(INTERSEX)Part 1

DISORDERS OF SEXUAL DEVELOPMENT

DR.PREKSHA JAIN

CONTENTS of Part 1

1. Development in brief

2. Introduction

3. Classifications

4. Incidence

5. 46 XX DSD

6. 46 XY DSD

Normal Sexual Differentiation

GENETIC SEX

GONADAL SEX

SEXUAL DIFFERENTIATION OF

BRAIN

HORMONE PRODUCTION AT

PUBERTY

SECONDARY SEXUAL DEVELOPMENT

HORMONE PRODUCTION DURING FETAL DEVELOPMENT

SEXUAL DIFFERENTIATION OF EXTERNAL GENITALIA

SEX OF ASSIGNMENT & REARING

GENDER IDENTITY

PHENOTYPIC SEX

Gonadal development

46XY 46XX

INDIFFERENT GONAD

TESTIS OVARY

SRY GENE

MISPARAMESONEPHRIC DUCT

TESTOSTERONEMESONEPHRIC

DUCT

DHTEXTERNAL GENITALIA

ESTROGEN

PARAMESONEPHRIC DUCT

EXTERNAL GENITALIA

2wks later

Internal genital organs development

Leydigcells

Sertolicells

Testosterone Mullerian inhibitingfactor

Wollfian duct 5a-reductase

Urogenital sinus

Regrsession of Mullerian ducts

Male external genitalia

Male internal Genital organs

DHT

Male development

9 weeks

10 weeks

12-14 weeks

Urogenital sinus

Female external genitalia. Lower part of vagina

Mullerian ducts

Female internal genitalOrgans

. Most of upper vagina

. Cervix and uterus

. Fallopian tubes

Neutral Development

Absence of androgen exposure

Female development

INTRODUCTION• DISORDERS OF SEXUAL DEVELOPMENT:

Congenital conditions characterized by atypical development of chromosomal, gonadal or phenotypic sex.

• 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.

• TRUE HERMAPHRODITISM:

Has both ovarian & testicular tissue.

• MALE PSEUDOHERMAPHRODITISM:

Has testes, but a female genotype.

• FEMALE PSEUDOHERMAPHRODITISM:

Has ovaries but a masculine genital characteristics.

CLASSIFICATION

Old classification

1.Sex chromosomal intersex

2.Autosomal intersex

3.Gonadal intersex

4.Hormonal intersex

5.Psychological intersex

6.Sex of rearing

New Classification

Disorders of gonadal (ovarian) dvp

• Ovotesticular disorder (True Hermaphroditism)

• Testicular disorder of sexual dvp (46XX male sex reversal)

• Gonadal dysgenesis

Androgen excess- Fetal origin (congenital adrenal hyperplasia)

• 21 Hydroxylase (P450c21) deficiency

• 11 β Hydroxylase (P450c11β) deficiency

• 3β Hydroxysteroid dehydrogenase deficiency

Androgen excess- Fetoplacental origin

• Aromatase (P450arom) def

• P450 oxidoreductase def

Androgen excess- Maternal (Gestational hyperandrogenism)

• Drugs

• Excess androgen production

Other disoders of genital dvp

• Cloacal extrophy

• Mullerian Agenesis (MRKH)

• MURCS

46XX DSD

Disorders of Gonadal (testicular) development

• Complete gonadal dysgenesis (Swyer syndrome)

• Partial Gonadal dysgenesis

• Testicular regression Syndrome

• Ovotesticular DSD

Disorders of androgen synthesis

• Steroid 5α reductase def

• 17 α hydroxylase def (P450c17)

