1. INTERSEX Prof. M.C.Bansal MBBS,MS,MICOG,FICOG Professor OBGY
Ex-Principal & Controller
Jhalawar Medical College & Hospital
Mahatma Gandhi Medical College, Jaipur.

2. Defining Sex and Gender
Gender identity (Psychological sex)
Inner sense of owns maleness / femaleness.
Sex of rearing
Gender role
Sexual identity (Organic sex)
The biologic sexual differentiation
Chromosomal sex
Gonadal sex
Internal genital sex
External genital sex
Hormonal sex

3. Human sexual differentiation
Chromosomal sex
Gonadal sex
Internal genital sex
External genital sex
SEX ASSIGNMENT
Sex of rearing
Gender identity
and role

4. Gonadal development Receptors For H -Y antigen SRY-gene (TDF)
Short arm of Y chromosome
Present
Absent
Bipotential Gonad
2 X chromosomes
Receptors
For H -Y antigen
TESTES
OVARY

5. Male development TESTIS Leydig cells Sertoli cells
Mullerian inhibiting
factor
Testosterone
Wollfian duct
5a-reductase
DHT
Regrsession of
Muuleian ducts
Urogenital sinus
Male internal
Genital organs
Male external genitalia

6. Female internal genital
Female development
Neutral
Development
OVARY
Urogenital sinus
Mullerian ducts
Female external genitalia
. Lower part of vagina
Female internal genital
Organs
. Most of upper vagina
. Cervix and uterus Fallopian tubes
Absence of androgen exposure

7. Summary of Normal Sex Differentiation
genetic sex is determined at fertilization.
testes develop in XY fetus, ovaries develop in XX fetus.
XY fetus produces MIS and androgens and XX fetus does not.
XY fetus develops Wolffian ducts and XX fetus develops Mullerian ducts.
XY fetus masculinizes the female genitalia to make it male and the XX fetus retains female genitalia.

8. INTERSEX
An individual in whom there is discordance between chromosomal, gonadal, internal genital, and phenotypic sex or the sex of rearing
INTERSEXUALITY:
Discordance between any two of the organic sex criteria
TRANSSEXUALITY:
Discordance between organic sex and psychological sex components

9. CLASSIFICATION OF INTERSEXUALITY
Disorders of fetal Endocrinology

10. CLASSIFICATION OF INTERSEXUALITY
Primary gonadal defect – Swyer syndrome

11. How many children are born with intersex conditions?
A conservative estimate is that 1 in 2000 children born will be affected by an intersex condition
98 % of affected babies are due to congenital adrenal hyperplasia

12. FEMALE PSEUDOHERMAPHRODITISM
EXCESS FETAL ANDROGENS
Congenital adrenal hyperplasia
 21 -hydrxylase deficiency
 11-hydroxylase deficiency
 3ß-hydroxysteroid
dehydrogenase deficiency
EXCESS MATERNAL ANDROGENS
Maternal androgen secreting tumors (ovary, adrenal)
 Maternal ingestion of androgenic drugs

13. Congenital Adrenal Hyperplasia
It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance.
The defect is expressed as adrenal enzyme deficiency.
5 major Enzymes deficiency are clinically important
21-Hydroxylase
11-b-Hydroxylase
17-a-Hydroxylase
3-b-Hsteroid hydrogenese
20,22 Desmolase deficiency

14. CAH
The most frequent is steroid 21-hydroxylase deficiency, accounting for more than 90 percent of cases.
The enzyme deficiency causes reduction in end-products, accumulation of hormone precursors & increased ACTH production.
The clinical picture reflects the effects of inadequate production of cortisol & aldosterone and the increased production of androgens & steroid metabolites.

15. Biochemistry
Steroid 21-hydroxylase (CYP21, also termed CYP21A2 and P450c21) is a cytochrome P-450 enzyme located in the endoplasmic reticulum.
It catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol, and the conversion of progesterone to deoxycorticosterone, a precursor of aldosterone.
Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency cannot synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by corticotropin and overproduces cortisol precursors.

17. Contd…
Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth)

18. Contd…
Some of these precursors are diverted to the biosynthesis of sex hormones, which may cause signs of androgen excess, including ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes.
Concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock.

19. 21-hydrxylase deficiency congenital adrenal hyperplasia
Cholesterol
Pituitary
Pregnenolone
Progesterone
ACTH
17-OH progesterone
Adrenal cortex
21-hydroxylase 
Androgens
Cortisol
Cortisol
Androgens

20. 21-hydrxylase deficiency congenital adrenal hyperplasia
Most common type, accounts for >80% of cases.
Incidence is 1:5000 to 1:15000 live birth.
Gene is located on the short arm of chromosome 6 near the C4 locus in close association with HLA genes.
Heterozygous carriers can be detected by ACTH stimulation test.

21. Contd..
It is characterized by reduced production of cortisol and aldosterone and increased production of progesterone; OH-progesterone, and sex steroids.
The urinary steroid metabolites (17-ketosteroids and pregnanetriol) are elevated above normal levels.

22. Contd..
Decreased secretion of aldosterone results in salt loss with hyponatremia and hyperkalemia; plasma renin activity is therefore elevated.
In partial enzyme deficiencies, the aldosterone deficiency is not expressed, and patients remain normonatremic and normokalemic.
The excess androgens causes virilization of girls & ambiguous genitalia & dark scrotum in boys.

23. Contd… There are 3 forms:
1. classic early virilization type with or without salt-losing crisis(typically identified at birth because of genital ambiguity)
2.Salt wasting (in which there is impairment of mineralocorticoid as well as glucocorticoid secretion),
3. non-classic type with late-onset virilization(in which heterosexual development occurs at the expected age of puberty).

24. Contd…
Male babies with non salt-losing non-classic type remains asymptomatic till late childhood when they may show signs of sexual precocity.
Because members of the same family may have classic, non-classic & asymptomatic forms, the disorder may be due to allelic variations of the same enzyme.
Mass neonatal screening using filter paper blood sample for 17-OH-Progesterone is used in the USA.

