disorders of sex development

1. DISORDERS OF SEX DEVELOPMENT AND
MANAGEMENT OF
CONGENITAL ADRENAL HYPERPLASIA
-Dr.K.Navanitha Reddy
-Dr.Arnab Sengupta

2. DEFINITION
• DSD (intersex): Defined as condition in which development of
chromosomal, gonadal, (or) anatomical sex is atypical
• Ambiguous(atypical) genitalia: When the external genitalia do not
have the typical anatomic appearance of normal male or female
genitalia, the condition is known as ambiguous genitalia

3. • Sexual differentiation: is the process of development of the
differences between male and female from an undifferentiated zygote
(fertilised egg).
• The term “gender” describes those characteristics of females and
males that are largely socially created, whereas “sex” encompasses
those characteristics that are biologically determined.

5. gonadal sex (primary sex determination)
 Whether the gonads develop as testes or ovaries. Depends on the
presence or absence of the SRY gene, usually found on the Y chromosome
 If SRY present in the indifferent gonad at 7 weeks, it gets activated. This in
turn activates other genes(SF1, SOX9 MAP3K1,DMRT1 DHH, ATRX,
TSPYL1), and the indifferent gonad is converted to a testes

6. gonadal sex (primary sex determination)
• In the absence of SRY, a different set of genes(RSPO1 WNT4,DAX1) is
activated, and the indifferent gonad becomes an ovary. Ovary
development is active process
• The germ cells, which actually become sperm or eggs, migrate into the
gonad about this time.

8. phenotypic sex (secondary sex determination)
 All of the internal and external structures develop along male or female lines
depending on which hormones are secreted by the gonads

12. WHEN TO SUSPECT DSD?
Neonatal period:
 A penis and bilaterally non palpable testes
 Unilateral cryptorchidism with hypospadias
 Penoscrotal or perineoscrotal hypospadias, with or without microphallus,
even if the testes are descended

13. WHEN TO SUSPECT DSD?
Neonatal period:
 Apparently female appearance with enlarged clitoris or inguinal
hernia
 Overtly abnormal genital development such as cloacal exstrophy
 Asymmetry of labioscrotal folds, with or without cryptorchidism
 Discordance of external genitalia with prenatal karyotype

14. HISTORY

15. MATERNAL DRUG EXPOSURE DURINGPREGNANCY
 Androgens-testosterone, danazol
 Drugs that interfere with androgen synthesis or action
-Finasteride
-Spironolactone
 Antiseizure medications
-Phenytoin
-Trimethadione

16. MATERNAL VIRILIZATION DURING PREGNANCY
 Due to poorly controlled maternal CAH
 Virilizing adrenal or ovarian tumor
 Placental aromatase deficiency

17. PLACENTAL INSUFFICIENCY
 First-trimester synthesis of testosterone in the fetal testis is
dependent on placental hCG due to its activation of the LH receptor

18. PRENATAL FINDINGS
 Genital ambiguity
 Sex chromosome mosaicism
 A karyotype discordant with phenotypic sex
 Associated conditions
-Oligohydramnios
-Renal anomalies (genitourinary malformations)
-Skeletal abnormalities (campomelic dysplasia)

19. FAMILY HISTORY
 CAH
 Atypical genitalia (severe degrees of hypospadias or
cryptorchidism
 Infertility
 Pubertal delay

20. FAMILY HISTORY
 Corrective genital surgery
 Genetic syndromes, or consanguinity.
 Neonatal death or unexplained death with features
such as vomiting/shock/dehydration in family may suggest
undiagnosed CAH

21. PHYSICAL EXAMINATION

22. EXTERNAL GENITALIA
 The examiner should note the stretched penile length, width of the
corpora
 Presence of chordee
 Position of the urethral orifice
 Presence of a vaginal opening
 Pigmentation and symmetry of the scrotum or labioscrotal folds

23. EXTERNAL GENITALIA
 The normal full-term male infant penile
-Length of at least 2.5 cm
(Measured stretched from the pubic ramus to the tip of the glans)
-Usually 1 cm or more in width
 Normal full-term female infant clitoris
-<1 cm in length
-<0.5 cm in width
 Posterior fusion of the labioscrotal folds is assessed by determining
the Anogenital ratio >0.5 indicates first-trimester androgen
exposure

24. GONADAL SIZE, POSITION, AND DESCENT
 A gonad below the inguinal ligament is usually a testis
-Normal or dysgenetic
 Ovotestis
 Uterus herniating into the inguinal canal
 abnormal genital development with bilateral non palpable gonads
should raise immediate concern for salt-wasting CAH

25. ASSOCIATED ANOMALIES
 Additional features may indicate a more generalized disorder,
although such features may not be present at birth
 WAGR-due to mutations of WT1 (11p13)
 Denys – Drash syndrome

26. ASSOCIATED ANOMALIES
 Smith – Lemli – Opitz,
 Robinow’s
 Goldenhar’s syndromes
 Campomelic dysplasia (SOX9 mutations); and trisomy 13

33. End organ resistance to testosterone

34. INVESTIGATIONS
 Serum electrolytes
 blood urea nitrogen (BUN), and creatinine
 First-line testing- 17-hydroxyprogesterone, LH, testosterone
 Other tests such as plasma renin activity, follicle-stimulating
hormone(FSH), AMH, or other adrenal precursors, hormones
 Chromosome analysis, karyotyping

