DISORDERS OF SEXUAL DIFFERENTIATION by Anena.pptx

Summarised normal sexual differentiation and the disorders

1. DISORDERS OF SEXUAL DIFFERENTIATION sexual ambiguity and intersex Presenters: DR. ANENA DR. OPIO Lecturer: DR.ODONGKARA BEATRICE

2. CONTENTS EPIDEMIOLOGY NORMAL SEXUAL DETERMINATION AND DIFFERENTIATION DISORDERS OF SEXUAL DIFFERENTIATION SEXUAL AMBIGUITY CLINICAL APROACH MANAGEMENT COMPLICATIONS REFERENCES

3. INTRODUCTION Disorders of Sex Differentiation (DSD) is defined as a condition in which the chromosomal sex is different from the phenotypic sex. This implies that the phenotypic sex cannot be classified as either male or female In Africa, where high premium socioeconomic value is placed on children (and in some culture, male children), the birth of a child brings relief of met expectations but when sex assignment becomes difficult or ambiguous, intense parental anxiety and problems of sex of rearing and in the future, problems of sex identity occur. This situation may set the template for intense social pressure, family strains and child abuse.

4. EPIDEMIOLOGY In Ghana, the incidence rate of DSD was 28 per 10 000 with only three of the infants diagnosed with 46 XY while a prevalence rate of 52.5% of 46 XY was reported among children with DSD in India. ( Ameyau et al, 2019) In Denmark, an incidence rate of 6.4 per 100 000 live-born females with 46 XY disorder was reported. The incidence of Congenital adrenal hyperplasia (CAH) and (mixed gonadal dysgenesis )MGD worldwide is 1:15,000 and 1:10,000, respectively, but varies considerably among different populations. ( E.emeyau et al)

5. Epidemiology Congenital adrenal hyperplasia (CAH) and mixed gonadal dysgenesis (MGD) are the most common causes of ambiguous genitalia, constituting approximately over 50% of all cases of genital ambiguity in the newborn period In a study in Kenya, A total of 44 patients were identified, 3 with cloacal exstrophy. Of the 41 remaining patients, the majority (n = 24) had ovotesticular DSD.(Eric Hansen et al, 2022) In a Kenyan study, The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common (Prisca Amolo et al, 2019)

6. Normal sexual determination and differentiation The undifferentiated human embryos of the two sexes differ only by their karyotypes. The sex-determining region on the Y chromosome (SRY) gene residing in the Y chromosome has now been documented as the mammalian sex-determining gene, which actively induces the formation of the testis and the male phenotype during embryonic life The gonads, internal genitalia (genital ducts) and the external genitalia, which are all bipotential are influenced by several genes and other factors necessary for sexual differentiation

7. Normal sexual determination and differentiation GONADS The gonads in the embryo remain undifferentiated until the sixth week of gestation. Subsequent development into either a testis or ovary is directed by the genetic sex (XY or XX). The testis develops more rapidly than the ovary. Fetal testicular differentiation begins in the seventh week of gestation , whereas ovarian development begins not earlier than the 16th week of gestation Female sex differentiation is not dependent on ovarian hormones, but there is evidence that Wnt signaling molecules play a role in Müllerian duct development and suppression of Leydig cell differentiation in ovary

8. Normal sexual determination and differentiation Testicular differentiation The SRY gene (with 204 amino acids) located on the short arm of Y chromosome (Yp11.3) is the trigger for testicular differentiation , by inducing development of Sertoli cells and subsequently, seminiferous tubules and Leydig cell formation in that order. The sex-determining region on the Y chromosome activates the following genes to induce differentiation of the bipotential gonad into a testis SOX 9 (SRY-homeobox-like gene) Autosomal gene (chromosome 17q24 ) Steroidogenic factor (SF1)

9. Normal sexual determination and differentiation Ovarian Differentiation Genes currently known to suppress testicular differentiation include: DAX 1 SOX 3 Wnt 4 DAX 1 and SOX 3 inhibit SF 1 and SOX 9 , preventing Sertoli cell differentiation, favoring granulosa cell development. Wnt 4 arrests the Leydig cell precursors and induces development of Müllerian ducts into Fallopian tubes, uterus, cervix and upper third of vagina. Though the effects of these genes have been considered to result in ovarian differentiation, it should be remembered that active testicular differentiation occurs much earlier when compared to the ovarian.