25. CLINICAL MANIFESTATIONS
1. In classic form(girls are born with ambiguous genitalia) having
enlarged clitoris
fusion of the labioscrotal folds and the urogenital sinus.
The internal female organs (including the uterus, fallopian tubes, and ovaries) develop normally because they are not affected by the increased androgen levels.
early pubic hair and rapid growth in childhood precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty)
excessive facial hair
Virilization
menstrual irregularity in adolescence
infertility due to anovulation
shallow vagina

26. clitoromegaly
Marked virilization with hypospadiac-appearing phallus
labioscrotal fusion

27. 2. In salt wasting 21hydroxylase deficiency hyponatremia hyperkalemia hypotension CLASSICAL CAH

28. Contd…
During childhood, untreated girls with either the classic or salt wasting form grow rapidly but have advanced bone ages, enter puberty early, experience early closure of their epiphyses, and ultimately are short in stature as adults. CAH, with appropriate therapy, is the only inherited disorder of sexual differentiation in which normal pregnancy and childbearing are possible.
Boys :
-no overt signs of the disease
except variable and subtle hyperpigmentation
and penile en-largement

29. BOYS WITH CAH
Are unrecognized at birth because their genitalia are normal.
They are not diagnosed until later, often with a salt wasting crisis resulting in dehydration, hypotension, hyponatremia and hyperkalemia or later in childhood with early pubic hair & phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation.
High blood pressure & hypokalemia may occur in those with 11-b-hydroxylase deficiency and 17-a-hydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone

30. (Williams Textbook of Endocrinology, 10th ed, 2003)
A and B, An untreated girl with the non–salt-losing form of congenital adrenal hyperplasia. Androgens caused disproportionate acceleration of bone maturation compared with stature. C, Virilized adult female with non–salt-losing adrenal hyperplasia. The patient had a deep voice, shaved daily, and wore a toupee for baldness. After treatment with cortisone, her 17-ketosteroid levels fell to normal values, her breasts enlarged, she underwent a normal menarche, and hair regrew on her head. Note short stature and short extremities. D, Female pseudohermaphroditism caused by maternal ingestion of an oral progestational compound from the 8th to 12th week of pregnancy. Labioscrotal fusion is sufficient to obscure the vaginal orifice and create a urogenital sinus. Clitoris is enlarged. There is no progressive virilizing tendency. (C, from Wilkins L. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd ed. Springfield, IL, Charles C Thomas, 1965.)
(Williams Textbook of Endocrinology, 10th ed, 2003)

31. 11-hydroxylase (P450c11) deficiency
Accounts for 5-10% of cases of CAH.
Gene is located on the long arm of chromosome 8.
caused by mutations in the CYP11B1 gene.
It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11-deoxycorticosterone.
Because of the strong mineralocorticoid activity of deoxycorticosterone, the condition is characterized by salt retention, hypertension & hypokalemic alkalosis.
The elevated plasma androgens may cause virilization of the female fetus.

32. 3ß-hydroxysteroid dehydrogenase deficiency
This is a very rare disorder that results in accumulation of DHEA, which is converted to testosterone in peripheral tissues.
Enzyme defects in adrenal and ovary in autosomal –recessive fashion
Caused by mutations in the HSD3B2 gene encoding the 3ß-HSDII enzyme affects the synthesis of glucocorticoids, mineralocorticoids, and sex steroids.
Cortisol ↓ & aldosterone ↓
Dehydroepiandrosterone ↑↑  the external genitalia ambiguity
It can cause virilization of female fetus and leads to ambiguous genitalia in the newborn.
A diagnosis based on baseline and ACTH-stimulated changes in steroid levels is not accurate ; indeed, in adult women, an apparent late-onset 3ß-hydroxysteroid dehydrogenase deficiency is almost always, if not always, a secondary response to anovulation and polycystic ovaries, accompanied by hyperinsulinemia

33. 17-hydroxylase deficiency
Genetic defect is on chromosome 10.
Corticosterone, 11-deoxycorticosterone ↑
Presents with similar features of those of 11-Hydroxylase deficiency except that Androgens are low, so no virilization in girls & genitalia is ambiguous in boys.
Hypertension (due to hypernatremia and hypervolemia), hypokalemia
Infantile female external genitalia & primary amenorrhea

34. ESSENTIALS OF DIAGNOSIS
Increased linear growth with advanced bone age and eventual short stature
Pseudohermaphorditism in girls due to androgen virilizing effect
Isosexual precocity in boys with small infantile testes.
Adrenal crisis with salt-loss & metabolic acidosis or Hypertension & hypokalemic alkalosis.
Low cortisol with high androgens, ACTH and steroid precursors e.g. 17-OH-Progest. or 11-Deoxycortisol.
Diagnosis is confirmed by measurement of ACTH, Cortisol, Aldosterone, 17-OH-progesterone, Testosterone & urinary 17-ketosteroids.
Needs alertness for the possibility in all babies with Diarrhea & Vomiting, hypoglycemia or  BP.

35. Diagnosis
Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17-hydroxyprogesterone, the main substrate for the enzyme.
The gold standard for differentiating 21-hydroxylase deficiency from other steroidogenic enzyme defects is the corticotropin (cosyntropin) stimulation test,measuring base-line and stimulated levels of 17-hydroxyprogesterone.
corticotropin (cosyntropin) stimulation test :
The most commonly used stimulatory test involves measurement of 17-hydroxyprogesterone 30 minutes after administration of a bolus of 250 mg of synthetic cosyntropin (Cortrosyn).

36. Contd… In normal women - this value seldom exceeds 400 ng/dL.
Patients with classic 21-hydroxylase deficiency - achieve peak levels of
3,000 ng/dL or higher.
Patients with nonclassic 21-hydroxylase deficiency-achieve levels of 1,500
ng/dL or more.
Heterozygous carriers achieve peak levels up to
about 1,000 ng/dL.
In hirsute women with hypertension, 11-deoxycortisol levels can be determined during the test. If both 11-deoxycortisol and 17-hydroxyprogesterone levels are increased, the rare 11-hydroxylase deficiency is present. Only measurements of several steroid precursors after corticotropin stimulation can identify individuals with nonclassic forms of 3-HSD deficiency.
The elevated levels of 17-hydroxyprogesterone present in all forms of 21-hydroxylase deficiency are rapidly suppressed by administration of exogenous corticoids. Even a single dose of a glucocorticoid such as dexamethasone will suppress 17-hydroxyprogesterone in CAH but not in virilizing ovarian and adrenal neoplasms.