• 3β Hydroxysteroid dehydrogenase def

• 17β Hydroxysteroid dehydrogenase def

• P450 oxidoreductase def

• Steroid acute regulatory (StAR) protein def

Disorders of Androgen Action

• Complete Androgen Insensitivity Syndrome

• Incomplete/Partial AIS

LH receptor defects

• Leydig cell hypoplasia

Disorders of AMH & its receptor

• Hernia uterine inguinale syndrome

46 XY DSD

SEX CHROMOSOME DSD

1. 45 XO TURNER SYNDROME & its variants

2. 47XXY KLINEFELTER SYNDROME & variants

3. 45 X/ 46 XY MIXED GONADAL DYSGENESIS/ ovotesticular DSD

4. 46 XX/ 46XY CHIMERISM/ ovotesticular DSD

Incidence

• A conservative estimate is that 1 in 2000 children born will be affected by an intersex condition.

• 90 % of affected babies are due to congenital adrenal hyperplasia

46XX DISORDERS OF SEXUAL DEVELOPMENT

Disorder of Gonadal (ovaries) development

TRUE HERMAPHRODITISM

• Ovotesticular DSD

• Mixed ovarian & testicular tissue.

• B/l ovotestes OR an ovotestis &C/l ovary or testis

• Majority 46XX, 7% 46XY, 10-40% Mosaics

• Rt- Testicular tissue, Lt- ovarian tissue

• Cause- translocation of TDF from Y to X

• Int gen- Both

• Ext gen- Ambiguous / male

• Gonadal biopsy is required for confirming diagnosis

TRUE HERMAPHRODITISM

46 XX Sex reversal• Testicular disorder of sexual devp

• Occurs in 1 of every 20,000 males

• Chromosomal sex (46 XX) not consistent with gonadal sex (testes).

• 2 types- Sry positive& Sry negative

• Cause-

90%- Recombination distal short arms of X & Y and transfer of sry from Y to X during male meiosis.

10%- Sry not detected

• Int genitalia- Testes

• Ext genitalia-

Sry-negative: ambiguous

Sry positive: Normal male but hypogonadism, gynaecomastia, infertility, features of Klinefelter but have

o Shorter (mean height, 168 cm) & more normal skeletal proportions than Klinefelter’spatients

o Infertile lack of germ cell elements

46 XX Pure Gonadal Dysgenesis

• Cause- Autosomal etiology (AR)

• Features:

• Normal female external genitalia

• Normal müllerian ducts with absence of wolffian duct structures

• Normal height

• Normal 46 XX

• Bilateral streak gonads elevated serum gonadotropins

(hypergondotropic hypogonadism)

• Sexual infantilism

• Management-

• cyclic hormone replacement with estrogen and progesterone.

• growth is basically normal so GH is not needed

Androgen excess-Female Pseudohermaphroditism

FEMALE PSEUDOHERMAPHRODITISM

FETAL ORIGIN-

Congenital adrenal hyperplasia

• 21 -hydroxylase deficiency

• 11-hydroxylase deficiency

• 3ß-hydroxysteroid dehydrogenase deficiency

MATERNAL ORIGIN

Gestational hyperandrogenism

• Drug

• Excess production-

Pregnancy Luteoma

Theca lutein cysts

FETOPLACENTAL ORIGIN

• Aromatase deficiency

• P450 oxidoreductasedeficiency

EXCESS ANDROGENS

Mineralocorticoid

Glucocorticoid

Congenital Adrenal Hyperplasia• >90% - 21 Hydroxylase def

• Basic pathophysiology-

Decrease cortisol stimulate ACTH adrenal hyperplasia

Increase steroid hormone proximal to enzyme block increase androgens

• Time, duration & LEVEL of exposure of androgen determine degree of clitoral enlargement, labial fusion, urethral & vaginal abnormalities

• <10 wk- no effect, as adrenals not functional, vg & urethra separate

• 10-12 wk- androgens labial fusion, clitoromegaly

• 12-14 wk- limited effect if androgens rise after this

• Female ext gen not completed until 20wks, size of clitoris depends on Level of androgens

• Ovaries, AMH normal & high local conc not achieved- Wollfian absent

21-Hydroxylase Deficiency

• Most common endocrine cause of neonatal death.