10. Normal sexual determination and differentiation Internal Genitalia Testosterone initially under the control of human chorionic gonadotropin is produced locally (paracrine) by Leydig cells of the fetal testis on either side. It helps in ipsilateral differentiation of the Wolffian ducts into epididymis, vas deferens, seminal vesicles and ejaculatory ducts. Anti-Müllerian hormones (AMH) secreted by the Sertoli cells cause ipsilateral involution of the Müllerian structures

11. Normal sexual determination and differentiation INTERNAL GENITALIA In female fetuses, Wolffian structures regress in the absence of testosterone and Müllerian ducts persist in the absence of (Anti-Müllerian hormones ) AMH. However, Wnt 4 gene appears to play an important role in Müllerian duct differentiation and fetal ovarian function

12. Normal sexual determination and differentiation External Genitalia From the initial undifferentiated stage of the external genitalia, masculinizing features develop in the male under the influence of dihydrotestosterone (DHT) formed peripherally from testosterone by the action of 5α-reductase. This process is dependent on an adequate number of functioning androgen receptors in the pubic skin. Formation of the female external genitalia does not require any active process and will persist with normal ovaries, in androgen insensitivity or even in the absence of gonads, sex chromosome abnormalities, streak gonads or non-functioning testes.

13. Normal sexual determination and differentiation

14. Normal sex determination and differentiation

15. ETIOLOGY OF DSD Excessive androgens producing virilisation in a female (the commonest cause of this is congenital adrenal hyperplasia) Inadequate androgen action, producing under virilisation in a male this can result from: inability to respond to androgens (a receptor problem-androgen insensitivity syndrome, which may be complete or partial) Inability to convert testosterone to dihydrotestosterone (5-α reductase deficiency) Abnormalities of the synthesis of androgens from cholesterol.

16. ETIOLOGY Gonadotrophin insufficiency, also seen in several syndromes such as Prader–Willi syndrome and congenital hypopituitarism, which results in a small penis and cryptorchidism Ovotesticular disorder of sex development (DSD) (previously known as true hermaphroditism), caused by both XX and Y containing cells being present in the fetus leading to both testicular and ovarian tissue being present and a complex external phenotype.

17. Abnormalities of sexual differentiation

18. Abnormalities of sexual differentiation

19. Ambiguous Genitalia Ambiguous genitalia may be defined as discordance between the external genitalia and the gonads If the genotype is XX, and the impalpable gonads are ovaries, but the external genitalia are virilized partially or fully, this is likely to be due to the exposure of a female fetus to excessive androgens during the period of sexual differentiation in early gestation E.G, CAH due to 21-hydroxylase deficiency, 11-β hydroxylase deficiency, 3-β hydroxysteroid dehydrogenase deficiency or maternal androgen excess due to a tumor or therapy

20. CAUSES OF VIRILIZATION IN THE FEMALE

21. AMBIGUOUS GENITALIA The most common cause of ambiguous genitalia is 21-hydroxylase deficiency in genetic females. ( Congenital virilizing adrenal hyperplasia ) There is impaired synthesis of glucocorticoids, but does not affect androgen production. The impaired cortisol secretion leads to adrenocorticotropic hormone (ACTH) hypersecretion, which stimulates hyperplasia of the adrenal cortex and excessive adrenal production of androgens

22. 46,XX Disorders of Sexual Development Masculinization of the external genitalia of genotypic females (except for isolated enlargement of the clitoris, which can occur from later androgen exposure) is always caused by the presence of excessive androgens during the critical period of development (8-13 weeks of gestation) The degree of virilization can range from mild clitoral enlargement to the appearance of a male phallus with a penile urethra and fused scrotum with raphe.