38. CONGENITAL ADRENAL HYPERPLASIA - Diagnosis
Normal infant :100ng/dl (17 -hydroxyprogesterone)
Affected infants : 3, ,000ng/dl ↑
The severity of hormonal abnormalities
: depends on the type of 21-hydroxylase def
Salt wasting : 17-hydroxyprogesterone: ng/dl
In adult , random 17-hydroxyprogesterone (17-OHP)
: baseline - 200ng/dl ↓
Levels greater 200ng/dl, but less than 800 ng/dl
-> Corticotropin stimulation test

39. Lab Findings
Demonstration of inadequate production of cortisol and/or aldosterone in the presence of accumulation of excess concentrations of precursor hormones is diagnostic.
In 21-hydroxylase deficiency, very high serum 17-hydroxyprogesterone is characteristic together with very high urinary pregnanetriol (metabolite of 17-hydroxyprogesterone).
Both are accompanied by elevated 24-hour urinary 17-ketosteroids, the urinary metabolites of adrenal androgens.

40. Other tests
Salt wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone, hyponatremia, hyperkalemia and elevated plasma renin activity indicating hypovolemia.
In contrast hypertensive forms of adrenal hyperplasia (11-b-hydroxylase deficiency and 17-a-hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia
A karyotype
is essential in the evaluation of the infant with ambiguous genitalia in order to establish the chromosomal sex.
Prenatal diagnosis of adrenal hyperplasia is possible through biochemical and genetic tests.

41. Imaging Studies
A pelvic ultrasound: in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies
A urogenitogram is often helpful to define the anatomy of the internal genitalia.
A CT scan of the adrenal gland to R/O bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure
A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth.

42. CONGENITAL ADRENAL HYPERPLASIA – Management
GOALS
According to the clinical course & hormonal level
Purpose
: Normal growth, B.Wt, pubertal development, optimal adult height
Growth velocity, body Wt velocity, bone age maturation
Classic 21-OH def
-> glucocorticoid : adrenal androgen secretion ↓
-> mineralocorticoid : electrolytes & plasma renin activity

43. MODE OF TREATMENT Steroid replacement Supportive therapy when needed
Treatment is life-long
Plastic surgery for ambiguous genitalia at early age
Genetic counseling
Psychological support

44. Treatment(1)-Glucocorticoids
Patients with classic 21-hydroxylase deficiency require long-term glucocorticoid treatment to inhibit excessive secretion of corticotropin-releasing hormone and corticotropin by the hypothalamus and pituitary, respectively, and to reduce elevated levels of adrenal sex steroids.
In children, the preferred drug is hydrocortisone (i.e., cortisol itself ) in maintenance doses of 10 to 20 mg per square meter of body-surface area per day in three divided doses.

45. Treatment(2)-Glucocorticoids
Doses of up to 100 mg per square meter per day are given during adrenal crises and life-threatening situations.
Even these maintenance doses exceed physiologic cortisol secretion (7 to 9 mg per square meter per day in neonates and 6 to 8 mg per square meter per day in children and adolescents).
The efficacy of treatment is best monitored by measuring 17-hydroxyprogesterone and androstenedione levels at a consistent time in relation to the administration of medication.

46. Treatment(3)-Glucocorticoids
The therapeutic goal is to use the lowest dose of glucocorticoid that adequately suppresses adrenal androgens and maintains normal growth and weight gain.
Children should also undergo radiography annually to determine bone age, and their linear growth should be carefully monitored.
Older adolescents and adults may be treated with prednisone (e.g., 5 to 7.5 mg daily in two divided doses) or dexamethasone (total, 0.25 to 0.5 mg given in one or two doses per day).

47. Treatment(1)-Mineralocorticois
Infants with the salt-wasting form of 21-hydroxylase deficiency require supplemental mineralocorticoid (usually 0.1 to 0.2 mg of fludrocortisone daily) and sodium chloride (1 to 2 g or 17 to 34 mmol of sodium chloride chloride daily in addition to glucocorticoid treatment).
Older infants and children usually do not require sodium chloride supplements, and they often have reduced requirements for fludrocortisone.

48. Treatment(2)-Mineralocorticoids
Plasma renin activity levels or direct renin immunoassays may be used to monitor the adequacy of mineralocorticoid and sodium replacement, taking into account the age-specific reference ranges for each laboratory.
Hypotension, hyperkalemia, and elevated renin levels suggest the need for an increase in the dose, whereas hypertension, edema, tachycardia, and suppressed plasma renin activity signify overtreatment with mineralocorticoids.

49. NEW TRENDS OF T/T
A New approach therapy is the combined use of 4 drugs:
glucocorticoid (to suppress ACTH and adrenal androgen production),
mineralocorticoid (to reduce angiotensin II concentrations),
aromatase inhibitor (to slow skeletal maturation),
flutamide (an androgen blocker to reduce virilization)

50. Management of Ambiguous Genitalia
Improvements in the surgical correction of genital anomalies over the past two decades have led to earlier use of single-stage surgery — between two and six months of life in girls with 21-hydroxylase deficiency, a time when the tissues are maximally pliable and psychological trauma to the child is minimized.
The long-term outcomes of the newer surgical procedures have yet to be evaluated.

51. SURGICAL T/T
Infants with CAH may require surgical evaluation and, if needed, corrective surgery.
Traditional approach is clitroplasty early in life, followed by vaginoplasty after puberty.
Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.