• Two categories:

(1) Classical-

Salt wasters (deficiency of cortisol & aldosterone & with virilization) severe shock

Simple virilizers (patients with virilization, but without circulatory collapse) ambiguous gen

(2) Nonclassical (those without evidence of virilization or salt wasting) hirsutism, Menstrual

irregularities

• 1 in 5000 live births. 2/3rd (75%) Salt wasting 1/3rd (25%) simple virilizing

• Autosomal recessive pattern

• CAUSE: 21-hydroxylase gene ( CYP-21 ) chromosome 6p

1. Non- Reciprocal gene conversions active CYP-21 gene into the inactive gene occur in 65%

to 90% of cases of classic 21-hydroxylase deficiency (i.e., salt wasting and simple virilizing

forms) and in all nonclassic cases

2. Gene deletions are responsible for 10% to 35% of the remainder of mutations that produce

21-hydroxylase deficiency

21-hydroxylase (P450c21) deficiency

Pituitary

ACTH

Adrenal cortex

Androgens Cortisol

Cholesterol

Pregnenolone

Progesterone

17-OH progesterone

21-hydroxylase

Androgens Cortisol

Classical Salt wasting Simple virilizing

Non classical

Presentation At birth At birth (F)Neonates, early infancy (M)

Childhood or early adolescence

Ext genitalia

Puberty

Ambiguous genitalia (F) (adrenogenital synd)Adrenal insufficiency (M)

Masculinization of the untreated female; Pubic and axillary hair develop prematurelyAcne Deepening of voice

Ambiguous genitalia (F)Young children with early virilization (M)

Normal

Signs of hyperandrogenismPrecocious pubertyHirsutismMenstrual irregularities

Fertility 1.Chronic anovulation2.Abnormalities of genital anatomy and psychosocial factors

Pregnancy Protective effect of placental aromatase from virilization of female fetus; increase GDM

Diagnosis 1. 17 OHP levels >3500ng/dl2. 11 deoxycortisol & 17 α hydroxypregnenolone3. For confirmation- ACTH stimulation test (>10,000ng/dl)4. Genotyping cells from CVS5. Urinary 17-ketosteroids and pregnanentriol are elevated. 6. A pelvic USG for presence of mullerian tissues.7. Neonatal screening

Not by neonatal screeningSerum 17OHP levels N or DHEAS - N1. 17 OHP >82 ng/dl in children2. Adult women morning levels

<200-exclude CAH>800- diagnostic200-800 stimulation test(>1500)

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

Cholesterol

Desmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD3 B HSD

21 OH

11 OH

21 Hydroxylase Deficiency:

90 % of CAH

1 : 5000 births

50-70 % salt wasting

Female = ambiguous,

Male =virlization

11 β-Hydroxylase Deficiency

• 2nd m/c/c of CAH (1 in 1,00,000 live births)

• 5-8% cases of adrenal steroid enzyme defect.

• Types: salt wasting, simple virilizing & late-onset.

• Excess production of androgens & mineralocorticoid action of 11 deoxycorticosterone.

• Features- FEMALES

At birth- virilization of ext gen; children- precocious puberty; adolescent-

hirsutism, menstrual irrg

• 2/3rd exhibit HYPERTENSION due to 11 deoxycorticosterone.

• Mutations in the CYP-11B1 gene

• Chromosome 8q

• Diagnosis- Raised 11-deoxycortisol, 11-DOC & testosterone. ACTH stimulation

• Urinary 17-ketosteroids and 17-hydroxycorticoids are increased.

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

Cholesterol

Desmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD 3 B HSD

21 OH

11 OH

11 Hydroxylase Deficiency:

5 - 8% of CAH

HTN

Female = ambiguous, Hyperpig

Male = HTN, hypokalemia

3β Hydroxysteroid Dehydrogenase Deficiency

• Precursor of all steroid hormones.