35.  Targeted genetic testing and/or chromosomal microarray
 Endoscopic examination of the genitourinary tract
 Pelvic ultrasound; renal and adrenal ultrasound
 Pelvic CT or MRI
 Voiding cystourethrogram (VCUG) or genitogram
 Exploratory laparoscopy

36. • Testosterone(T), DHT, androstenedione(ASD) D2
• N T at birth 100ng/dl 50 in the 1st WK
↑T at 4-6Wk T at 6M rarely detectable
• ↑ T:DHT 5α reductase deficiency
• ↑ ASD:T 17 ketosteroid reductase deficiency.
•

37.  Human chorionic gonadotropin stimulation test to assess the
testicular function
 Adrenocorticotropin (ACTH) stimulation tests to assess testicular and
adrenal steroid biosynthesis
 Urinary steroid analysis by gas chromatography mass spectroscopy
(GCMS)
 Imaging studies (Pelvic CT or MRI abdomen)
 Biopsies of gonadal material

38. Ideal tests to confirmclinical diagnosis
CLINICAL DIAGNOSIS BEST TESTS
CAH (21-hydroxylase deficiency) Serum 17-hydroxyprogesterone
Serum electrolytes
Glucose
Gonadal dysgenesis Chromosome analysis, Pelvic ultrasound
Serum FSH, LH, AMH
Gonadal biopsy
Androgen insensitivity Chromosome analysis
Serum AMH
hCG stimulation test (measure testosterone before and
after )
Testosterone biosynthetic defect Chromosome analysis
Serum AMH
hCG stimulation test (measure testosterone before and
after )

39. Pediatric endocrine disorders-3rd edition by
M.P. Desai, P.S.N Menon , V Bhatia
Indicator POSSIBLEIMPLICATION
Perineal hypospadias Severe defect in androgen secretion or
action.
Absence of one or both testes with
abnormal phallus
Gonadal dysgenesis or possibly
external virilisation of a genetic female
Systemic illness in a child with genital
anomaly
Adrenal insufficiency due to CAH
Hyperpigmentation of genital skin
with abnormal genitalia
Increased ACTH secretion associated
with adrenal insufficiency
Asymmetry of genitalia MGD or ovotesticular DSD
Virilisation in mother Virilising tumor in mother or placental
aromatase deficiency.

40. CONGENITALADRENAL HYPERPLASIA

41. PRADER STAGING

42. CLINICAL FEATURES
 Dehydration, hypotension, or shock out of proportion to severity of
current illness
 Nausea and vomiting with a history of weight loss and anorexia
 Abdominal pain, so-called acute abdomen
 Unexplained hypoglycemia

43. CLINICAL FEATURES
 Unexplained fever
 Hyponatremia, Hyperkalemia, Hypercalcemia
 Azotemia
 Eosinophilia
 Hyperpigmentation

44. MANAGEMENT
 Establish intravenous access with a large-gauge cannula
 Draw blood for immediate serum electrolytes and glucose, routine
measurement of plasma cortisol and ACTH
 Hypoglycaemia- D10% bolus
 Hypovolemic shock-0.9%NS @ 20ml/kg

45. MANAGEMENT
 D 5% in 0.9% saline infuse as maintenance fluid to correct
hypoglycemia, hypovolemia, and hyponatremia. Twice the
maintenance dose.
 If severe hyperkalemia-IV calcium and/or bicarbonate
-Intrarectal potassium-binding resin
(Kayexalate)
-Intravenous infusion of glucose and insulin

46. MANAGEMENT
 In an infant suspected of 21-OHase deficiency, treatment should be
started as soon as the laboratory tests mentioned have been obtained

GLUCOCORTICOIDS:
 Hydrocortisone 20 mg/m2/day, divided into dosing every
8 hours, should be given to all infants suspected of 21-OHase deficiency

Body surface area (m2) = Square root of
Length (cm)*weight (kg)
___ -----------------------------
3600

47. MANAGEMENT
 Neonates with CAH presenting in adrenal crisis:
 Stress dosage of steroids, initial bolus of 25 mg hydrocostisone, followed
by 50 to 100 mg/m2/day TDS or QID
 Hydrocortisone dose is reduced to reach the maintenance dose once
baby is clinically stable

48. MINERALOCORTICOIDS:
 In cases of salt-wasting CAH
 Fludrocortisone acetate (Florinef)-0.1 to 0.2 mg daily
 Salt-wasting crises usually develop between the 5th and the 14th day of
life but can occur as late as 1 month and may occur even in affected
infants whose virilization is not severe
 Weight, fluid balance, and electrolytes-monitored closely
 Blood samples at least every 2 days during the first few weeks of life to
detect hyponatremia or hyperkalemia

49.  If salt wasting occurs
 Salt loss should be replaced initially with intravenous normal saline with
glucose added
Salt wasting due to aldosterone deficiency-requires replacement of about
8 mEq/kg/day of sodium
 Once the infant is stabilized, salt 1 to 2 g daily QID,
should be given mixed with milk in the initial days of life
(each gram of salt, NaCl, contains 17 mEq of sodium)

50. REFERENCES
 Cloherty and Stark’s Manual of Neonatal Care,8th Edition
 Avery’s Diseases of the Newborn,10th Edition
 Fanaroff’s Neonatal & Perinatal Medicine,11th Edition

51. THANK YOU