52. Prenatal diagnosis and t/t
Done by chorionic villus sampling at 8-12 wk & amniocentesis at wk.
HLA typing in combination with measurement of 17-OH-progesterone & androstenedion in amniotic fluid is used for antenatal diagnosis.
Prenatal treatment of 21-hydroxylase deficiency prevents intrauterine virilization of female fetuses.
According to the protocol proposed by Carlson et al, the mother is treated with dexamethasone (20 m/kg/d in 3 divided doses) as soon as the pregnancy is recognized to suppress fetal ACTH secretion & prevent the fetal adrenal gland from overproducing adrenal androgens.

53. .

54. Incompletely Masculized Males

55. Male pseudohermaphroditism (XY- FEMALE)
Failure to utilize
testosterone
 Androgen receptor deficiency
* Complete androgen Insensitivity (TFS)
* Incomplete androgen Insensitivity
 5-alpha reductase deficiency
Failure to produce
testosterone
 Defects in testicular
steroidogenesis
 Gonadotropin-resistant
testes (LH receptor mutation)
 Congenital lipoid adrenal
hyperplasia
 Defective synthesis,
secretion, or response to
anti-mullerian hormone

57. What is AIS?
A genetic condition where affected people have male chromosomes & male gonads with complete or partial feminization of the ext. genitals
An inherited X-linked recessive disease with a mutation in the Androgen Receptor (AR) gene resulting in:
Functioning Y sex chromosome
Abnormality on X sex chromosome
Types
CAIS (completely insensitive to AR gene) External female genitalia Lacking female internal organs
PAIS (partially sensitive-varying degrees) -External genitalia appearance on a spectrum (male to female)
MAIS (mildly sensitive, rare) -Impaired sperm development and/or impaired masculinization
Also called Testicular Feminization

58. Normal Sexual Development
MALE
Sex Chromosome = XY
Gonads = Testes
External Genitalia = Male
FEMALE
Sex Chromosome = XX
Gonads = Ovaries
External Genitalia = Female
Normally chromosome sex determines gonad sex which determines phenotypic sex
WHAT HAPPENS IN AIS?

59. Androgen Receptor Gene
AIS results from mutations in the androgen receptor gene, located on the long arm of the X chromosome (Xq11-q12)
The AR gene provides instructions to make the protein called androgen receptor, which allows cells to respond to androgens, such as testosterone, and directs male sexual development
Androgens also regulate hair growth and sex drive
Mutations include complete or partial gene deletions, point mutations and small insertions or deletions

60. The Process of Sexual Development
In AIS the chromosome sex and gonad sex do not agree with the phenotypic sex
Phenotypic sex results from secretions of hormones from the testicles
The two main hormones secreted from the testicles are testosterone & mullerian duct inhibitor
Testosterone is converted into dyhydrotestosterone
Mullerian duct inhibitor suppresses the mullerian ducts & prevents the development of internal female sex organs in males
Wolffian ducts help develop the rest of the internal male reproductive system and suppress the Mullerian ducts
Defective androgen receptors cause the wolffian ducts & genitals to be unable to respond to the androgens testosterone & DHT

61. AIS Fetus Development
Each fetus has non-specific genitalia for the first 8 weeks after conception
When a Y-bearing sperm fertilizes an egg an XY embryo is produced and the male reproductive system begins to develop
Normally the testes will develop first and the Mullerian ducts will be suppressed and testosterone will be produced
Due to the inefficient AR gene cells do not respond to testosterone and female genitalia begin to form
The amount of external feminization depends on the severity of the androgen receptor defect
CAIS: complete female external genitalia
PAIS: partial female external genitalia
MAIS: Mild female external genitalia, essentially male

62. Testicular feminization syndrome
46-XY/SRY
Testicular feminization syndrome
TESTIS  MIF
Testosterone
5--reductase
DHT
Absent androgen receptors
Female
External
Genitalia
Male Internal Genitalia
Incomplete form  Ambiguous genitalia

63. Complete Androgen Insensitivity
Testicular Feminization SD (female phenotype)
female-appearing external genitalia, and absence of müllerian derivatives
Blind ending vagina, reduced pubic hair
1 in 20-60,000 males, X-linked trait
In utero loss of androgen, & MIS secretion means loss of internal genitalia
2% of males with an inguinal hernia have Complete androgen sensitivity so vaginoscopy pruden
Usually diagnosed amenorrhea, absence of pubic hair or hormonal profile
Gonadectomy and Oestrogen replacement therapy

65. Incomplete Androgen Insensitivity (Reifenstein’s Syndrome)
Incomplete male pseudohermaphroditism
Ambiguous genitalia to varying degrees
male with perineoscrotal hypospadias, cryptorchidism, rudimentary Wolffian duct structures, gynecomastia, and infertility
the phenotypic spectrum can range from hypospadias and a pseudovagina to gynecomastia and azoospermia
etiology:
(1) a reduced number of normally functioning androgen receptors
(2) a normal receptor number but decreased binding affinity
Gender assignment is often dictated by phenotype and degree of virilization
Normal testosterone, LH and testosterone/DHT ratio
All intermediate type of androgen insensitivity

66. Infertile male syndrome
normal male phenotype but are azoospermic or severely oligospermic
normal to elevated serum testosterone
normal to elevated LH
decreased androgen receptor binding to DHT in genital skin fibroblasts

67. Testing for AIS Tests During Pregnancy
Chorionic Villus Sampling (9-12 weeks)
Ultrasound and Amniocentesis (after 16 weeks)
After Birth
Presence of XY Chromosomes
Buccal Mouth Smear
Blood Test
Pelvic Ultrasound
Histological Examination of Testes

68. Biochemical Testing for Carriers
Tests
s: Skin biopsies-evaluate androgen binding capacity
Carries: 50% androgen binding
Problem: some cases skipped because mutation did not always take place in the binding region of the gene
1990s: DNA Testing
blood or mouth cavity smears
Now:
Measure length of base pair repeat region in first exon of gene and compare it to a female relative’s repeat region to determine if they are a carrier

69. Non-Biochemical Testing
Maternal relatives affected by AIS
In an XX female
Delayed puberty
Reduced pubic-auxiliary hair
Asymmetric pubic-auxiliary hair
Reduced bone density

70. Treatments Surgery Orchidectomy or gonadectomy Removal of the testes
Vaginal lengthening
Genital plastic surgery
Reconstructive surgery on the female genitalia if masculinization occurs
Phalloplasty
Vaginoplasty
Pressure dilation
Clitorectomy
Debate
What age?
Who decides?