• 2 types of 3β HSD enzymes-

1. Activity in placenta & peripheral tissues (skin, breast, prostate)

2. Adrenal, ovaries, testes

• Type 2 enzyme defect common.

• Pregnenolone, 17 Pregn, DHEA increased

• Types- Salt wasting & Non salt wasting.

• Features- Symptoms of gluco & mineralocorticoid def

• FEMALES: At birth- virilized ext gen;

Late-onset- premture pubarche, signs of hyperandrogenism (mild

clitoromegaly and labial fusion)

• MALE: Incomplete masculinization

• Autosomal recessive inheritance pattern

• Diagnosis-

1. 17 α Hydroxypregnenolone, pregnenolone, DHEA, DHEAS raised

2. Most reliable criteria- serum 17 α HP levels after ACTH stimulation

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

Cholesterol

Desmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD 3 B HSD

21 OH

11 OH

Survival is rare due to more proximal enzyme block

Weak Androgen3 B Hydroxy steroid DH Deficiency:

TREATMENT OF CAH

GOALS-

• Classical forms of CAH – provide cortisol , reduce ACTH & prevent androgen effect.

• Mothers- prevent masculinization of female fetus

• Neonates- life saving t/t, prevent virilization

• Children- to permit normal growth & sexual maturation

• Adults- hirsutism, menstrual irreg, infertility

1. PREIMPLANTATION GENETIC DIAGNOSIS IN COUPLES AT RISK- single cell removed from 6-8 cell stage embryo

2. PRENATAL TREATMENT OF MOTHERS AT RISK –

• Dexa upto 1.5mg daily divided doses

• Begin at 4-5 wks but not later than 9wk

• S/e- failure to thrive, psychomotor devp delay (neonate), severe abd striaehyperglycemia, HTN, GI symp (mother)

• 1 in 4 female fetus benefited. Early CVS , genotyping, sex determination recommended

3. NEONATAL TREATMENT: Present with ambiguity or adrenal crisis

• Hypotension– 10-20ml/kg 0.9% saline

• Hypoglycemia – 2-4 mg/kg 10% dextrose

• Hyperkalemia- Insulin & glucose

• Withdraw a blood sample for 17OHP etc

• 50-100 mg/m2 iv hydrocort 4 hrly until stable & feeding normally

• 0.3mg daily fludricortisone & Na Cl 1-3 g daily

4. CHILDREN: to promote growth & decrease sex steroid production

• Hydrocort 12-18mg/m2

Long acting glucocort can cause early closure of epiphysis

• Fludrocortisone 0.05- 0.2 mg in classical 21 HD

Overt/t- impair growth, Inadeq t/t- stimulate steroidogenesis

• Monitor- 3mthly infants, 4-12 mthly in children

• Measure- 17OHP (400-1200ng/dl) , Androstenedione, Plasma renin activity, growth velocity, skeletal maturation (Bone age & growth rate )

• GnRH agonist to prevent central precocious puberty.

• ILLNESS- ppt crises – increase hydrocort 2-3 folds (100mg), decrease gradually

• Growth hormone & long acting GnRH agonist to maximize height.

• S/e corticosteroid- Obesity & HTN

• SURGICAL M/m- Clitoroplasty, Separation of labial folds, Vaginoplasty.

Postponed until child is older & can participate in decision

5. ADULTS: goal is to lower & maintain androgens & adr precursors (17 OHP)

• After epiphysial closure – Long acting glucocorticoid

• Dexa 0.25-0.75mg btwn 2AM to 10 AM

• Others- Prednisone, hydrocort

• s/e- osteoporosis, cushing syndrome

• Fludrocort 0.1-0.2mg/d

6. PREGNANCY: Hydrocort dose increased

Cesarean section

FETOPLACENTAL ORIGIN ANDROGEN EXCESS

1.Aromatase deficiency:

• 19 c androgen to aromatic 18 c estrogen.