23. Ambiguous Genitalia If the genotype is XY, the gonads which are palpable are testes and the external genitalia is incompletely virilized or ambiguous, this may be due to a testosterone biosynthetic defect If the external genitalia is completely female, this may be a case of complete androgen insensitivity syndrome. If both ovarian and testicular tissues are present either in the same gonad (ovotestis) or opposite gonads—one gonad may be palpable or both gonads impalpable— this may be a case of ovotesticular DSD

24. 46,XY Disorders of Sexual Development CHARACTERISTICS The penis is small Various degrees of hypospadias (penile or perineal) Associated chordee or ventral binding of the phallus Unilateral, but more often bilateral, cryptorchidism may be present. The testes should be sought carefully in the inguinal canal or labioscrotal folds by palpation or ultrasound. Rarely a palpable gonad in the inguinal canal or labioscrotal fold represents a herniated ovary or an ovotestis. NB: Swyer syndrome (XY complete gonadal dysgenesis)

25. AMBIGUOUS GENITALIA

26. CAUSES OF INADEQUATE MASCULINIZATION IN MALES

27. Complete Form Of Androgen Resistance ( androgen insensitivity syndrome ) Is the most dramatic example of resistance to hormone action by defects in the androgen receptor. Affected patients have: a 46,XY karyotype normally formed testes (usually located in the inguinal canal or labia majora) female external genitalia with a short vagina and no internal müllerian structures. At the time of puberty, testosterone concentrations increase to normal or above normal male range. Because a portion of the testosterone is normally converted to estradiol in peripheral tissues and the estrogen cannot be opposed by the androgen, breast development ensues at the normal age of puberty without growth of pubic, facial, or axillary hair or the occurrence of menstruation .

28. 5α- Reductase deficiency 5α- Reductase deficiency presents at birth with predominantly female phenotype or with ambiguous genitalia, including perineoscrotal hypospadias. The defect is in 5 α reduction of testosterone to its metabolite DHT. At puberty, spontaneous secondary male sexual development occurs.

29. Sex Chromosome and Ovotesticular Disorders of Sexual Development Turner syndrome Klinefelter syndrome Mixed gonadal dysgenesis (45,X; 46,XY) often may present with genital ambiguity, asymmetric external genitalia, and inguinal hernias

30. Turner syndrome

31. Klinefelter syndrome

32. CLINICAL APPROACH Clinical evaluation of the infant with a suspected DSD should be done to The major goal is a rapid identification of any life-threatening disorders (salt loss and shock caused by the salt-losing form of CAH) Decide assignment of sex Plan the long-term management of the infant’s condition.

33. HISTORY TAKING History taking should include: Details regarding parental consanguinity Maternal drug intake History of previous sibling deaths due to salt loss in the neonatal period Affected siblings or family members with DSD History of low-birth weight or intrauterine growth retardation X-linked mode of inheritance (in cases of androgen insensitivity).

34. Physical assessment Should include; Examination for dysmorphic features, midline defects in cases of microphallus due to pituitary defects Hypo- or hypertension Dehydration Virilization in case of girls Undervirilization in case of boys Presence or absence of gonads Hyperpigmentation of the skin

35. Physical assessment It is essential to note where the urethral opening lies and whether there is fusion of the anterior portion of the labioscrotal folds. If the vaginal opening is normal, and there is no fusion, but the clitoris is enlarged without ventral fusion of the ventral urethra, the patient likely had later exposure to androgens. In a patient with a fully formed scrotum, even if small, and a normally formed but small penis, termed a microphallus , the patient likely had normal exposure to and action of androgen during 9-13 weeks of gestation.

36. INVESTIGATIONS INVESTIGATION REMARK Serum sodium and potassium Hyponatremia , hyperkalemia Blood glucose May be normal or derranged Arterial blood gases May be deranged in CAH due to metabolic acidosis Serum 17-hydroxyprogesterone High in CAH (>5000ng/dl) Plasma rennin activity High in case of adrenal disorders; Addissons disease, primary aldosteronism Serum cortisol Low in adrenal insufficiency Serum dehydroepiandrosterone(DHEA) Low in adrenal insufficiency High in androgen secreting adrenal tumors

37. INVESTIGATIONS INVESTIGATION REMARK Serum testosterone May be high in androgen insensitivity syndrome, females with DSD Ultrasound pelvis and abdomen the presence of uterus or cervix or of testes in the inguinal region or abdomen Retrograde genitogram To determine the anatomy of the urogenital sinus, and identify location of the vagina, uterus and bladder. It involves introducing contrast medium into the urogenital opening and using x.rays ()fluoroscopy to visualize structures Karyotype Determine karyotypes Laparoscopy Clear, real time view of the gonads and sex dcts which are difficult to locate with ultrasound plasma concentration of androstenedione VERY ELEVATED