71. Treatments Hormone Replacement Therapy (HRT) Types Female: Estrogen
Progesterone (sometimes take to reduce risk of breast or uterine cancer)
postorchidectomy
Male: Testosterone and DHT
Form
Oral, transdermal, implant, injection, vaginally
Prevents osteoporosis (age 10 or 11)
Body responds as if it is post-menopausal, thus body density decreases and osteoporosis occurs

72. The Androgen Insensitivity Syndromes
Infertile
Reifenstein
Incomplete
Complete
5α-redutase
X-linked recessive
Autosomal recessive
Inheritance
Decreased
Absent
Spermatogenesis
Mullerian
Male
Wolffian
Hypospadia
Female
Clitomegaly
External
Gynecomastia
Breasts

73. 5-alpha reductase deficiency
Secondary to mutations in the type II gene
Phenotype may vary from penoscrotal hypospadias to, more commonly, markedly ambiguous genitalia
Normal internal genitalia
: testes secrete T, MIH causes Mullerian ducts to degenerate
Lack of DHT leads to inadequate masculinization of external genitalia at birth
Testes in labia or inguinal canal
Urogenital sinus: urethra & blind vagina
Prostate gland: small or absent
At puberty, lots of T
 testes descend, scrotum darkens, phallus enlarges, muscular &
deep voice

74. 5-alpha-reductase deficiency Female or Ambiguous external Genitalia
46-XY/SRY
Testis  MIF
Testosterone
5--rductase
DHT
Female or Ambiguous external Genitalia
Male Internal Genitalia

75. Male Pseudohermaphroditism
Disorders of Testosterone Biosynthesis
Defect in any of the five enzymes  incomplete (or absent) virilization of the male fetus during embryogenesis
Inheritance is autosomal recessive
Cholesterol Side Chain Cleavage Deficiency (StAR Deficiency)
a defect in cholesterol transport prevents conversion of cholesterol to pregnenolone
46,XY individuals have female or ambiguous external genitalia
a blind-ending vaginal pouch
intra-abdominal, inguinal, or labial testes
absence of müllerian structures & Wolffian ducts are present but rudimentary
severe adrenal insufficiency and salt wasting
suspect this if nonvirilized female external genitalia with:
cortisol and aldosterone deficiency
hyponatremia, hyperkalemia, and metabolic acidosis.
Abdominal CT scanning demonstrates large, lipid-laden adrenal glands
Because testosterone production never significant, brain imprinting not a factor in gender assignment.

76. Testosterone Biosynthesis
5 enzymes involved in the conversion of cholesterol to
testosterone
3 in the adrenal & testis
2 in the testis only
Cholesterol side change cleavage
3β OH steroid Dehydrogenase
17α Hydroxylase
17,20 Lyase Deficiency
17β OH steroid Dehydrogenase

77. Testicular enzymatic failure
46-XY/SRY
Testis  MIF
(defects in testosterone
Synthesis)
Autosomal recessive enzyme deficiency : desmolase ß-ol-dehydrogenase  -hydroxylase ,20-desmolase ß –OH steroid dehydrogenase
 testosterone precursors DHT
Ambiguous
External
Genitalia
Male Internal Genitalia

78. Leydig Cell hypoplasia /LH receptor mutation
-46,XY male karyotype, normal-appearing female phenotype
Palpable testes but ↑LH and ↓Testosterone
No stimulation of testosterone with HCG
spectrum  absent Leydig cells to Leydig cells with abnormal LH receptor
autosomal recessive trait
No Mullerian structures / short vagina
DDx = androgen insensitivity syndrome or a terminal defect in androgen synthesis.
Testis histology = absent of Leydig cells in intratubular spaces, normal Sertoli cells

79. ( partial/ complete absence
Leydig-cell agenesis
46-XY/SRY
TESTIS  MIF
( partial/ complete absence
Of leydig-cells)
No or  testosterone
No or  DHT
Female or ambiguous external Genitalia
± Male
Internal
Genitalia

80. Hernia Uterine Inguinale (persistant mullerian structures)
Normal phallus, uterus and tubes in the inguinal hernia sac
Poor sperm and hormone production
Gonad cancer risk
Can be familial
Presumed failure of AMH function
Fertility – rarely preserved

81. Testosterone precurcers
Diagnosis of XY Female
Testosterone concentration
Low
Normal
Male level
Concentration of
Testosterone precurcers
DHT
High
Low
Low
Normal
Testicular
enzyme
Failure
Absent testes or
Absent leydig-cell
Testicular
Feminization
Syndrome
5 -reductase
Deficiency
Surgical exploration

82. Seminiferous Tubule Dysgenesis (Klinefelter's syndrome)
Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes, 47,XXY karyotype
nondisjunction during meiosis
1 of 1000 liveborn males
associated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXY
Gynecomastia can be quite marked at pubertal development
8 X risk for breast carcinoma compared with normal males
Seminiferous tubules degenerate and are replaced with hyaline
Fertility, with the benefit of ICSI, has been reported in one patient
decreased androgens prevents normal secondary sexual development
poor muscle development, the fat distribution is more female than male.
Normal amounts of pubic and axillary hair, but facial hair is sparse.
Patients tend to be taller than average, due to disproportionately long legs
Predisposed to malignant neoplasms of extragonadal germ cell origin.
Androgen supplementation to improve libido & reduction mammoplasty
surveillance for breast carcinoma
At least one Y and two X to be Klinefelter’s.
ICIS intracytoplasmic sperm injection

83. Klinefelter's syndrome
A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter's syndrome). The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low normal. Note normal virilization with long legs and gynecomastia (B, C). The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. D, A 48-year-old male with 47,XXY Klinefelter's syndrome with severe leg varicosities.
(Williams Textbook of Endocrinology, 10th ed, 2003)