• Chrm 15, AR

• Female fetal virilization , low maternal estrogen and maternal hirsutism.

• Ambiguous genitalia, 1ry amenorrhoea with hyperandrogenism.

2.P450 oxidoreductase deficiency:-

• Chrm 7

• 46 XX (female virilization) & 46XY (incomplete male virilization)

• Partial deficiencies in 21 hydroxylase, 17, 20 lyase & to less extent 17 alpha hydroxylase ,aromatase.

• Cortisol levels usually Normal, Raised 17OHP, Low DHEA & andrestenedione

• Female Virilization in utero by “backdoor androgen pathway”

MATERNAL ORIGIN ANDROGEN EXCESS

Gestational hyperandrogenism

Hirsutism, temporal balding, clitoromegaly,deepning of voice in pregnant women.

Early pregnancy exposure- labioscrotal fusion & clitoromegaly of female fetus

> 12wks- clitoromegaly

1. DRUGS-

• Danazol for endometriosis

• Progestins for threatened/ recurrent abortions

Testosterone DiazoxideMinoxidil Danocrine

Phenytoin sodium Streptomycin Penicillamine

2. EXCESS ANDROGEN PRODUCTION-

• M/c/c- Luteomas & Theca lutein cysts

• Pelvic USG – All theca lutein cyst & ½ Luteomas are bilateral

• Surgery rarely needed as regress after delivery.

a) PREGNANCY LUTEOMA- Hyperplastic masses of lutenized cells

6- 10 cm in size

1/3 rd – maternal hirsutism

no risk to female fetus if mother not virilized

regress after delivery

b) THECA- LUTEIN CYST - Associated with increased hCG

10-20% with GTD

10- 15 cm

30% hirsute or virilize

OTHER DISORDERS

1. CLOACAL EXTROPHY- rectum, vg, urinary tract single orifice, omphalocoele, imperforate anus

2. MRKH

3. MURCS- Mullerian renal cervico thoracic somatic dysplasia

46 XY DISORDERS OF SEXUAL DEVELOPMENT

Disorders of Gonadal (testes) Development

Complete Gonadal Dysgenesis(SWYER SYNDROME)

• Streak gonads with no AMH nor androgens

• Int gen & ext gen – female

• Cause- 10-15% Sry inactivation

• Features- Delayed puberty, 1ry amenorrhea, normal pubic hair & normal int , ext gen

• Treatment- Gonadectomy soon after diagnosis

Female sex assignment

Estrogen for breast devp

Cyclic E & P for sexual maturation

Pregnancy by donor oocytes (IVF)

Partial Gonadal Dysgenesis

• Varieties of genetic mutations –

Single gene disorders (WT1, SRY, SF1, SOX9 etc)

Chrom Aberrations (Wnt4, Dax1, DMRT1)

• Mullerian struct absent or present

• Ext Gen female/ ambiguous/ male

• Other devp anomalies

Testicular Regression Syndrome

• Developmentally normal testes during but fetal life regressed / lost later

• Unilateral/ bilateral

• Partial/ Complete absence of testicular tissue

• Normal male Ext Gen

• Cause- Might be catastrophic event (torsion)

• Features- Late in pregnancy- Int & Ext Gen virilize, anorchia, small phallus, incomplete masculinization

Disorders of Androgen Synthesis

5 α Reductase Deficiency

• AR, Type 2 enzyme defect

• Testosterone DHT Blocked impaired virilization

• 46XY with severe perineal hypospadias (phallus size btwn penis & clitoris, chordee tethering phallus into perineum, urethra on perineum, small vg)

• Ext Gen- Female

• Int Gen- Male

• Testes in inguinal canal/ labia majora/ scrotum & impaired spermatogenesis

• Virilize to varying degrees at puberty

• Breast like normal male (contrast to AIS)