38. Pelvic ultrasound Pelvic ultrasound determines, the presence of uterus or cervix or of testes in the inguinal region or abdomen

39. DIAGNOSTIC CHANNELS

40. DIAGNOSTIC APPROACHES

41. DIAGNOSTICS CHANNELS

42. DIAGNOSTIC CHANNELS

43. MANAGEMENT It is often the responsibility of the pediatric endocrinologist or primary care physician to inform the parents of an infant born with uncertain sex and to discuss with them in detail about: The nature of the defect observed The need for the investigations to establish the diagnosis The sex of rearing best suited for the infant. Multidisciplinary team is ideal, With pediatric endocrinologist, neonatologist, family pediatrician, pediatric surgeon or urologist, gynecologist, radiologist, ultrasonologist, biochemist, cytogeneticist, pediatric psychologist/psychiatrist as well as nursing colleagues and social workers.

44. MANAGEMENT Support group of parents with similarly affected children will also be helpful. Most importantly, the parents should be included in all discussions concerning the evaluation and management of the infant with a DSD. It is always important to collect together all possible evidence for arriving at a diagnosis and then have discussions with the parents. Although urgency is still necessary, most parents will be willing to wait for a few days longer before making their decision about their child’s future.

45. Management Until the decision is made, it is better to refer to the infant as “baby”, and not as “he” or “she” Recommendations for assignment of sex in an individual with fully virilized male external genitalia and presence of female internal sex structures are still controversial. Reconstructive surgery for hypospadias is needed in those with 5α-reductase deficiency at the time of puberty.

46. Management Assignment of a female sex to an individual with microphallus and fused scrotum is being reconsidered and not always accepted today by many. Testosterone therapy is recommended for microphallus and fused scrotum Experts recommend waiting until the child is able to be part of the dialogue regarding gender identity and reconstruction when appropriate

47. MANAGEMENT Karyotype determination is only one of many factors needed to assist the family in the decision of sex of rearing. NB: T he SRY gene may be found on chromosomes other than the Y chromosome, and, conversely, a Y chromosome may lack an SRY gene (it may have been translocated to an X chromosome, leading to the development of a 46,XX male-XX sex reversal, testicular DSD)

48. karyotyping

49. Other genetic tests

50. SURGERY Surgical restoration to make the individual look more appropriate for the gender of rearing, and psychological support of the whole family. Gonads and internal organs discordant for the gender of rearing may be removed. Dysgenetic gonads with Y-genetic material always should be removed because gonadoblastomas or dysgerminomas may develop in the organ. Age at which reconstructive surgery is recommended is controversial; some advocate that surgery not be performed in infancy or early childhood so that the child or young adolescent can be involved in the decision.

51. HORMONAL REPLACEMENT THERAPY Replacing deficient hormones (cortisol in adrenal hyperplasia or testosterone in a child with androgen biosynthetic defects who will be raised as male)

52. examples

53. Examples

54. Complications Neonatal salt wasting (from CAH) Gonadal tumors Infertility Psychological issues related to gender identity Delayed puberty Precocious puberty Congenital heart diseases eg Turner syndrome is associated with higer incidence of congenital heart disease Higher incidence of autism spectrum disorders

55. Recommendations There is a need to train health care workers/medical students for early diagnosis. A national guideline should be developed for diagnosis and management of DSD during and beyond the paediatric age group, and this should be re evaluated and modified regularly according to emerging evidence and available resources. Every child with DSD should have a karyotype done.

56. Conclusion The management of Disorder of Sex Differentiation places a huge burden on both the parents and the healthcare providers. The availability of sound interdisciplinary collaborations, necessary diagnostic facilities and provision of psychosocial support to parents are essential.

57. References Nelson text book of pediatrics 21 st edition IAP Text book of pediatrics Medscape Nasir AA, Abdur -Rahman LO, Adesiyun OO, Bamigbola KT, Adegboye MB, Raji HO, et al. Analysis of presentations and outcomes of care of children with Disorders of Sexual Development in a Nigerian Hospital. J Pediatr Adolesc Gyn 2019; 32(1): 21-26. Swyer syndrome. Genetic Home Reference 2015. Available at http://ghr.nlm.nih.gov/condition/swyer

58. References Management of Differences in Sexual Development: Evolution of an Approach for a Resource-Limited Setting Erik Hansen, 2022 Amolo et al.