84. 46,XX maleness Occurs in 1 of every 20,000 males
Testicular development in subjects who have two X chromosomes and lack a normal Y chromosome.
Most of these subjects have normal male external genitalia, but 10% have hypospadias and all are infertile
80% are Sry positive and rest are Sry negative
Sry -positive group rarely have genital abnormalities, but they have phenotypic features of Klinefelter's syndrome
Shorter (mean height, 168 cm) and have more normal skeletal proportions than Klinefelter’s patients
Due to translocation of Y chromosomal material, including SRY, to the X chromosome
Infertile  lack of germ cell elements
Characterized by …
Patients typically present for evaluation of gynecomastia.
Androgen replacement and reduction mamoplasty in selected pts.
Lack of germ cell elements obviates testicular biopsy & ICSI (intracytoplasmic sperm injection)

85. Disorders of Gonadal Development

86. Gonadal Dysgenesis Turners Syndrome (45 X0)
Features:
1. Female Phenotype
2. Short Stature
3. No Secondary Sexual
Characteristics
4. Somatic Abnormalities
- Webbed Neck
- Broad Chest
- Short Ring finger
Occult Y Ch. Material:
Predisposed to Virilisation
and Gonadoblastoma (30%) and other GCT (50%).
Presence of one functioning X Chromosome
1 in 2500 females. Mosaicism 45 X/46 XX (10%) or 45 X/46 XY (3%)
Oocytes degenerate leaving streak gonads (in broad lig.) at birth
Reduced Oestrogen, Raised FSH/LH. No pubertal development
Management includes:
Growth Hormone to Children & estrogens at puberty
Up to one third may have functioning ovaries
- so pregnancy is possible
Remove Streak gonads in Mosaic patients
Alternative Names:Bonnevie-Ullrich syndrome; Gonadal dysgenesis; Monosomy X
Renal Anomalies:
90% Multiple Renal Arteries
20% Renal agenesis/Duplication
15% Malrotation
10% Horseshoe kidney

88. Symptoms

89. Turner syndrome Karyotype 45,X (60%)
(45,X/46,XX, structural abnormalities of X chromosome)
Short stature (final height cm)
Gonadal dysgenesis - streak gonad & sexual infantilism
Skletal abnormalities & dysmorphic face
Cardiac and kidney malformation
Autoimmune ds : Hashimoto’s thyroditis, Addison’s ds
Mild insulin resistance & hearing loss
Lymphedema
Essential hypertension
No mental defect
Impairment of cognitive function : mathematical ability↓
Visual–motor coordination, spatial-temporal processing↓
H. Tuner, 1938

90. Turner syndrome – work up
IVP or renal USG
Echocardiography
Audiometry
Lipid profile & glucose metabolism (annually)
Annual pelvic examination & appropriate screening for gonadal neoplasm as an adnexal mass
Expert consultation to pursue further analysis with X- and Y- specific DNA probes

91. Pure Gonadal Dysgenesis
All subjects with female genitalia, normal mullerian structure & streak gonads ( with either 46,XX or 46,XY karyotypes)
None of Turner phenotype anomalies

92. (Williams Textbook of Endocrinology, 10th ed, 2003)
Gonadal dysgenesis
Three patients with 45,X/46,XY sex chromosome mosaicism who illustrate the highly variable phenotype in this variant of the syndrome of gonadal dysgenesis. (Numbers of the patients refer to designation in Table ) A, Patient 1, a phenotypic female, was age 15 years, 4 months. She had short stature (-3.1 SD), an increased number of pigmented nevi, puffiness over the dorsa of fingers, and broad and short hands, and she was sexually infantile (breast development seen in photograph followed estrogen therapy) except for sparse pubic and axillary hair. The urinary gonadotropins were markedly elevated. B, Patient 3, aged 3 years, 1 month, had ambiguous external genitalia, perineal hypospadias, and undescended gonads. He was of average height and had a broad chest and a duplication of the left kidney. C, Patient 9, aged 8 years, 1 month, was a phenotypic male with a penile urethra and unilateral undescended gonad, average height, cubitus valgus, short fourth metacarpals, and puffiness of dorsa of fingers. By age 15, male secondary sexual characteristics were well advanced and a left scrotal testis, which was normal in histologic appearance, measured 4.0 × 2.4 cm.
(Williams Textbook of Endocrinology, 10th ed, 2003)

93. 46,XX pure gonadal dysgenesis
Features:
normal female external genitalia
normal müllerian ducts with absence of wolffian duct structures
a normal height
bilateral streak gonads
sexual infantilism
normal 46,XX karyotype
streak gonads elevated serum gonadotropins
Management of 46,XX "pure" gonadal dysgenesis:
cyclic hormone replacement with estrogen and progesterone.
growth is basically normal so GH is not needed
possibly autosomal recessive trait
Closely related to Turner’s syndrome
In contrast to Turner’s growth hormone here is normal.

95. 46,XY Complete Gonadal Dysgenesis
Characterized by :
normal female genitalia
well-developed müllerian structures
bilateral streak gonads
nonmosaic karyotype
Ambiguity of genitalia is not an issue
Sexual infantilism is the primary clinical problem
present in their teens with delayed puberty
An abnormality of the Sry gene function, or loss of another gene downstream from Sry that is necessary for SRY protein action
LH elevated  clitoromegaly
30% risk of germ cell tumor development by age 30 years
gonadoblastoma is most common
embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and immature teratoma have also been reported
Management  removal of both streak gonads and proper cyclic hormone replacement with estrogen and progesterone
Elevated LH  likely responsible for androgen production  clitoromegaly

96. Gonadal Dysgenesis Multiple X female (47,XXX)
Normal development & reproductive function
Mental retardation- frequent
Secondary amenorrhea & eunuchoidism