• Less body hair, less temporal hairline recession, no acne (Less DHT)

• Females- Body hair reduced, delayed menarche

urogenital sinus with separate urethral and vaginal openings, and posterior labioscrotal fusion

clitoromegaly with marked labioscrotal fusion and small vaginal introitus

Diagnosis -

• Infants with ambiguous genitalia , Adolescents phenotype

• serum hormone profile (normal testosterone, increased TT/DHT ratio > 10 infants, >20 in children & adults)

• hCG stimulation test- measure testosterone & DHT before & after (3rd & 6th

day) administration of 1500 IU/m2 hCG

Management- Sex assigned according to sex of rearing & psychological sex .

• Female- Gonadectomy , Clitoroplasty, Vaginoplasty, Estrogen t/t at puberty or after gonadectomy

• Male- Hypospadias & cryptoorchidism correction, Testosterone t/t

3β-Hydroxysteroid Dehydrogenase Deficiency• incomplete masculinization with salt-wasting impaired aldosterone and

cortisol synthesis

• a small phallus, hypospadias with labioscrotal fusion, a urogenital sinus, and a blind-ending vaginal pouch. Testes are often scrotal, and wolffian ducts develop normally

• diagnosis: increased levels of 3β-hydroxysteroids (pregnenolone, 17-hydroxypregnenolone, and DHEA)

17α-Hydroxylase Deficiency • conversion of pregnenolone and progesterone to 17-hydroxypregnenolone

and 17-hydroxyprogesterone

• impaired cortisol production ACTH hypersecretion increased DOC, corticosterone, and 18-hydroxycorticosterone in the adrenals

• These mineralocorticoids salt and water retention, HTN, and hypokalemia

• FEMALE- 1ry amenorrhea, delayed puberty, hypergonado hypogonadism, HTN hypokalemia

• MALE- Ext g- female, Int Gen- Male & Intraabd testes

• T/t- Glucocort, Estrogen therapy

17,20-Lyase Deficiency • cortisol and ACTH secretion are normal aldosterone normal no HTN

• ambiguous rather than totally female genitalia at birth

• suspect this dx if absent müllerian derivatives and no defect in glucocorticoid or mineralocorticoid synthesis.

17β-Hydroxy steroid Dehydrogenase Deficiency• Most common hereditary defect in testosterone synthesis

• Type 3 convert Androstenedione androgen, testosterone

• Male- normal int gen & undescended testes, Ext gen- female (blind vagina)

At puberty Virilization phallic growth and male secondary sexual characteristics

• Diagnosis- Androstenedione increased to 10 to 15x normal

Testos/ Androstn <0.8- 0.9 after hcg stimulation

• T/T- Gonadectomy, Estrogen therapy (if reared as F)

P450 Oxidoreductase deficiency-

As described earlier

StAR protein deficiency- Chrm 8p

• Congenital Lipoid Adrenal Hyperplasia

• Rarest & severest form of CAH

• Def of all adr & gonadal steroid hormones, raised ACTH, Adr hyperplasia, cholesterol ester accumulation

• Infants- Severe adrenal insufficiency

• Male- Ext g is female, a blind-ending vaginal pouch

intra-abdominal, inguinal, or labial testes

absence of mullerian structures & Wolffian ducts are present but rudimentary

• Female- Normal genitalia & puberty

• T/t- Gluco & mineralo

• Abdominal CT scan- large, lipid-laden adrenal glands

Disorders of Androgen Action

ANDROGEN INSENSITIVITY SYNDROME

Complete Androgen insensitivity syndrome

• Testicular Feminization syndrome

• 1 in 20,000 to 1 in 60,000 males

• Chrm Xq12 (X linked recessive)

• Normal testes AMH suppress mullerian & descent of testes up to inguinal canal

• Ext G- Female, Axillary & Pubic hair absent, Breast enhanced, Good height

• Presentation- