed gonadal dysgenesisare the most common causes of ambiguous genitalia, constituting approximately over 50% of all cases of genital ambiguity in the newborn period 6

  9. Percentage of DSD per diagnosis among our population(2003-2013)1

  10. Number of DSDs per diagnosis1

  11. Embryology7

  12. XY female:Gonadaldysgenesis8

  13. XY female 8

  14. XX Male 8

  15. Abnormal karyotype 8

  16. MDT8 • Neonatologist or General Paediatrician • Paediatric Endocrinologist • PaediatricRadiologist • Paediatric Urologist • MDT PaediatricSpecialist Nurse • Clinical Psychologist • Clinical Endocrine Biochemist • Clinical Geneticist • Gynaecologist • Adult Endocrinologist

  17. Professionalism-based model9

  18. History2 • Ambiguity, hirsutism • Precocious puberty, amenorrhea, • Infertility, • Unexplained sudden infant death, or consanguinity. • Maternal exposure to hormones including the assisted reproductive techniques and the oral contraceptives during pregnancy • Prenatal androgen exposure is clearly associated with psychosexual development

  19. Physical Examination2 • Any abnormal virilized or cushingoid appearance of the mother . • Clinical features of associated anomalies like impaired hemodynamics. • Through a rectal exam, to confirm the presence of a uterus and cervix. • Criteria of physical findings suggestive of DSD include: • Overt genital ambiguity (e.g., cloacalextrophy); • Apparent female genitalia with an enlarged clitoris and posterior labial fusion (e.g., CAH); • Apparent male genitalia with bilateral undescended testes, hypospadias, or micropenis; and • Discordance between genital appearance and a prenatal karyotype .

  20. External MuscularizationScore 10

  21. Laboratory tests

  22. QF of FISH and banking11

  23. Laboratory tests 2,12 • Steroid metabolites to r/o CAH including : • Screen newborns for CAH by use of filter-paper blood spot 17-hydroxyprogesterone measurements • Liquid chromatography linked with tandem mass spectrometry (LC-MS/MS) • Urinary steroid profile analysis by gas chromatography mass spectrometry (GC-MS) • Androgen levels • Gonadotropins • Tumor markers like a-FP,hCG8,Ca-125,m-RNA, high-risk SNPs • Anti- müllerian hormone

  24. AMH 8

  25. Localization • U/S 2 : • Female internal organs and possible adrenal anomalies. inguinal gonads and mülleriananatomy. • limited accuracy in intra-abdominal testes • MRI is the study of choice 13 : • with accuracy 100% for evaluation of Mullerian anomalies and testes position by sagittal and transverse T2-weighted images and T1-weighted images • But of less value for intra-abdominal testes or streak gonads. • MRI is important to plan gonadectomy and is used with tumor markers, for patients who refuse surgical removal of the testes in follow-up • Genitoscopy8 : • length of the urogenital sinus, the associated Mu¨llerianstructures and the relationship of the urethra and its sphincter. • Laparoscopy 2 : • facilitates direct inspection,mobilization , biopsy or excision of intra-abdominal gonads. • can only visualize intraperitonealstructures

  26. HCG stimulation test 6

  27. Disclosure of diagnosis 14 • To give true informed consent and cooperation for investigations, treatments such as, for example, timing of gonadectomyand type of genital surgery., genetic testing and research. • To seek support and information from other affected individuals, and to allow for family screening. • Done gradually in childhood and adolescence • Parents are also told that the team will help them educate their child about their DSD, including the basis for gender assignment, as he or she matures.

  28. Gender assignment • Influencing factors 15 : • Diagnosis • Genital appearance • Diagnosis-specific psychosexual outcome • Fertility potential • Therapeutic/ surgical options • Familial views or circumstances relating to cultural biases and the

  29. Gender assignment 15

  30. SURGICAL MANAGEMENT OF AMBIGUOUS GENITALIA11,14 • Surgical corrections usually concern : • the gonads • the outer genitalia • the urogenital sinus • Three main steps in feminizing surgery: clitoroplasty, vaginoplasty, and perineoplasty (labioplasty) • The aims of surgery: • to make ambiguous external genitalia compatible with assigned gender • To prevent urinary obstruction or infections • To preserve sexual and reproductive potentials • To relieve parental distress and improve attachment between the child with DSD and the family.