97. Mixed Gonadal Dysgenesis
Features:
Unilateral testis (undescended)
Contralateral Streak Gonad
Persistent Mullerian Structures
Some masculinisation
Mostly females with;
Enlarged phallus
Labioscrotal folds
Uterus /vagina & tubes
Mosaicism: 45 XO/ 46 XY
Second most common cause for Ambiguous genitalia
Mostly phenotypic females, but entire spectrum covered
Due to lack of MIS production in unilateral dysgenetic
testis with ipsilateral fallopian tube
Management includes Gender assignment (2/3 female),
Appropriate gonadectomy & screen for Wilm’s tumor
Increased risk of:
Gonadoblastoma (20%)
- testis > streak gonad
Wilm’s tumor
Denys-Drash Syndrome
- Nephropathy /CRF
- Genital Abnormalities
- Wilms tumour
- XX/XY mosaicism
May need prophylactic bilateral nephrectomy

98. Mixed Gonadal Dysgenesis
Karyotype 46XY / 45X0
Combined features of Turner’s SD & male pseudohermaphroditism
Short stature
Streak gonad on one side with a testis on the other side
Unicornuate uterus & fallopian tube- side of streak gonad
Considrable variation in the sexual phenotype

99. Surgical Removal of Gonadal Tissue
Gonadal Dysgenesis
Surgical Removal of Gonadal Tissue
The gonadal tissue having any Y chromosome component in phenotypic females  removal as soon as the diagnosis is made to avoid the risk of malignant gonadal tumor
(except complete androgen insensitivity)
: Laparoscopy or laparotomy
The uterus and tubes should be preserved for the possibility of pregnancy with donor oocytes

100. Hormone Treatment of Patients Without Ovaries
Gonadal Dysgenesis
Hormone Treatment of Patients Without Ovaries
Starting when the bone age is 12 with unopposed estrogen ( 0.3mg conjugated estrogens or 0.5mg estradiol daily)
After 2 years , a sequential program is initiated with 0.625mg conjugated estrogens or 1.0mg conjugated estrogens
+ 5mg medroxyprogesterone acetate for 14days (if a uterus is present)
In patients with genetic shortness in stature (e.g. Turner SD)  Estrogens treatment is not started until bone age is 12
(to avoid epiphysial closure)

101. Gonadal Dysgenesis
Stimulation of Growth
Growth hormone treatment for short stature in turner syndrome
: Optimal response  an early onset of Tx around age 6~7
Now that the success of GH treatment in recognized & accepted, an argument can be made for chromosomal screening by molecular analysis of all growth-retarded girls

102. The Possibility of Pregnancy
Gonadal Dysgenesis
The Possibility of Pregnancy
In women who have variants of gonadal dysgenesis and who menstruate, pregnancy can occur
30% incidence of congenital anomalies in the offspring
 amniocentesis or chorionic villus biopsy
Donated oocytes yields excellent results
Fatal aortic events (aneurysm, dissection, or rupture) can occure during pregnancy in patients with gonadal genesis. A cardiology consultation with a echocardiogram is strongly advised

103. Swyer’s syndrome (Bilateral dysgenesis of the testes)
46, XY
No SRY OR its receptors
STREAK GONADS NO MIF (Uterus +) NO SEX STEROIDS
Female external
Genitalia
Female Internal Genitalia

104. Embryonic Testicular Regression and Bilateral Vanishing Testes Syndromes
46,XY karyotype and absent testes but clear evidence of testicular function during embryogenesis
"embryonic testicular regression" = loss of testicular tissue within the first trimester and is associated with ambiguity of external genitalia
"bilateral vanishing testes syndrome" refers to individuals in whom male sexual differentiation of ducts and genitalia took place but loss of testicular tissue occurred subsequently in utero
Diagnosis can be made on the basis of a 46,XY karyotype and castrate levels of testosterone despite persistently elevated serum LH and FSH
bilateral vanishing testes syndrome, agonadal XY phenotypic males with fully developed wolffian structures, but an empty scrotum, absent prostate, and microphallus
intermediate point presentation is the 46,XY patient with absent gonads and internal ductal structures but with ambiguous genitalia  incomplete elaboration of androgen
most severe form, agonadism is discovered in a 46,XY phenotypic female with no internal genital structures;  the testis has elaborated MIS but vanishes at days before elaboration of androgen
The syndrome entails the presence of testes that "vanish" during embryogenesis and is distinguished from pure gonadal dysgenesis, in which there is no evidence of testicular function in utero.
Possible etiology genetic mutation, teratogen, bilateral torsion.
At puberty males get androgens and females get estrogen supplementation.
Spectrum of presentation

105. Testicular regression syndrome Congenital Anorchia
46-XY/SRY
Testis  MIF
(self destruction)
± testosterone
± DHT
Male
Infantile
External
genitalia
± Male Internal genitalia

106. TRUE HERMAPHRODITISM • Gonads :
- ovary one side and testis on the other side of the abdomen
- bilateral ovotestis
• Karyotype :
46,XX most common(70%); XY and XX/XY
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis

107. (Williams Textbook of Endocrinology, 10th ed, 2003)
True Hermaphroditism
Individuals who have both testicular tissue with well-developed seminiferous tubules and ovarian tissue with primordial follicles, which may take the form of one ovary and one testis or, more commonly, one or two ovotestes.
External genitalia and internal duct structures of true hermaphrodites display gradations between male and female
75% raised male; hypospadius and chordee in about 80%.
Virtually all have UG sinus present and most have uterus present.
2/3 are 46,XX karyotype but 46,XY and mosaics occur less commonly.
Fallopian tubes present on the side of ovary and vas deferens present adjacent to testis.
A 17-year-old true hermaphrodite with bilateral scrotal ovotestes and a 46,XX sex chromosome constitution in cultures of peripheral blood and skin, perineal hypospadias (partially repaired in photograph), moderate bilateral gynecomastia and pubic hair (recently shaved in picture), sparse axillary hair, a high-pitched voice, and absent facial hair. Height was 168 cm. Urinary 17-ketosteroid level was 1.3 mg/day; urinary gonadotropin levels were elevated. A male type of urethra, bilateral scrotal fallopian tubes and ovotestes, and rudimentary bicornuate uterus and vagina attached to the posterior urethra were seen at operation. The photomicrographs show histopathology of the ovarian and testicular portion of one ovotestis. B, Immature seminiferous tubules lined with Sertoli cells and spermatogonia and Leydig cells. C, Ova and follicles. (From Grumbach MM, Barr ML. Cytologic tests of chromosomal sex in relation to sexual anomalies in man. Recent Prog Horm Res 1958; 14:255–334.)
(Williams Textbook of Endocrinology, 10th ed, 2003)

