Disorders Sex Development

brief ,illustrated presentation about disorder of sex development in paediatrics

1. Disorders of Sex Development [DSD] Presented by: Dr . Mona Mohammed Ali

2. Introduction: Disorders of sex development (DSDs), formerly termed intersex conditions, are seen in infants who are born with ambiguous or abnormal genitalia and may have indeterminate phenotypic sex. 

3. Classification: In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) published new classification. Previous Term Revised Term Female pseudohermaphrodite 46,XX DSD Male pseudohermaphrodite 46,XY DSD True hermaphrodite Ovotesticular DSD XX male 46,XX testicular DSD XY sex reversal 46,XY complete gonadal dysgenesis

4. As examples, classifications of sex chromosome DSD include the following: 45,X (  Turner syndrome  and variants) 47,XXY (  Klinefelter syndrome  and variants) 45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD) 46,XX/46,XY (chimeric, ovotesticular DSD)

5. Classifications of 46,XY DSD include the following: Disorders of testicular development (complete and partial gonadal dysgenesis) Disorders of androgen synthesis (complete and partial  androgen insensitivity , disorders of antimüllerian hormone [AMH]/receptor, androgen biosynthesis defect) Other (severe  hypospadias ,  cloacal exstrophy

6. Classifications of 46,XX DSD include the following: Disorders of ovarian development (ovotesticular DSD, testicular DSD, gonadal dysgenesis) Androgen excess (fetal [eg,  congenital adrenal hyperplasia  (CAH)], fetoplacental, maternal) Other (  vaginal atresia , cloacal exstrophy)

7. History: Evaluation of a newborn with ambiguous genitalia requires a team effort. The most common disorder of sex development (DSD),  congenital adrenal hyperplasia  (CAH), results in virilization of a 46,XX female and thus is classified under the heading of 46,XX DSD. The clinician's challenge is to distinguish CAH from other, less common causes of ambiguous genitalia. A detailed family history is essential; the following considerations should be kept in mind: A family history of genital ambiguity, infertility, or unexpected changes at puberty may suggest a genetically transmitted trait .Recessive traits tend to occur in siblings, whereas X-linked abnormalities tend to appear in males who are scattered sporadically across the family history A history of early death of infants in a family may suggest a previously missed adrenogenital deficiency Maternal drug ingestion is important, particularly during the first trimester, when virilization may be produced exogenously in a gonadal female Although extremely rare, a history of maternal virilization may suggest an androgen-producing maternal tumor (arrhenoblastoma)

8. Physical Examination: Certain physical characteristics may suggest the directions toward which a successful investigation might be pursued. Examination of the external genitalia should include the following : Note the size and degree of differentiation of the phallus, since variations may represent clitoromegaly or hypospadias Note the position of the urethral meatus Labioscrotal folds may be separated or folds may be fused at the midline, giving an appearance of a scrotum . Labioscrotal folds with increased pigmentation suggest the possibility of increased corticotropin levels as part of adrenogenital syndrome

9. Physical Examination: Gonadal examination should include the following: Documentation of palpable gonads is important; although ovotestes have been reported to descend completely into the bottom of labioscrotal folds, in most patients, only testicular material descends fully. If examination reveals palpable inguinal gonads, diagnoses of a gonadal female,  Turner syndrome , and pure gonadal dysgenesis can be eliminated Impalpable gonads, even in an apparently fully virilized infant, should raise the possibility of a severely virilized 46,XX DSD patient with CAH. Rectal examination should include the following: Rectal examination may reveal the cervix and uterus, confirming internal müllerian structures The uterus is relatively enlarged in a newborn because of the effects of maternal estrogen, permitting easy identification

10. Differential Diagnosis: 1. 3-Beta-Hydroxysteroid Dehydrogenase Deficiency 3. 5-Alpha-Reductase Deficiency 5. Androgen Insensitivity Syndrome 7. Congenital Adrenal Hyperplasia 9. Denys- Drash Syndrome 11. Gender Identity 13. Genital Anomalies 15 . Precocious Puberty 2. Gonadoblastoma 4. Hypogonadism 6. Hypospadias 8. Menstruation Disorders in Adolescents 10. Microphallus 12. Paediatric Hydrocele and Hernia Surgery 14. Paediatric Hypopituitarism 10

11. Workup: Lab tests: A logical workup in infants with ambiguous genitalia includes the following: Chromosomal analysis Endocrine screening Serum chemistries/electrolyte tests Androgen-receptor levels 5-Alpha-reductase type II levels Antimüllerian hormone (AMH)/müllerian-inhibiting substance (MIS) level

12. Workup: Renal/bladder ultrasonography (US). . In a neonate, ambiguous genitalia, enlarged adrenal glands, and evidence of a uterus are virtually pathognomonic for CAH. Genitography helps determine ductal anatomy. Computed tomography (CT) and magnetic resonance imaging (MRI) are usually not indicated but may help identify internal anatomy. Cystourethroscopy. Open exploration, though rarely used nowadays, Laparoscopy under  general anesthesia to identify the exact anatomy and biopsy the gonads

13. Management: Approach Considerations Factors to consider when planning for definitive management of disorders of sex development (DSDs) include the following: Phenotype Functional potential of the external and internal genitalia Tumor risk of the gonads Fertility potential Psychosexual issues (gender identity and sexual orientation)

14. Medical Care: Medical therapy for DSDs depends on the underlying cause and is indicated for the conditions associated with ambiguous genitalia, including  congenital adrenal hyperplasia  (CAH). Supplemental hormone therapy may be implemented if gonadal function is compromised.

15. Surgical Care: There remains considerable controversy surrounding the treatment of DSDs.  In a virilized female, the surgical procedure is termed feminizing genitoplasty and includes vaginoplasty, labiaplasty, and clitoroplasty (see the images below ).   The optimal timing of feminizing genitoplasty has not been determined.  

16. Patient with congenital adrenal hyperplasia (CAH; 46,XX DSD). Note phalluslike clitoris and empty scrotal appearance of labia majora . Same patient with congenital adrenal hyperplasia (CAH; 46,XX DSD), after feminizing genitoplasty surgery. Note achievement of three components of surgery: clitoroplasty, vaginoplasty. and labiaplasty. Upper catheter is in urethra

17. Undervirilized males typically have hypospadias requiring surgical reconstruction. The limited data available on the timing of reconstructive hypospadias surgery derive mainly from reconstructive studies and expert opinion; until more and better data become available, it may be reasonable to advocate early surgery, between the ages of 6 and 18 months.     Gender reassignment may be considered in patients with 46,XY DSD and genital inadequacy. Surgical Care:

18. Consultations: The following consultations may be obtained: Genetics/genetic counseling Endocrinology Pediatric gynecology Pediatric urology Psychology Social work

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