  31. Timing of surgery 2,14 • American Academy of Pediatrics :early surgical treatment, between 2 and 6 months of age: • Better quality of genital tissues,bettervascularization secondary to postnatal maternal oestrogens. • Reduction in the anxiety of parents and children regarding the appearance of their external genitalia . • Preventing potentially harmful effects from the communication between the urinary tract and peritoneum through the fallopian tubes. • Alleviating the risks of stigmatization and gender-identity confusion. • Some studies have demonstrated satisfactory outcomes from early surgery . • Detractors of early surgery base their approach on the concern that: • Insufficient evidence that early surgery benefits gender identity, • Potential impairment in clitoral sensitivity and • High rates of revision for repetitive corrective surgery . • Lack of urgency ,wait for the child’s consent • Improve compliance with postoperative treatment .

  32. Risk of malignancy 12

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  34. Medical and psychological treatment • Medical treatment2 • Corticosteroid replacement in SW CAH • Hormonal replacement therapy • Psychological support 11 • With ongoing counseling to identify maladaptive coping strategies • A Danish study shows that suicidal thoughts and psychological and psychiatric counseling is more abundant among patients with disorders of sex development than in normal females . • The point of transfer from paediatric to adult services offers an ideal opportunity for a routine assessment of the need for clinical psychology input. • Support group

  35. Fertility • Generally subfertility-infertility • Fertility potential is variable according to the severity and the concordance between the sex of rearing and the gonads • Highest fertility is in patients XX or XY CAH, especially nonclassicCAH 16 • Infertility is mainly due to anovulation and arrested folliculogenesis,gonadaldygenesis,premature ovarian failure,cryptorchidism and streak gonads in females andtesticular adrenal rest tumors (TARTs) ,suppression of the hypothalamic-pituitary-gonadal axis by high systemic levels of androgens histology ,azospermia and hypospadias .17 • Fertility can be improved by ART

  36. Challenges in DSD • DSDs are challenging disorders,the molecular basis of many DSD is still mysterious • The complexity of the problem requires early individualized management by well integrated multidisciplinary team,whose dynamics is complex • The availability of the the national registry of DSD cases necessiates collaboration between different health care facilities • Fertility potential is limited ,improved by assissted techniques • Social stigmatism and ethical issues mandate a proper education and a skillful psychological support

  37. References • (1)The national resistry of kuwaiti DSD committee ;2013 • (2)Kun Suk Kim, Jongwon Kim; Korean J Urol 2012;53:1-8 • (3)HoukCP, Hughes IA, Ahmed SF, Lee PA; Pediatrics 2006;118:753-7 • (4) Blackless M, et al ;Am J Hum Biol2000;12:151-66 • (5) Reindollar RH, Tho SPT, McDonough PG.. Trans Am GynecolObstetSoc8:146–162. • (6) Thyen U, Lanz K, Holterhus PM, HiortO;Horm Res 2006;66:195-203 • (7) Kenichi Kashimada1 and Peter Koopman; Development 137, 3921-3930 (2010) • (8) UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development ;S. Faisal Ahmed,etal;Clinical Endocrinology (2011) 75, 12–26…. • (9)Advances in Urology;J¨urg C. Streuli et al,volume2012, Article ID 185787, 8 pages • (10) Ahmed, S.F. et al (2000). British Journal of Urology International, 85, 120–124. • (11) Pernille Bach Jorgensen;FertilSterily2010;94:105–13. • (12) Yvonne G. van der Zwan et al;EUROPEANUROLOGY 6 7 ( 2 0 1 5 ) 6 9 2 – 7 01 • (13) Ahmed Mohammed SamyEl-Agwany;TheEgyptian Journal of Radiology and Nuclear Medicine (2016) 47, 607–609 • (14) LinaMichala; Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 139–148 • (15) Blake W. et al , Journal of Pediatric Urology (2012) 8, 7e16 • (16) Claahsen-van der GrintenHL et al;. J PediatrEndocrinolMetab 2006;19:677e85. • (17) J.P. Van Batavia, T.F. Kolon; Journal of Pediatric Urology (2016) 12, 418e425

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