108. True Hermaphroditism
In most patients, the external genitalia are ambiguous but masculinized to variable degrees, and 75% are raised as male
Internal ductal development are influenced by ipsilateral gonad
Fallopian tubes are consistently present on the side of the ovary
a vas deferens is always present adjacent to a testis
Fallopian tube is present with 66% of ovotestes, vas or both in 33%
Most have urogenital sinus and and uterus
80% of those raised as male have hypospadias and chordee
Ovaries usually on left in normal position, testis usually on right and located anywhere along path of descent
60% of gonads palpable in canal or labia are ovotestes

109. True Hermaphroditism
Ovarian portion of the ovotestis is frequently normal, whereas the testicular portion is typically dysgenetic
66% of patients are 46 XX
Gonadal tumors is approximately 10% in 46,XY true hermaphroditism and 4% in 46,XX true hermaphroditism
Most important aspect of management in true hermaphroditism is gender assignment
Sex assignment should be based on the functional potential of external genitalia, internal ducts, and gonads, according to the findings at laparoscopy or laparotomy.
Unlike patients with most other forms of gonadal dysgenesis, true hermaphrodites have the potential for fertility if raised as female with the appropriate ductal structures
Males, remove ovaries and/or ovotestis and mullerian duct structures consider gonadectomy
Females remove all testicular and wolffian structures
Partial gonadectomy possible in female but stimulate the bHCG post op to ensure all testicular tissue removed.

110. Noonan syndrome
Both affected males and females have apparently normal chromosome complements and normal gonadal function
The phenotype appearance of Turner syndrome
: short stature, webbed neck, shield chest & cardiac malformations
(esp, pulmonic stenosis)
The trait as autosomal-dominant with variable expression

111. MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA
GENERAL GIUDELINES
Medical and social emergency
Avoid immediate declaration of sex
Proper counselling of the parents
Team management; obstetrician, neonatologist, pediatric endocrinolgist, genetist and paediatric surgeon.

112. EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA
Medical and psychosocial emergency to be handled with great sensitivity toward the family
Goals:
precise diagnosis of the intersex disorder
assign a proper sex of rearing based on the diagnosis
determine the status of the child's anatomy
delineate the functionality of genitalia and reproductive tract
Valuable history points:
infant death
infertility
amenorrhea
hirsutism
maternal medications (i.e. steroids , OCP), during pregnancy
Physical examination: the presence of one or two gonads
Distinctly palpable gonad along the pathway of descent is highly suggestive of a testis
Presence of one or two gonads on exam rules out female pseudohermaphroditism
Because ovaries do not descend…

113. MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA
DIAGNOSIS
History : pregnancy; family
Detailed examination
; Abdomen; pelvis; external genitalia; urethral and anal openings
Are gonads palpable?
What is the phallus length?
What is the position of the urethral meatus?
To what degree are the labioscrotal folds fused?
Is there s vagina, vaginal pouch, or urogenital sinus?
Dehydration, hypotension, hyperpigmentation in adrenal hyperplasia

114. DDx Algorithm
Diagnostic algorhythm for newborn with ambiguous genitalia based on gonadal palpability, presence or absence of mullerian structures, 17, hydroxyprogesterone concentration, and karyotype
If no testes check for elevated LH or stimulate with hCG to demonstrate testicular tissue.

115. EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA
Posterior urethral meatal position is a strong predictor of intersex 65%, versus 5% to 8% with a midshaft to anteriorly located hypospadiac meatus
Penile size should be assessed and an accurate measure of stretched penile length recorded.
Precise means of assessing müllerian anatomy is by pelvic ultrasound
Karyotype should be obtained
Serum studies should be immediately sent to rule out a salt-wasting form of CAH.
Serum electrolytes, testosterone and DHT should be measured early
Study by Kaefer and associates 1999, studied incidence of intersex in pts with chriptorchidism and hypospadius without ambiguous genitalia.
Karyotype usually takes 2-3 days, but can get rapid analysis with FISH (fouorescent in situ hybridizaiton) few hrs.

116. MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA
Investigations
• Pelvic US and sometimes MRI or Genitogram
• Karyotype
• Rule out Cong. Adrenal hyperplasia
Serum electrolytes; 17-OHP level,11-DOC & urinary levels of 17-ketosteroids
• Serum androgen (androstenedione, testosterone, DEA, DEAS)
• Laparoscopy
• Gonadal biopsy (Laparotomy)

118. Gender Assignment
Issues related to the diagnosis-specific potential for normal sexual functioning and fertility and the risk of gonadal malignancy should be addressed
In the setting of a 46,XX karyotype, gender assignment is usually appropriately female
If the karyotype is 46,XY, the issue is a more complex one and includes factors such as penile length and evidence of androgen insensitivity
The degree of masculinization of the external genitalia appears to vary with the amount of testicular tissue present
gender assignment depends on the functional potential of the gonadal tissue, reproductive tracts, and genitalia
Parameters of Optimal Gender Policy (Meyer-Bahlberg, 1998)
Reproductive potential (if attainable at all)
Good sexual function
Minimal medical procedures
An overall gender-appropriate appearance
A stable gender identity
Psychosocial well being
High quality data regarding long-term psychosocial outcomes of gender assignment are lacking at this point but longitudinal studies are being persued.
46, XX Normal ovaries, mullerian ducts, and reproductive potential.
46, XY if complete androgen insensitivity then female appropriate gender, whereas 5a-reductase deficiency more appropriately male.
Most frequent abnormal karyotype is 45X/46XY mosaicism  variable phenotypic pattern.
Ultimately this is a challenging and humbling process to say the least

119. Thank you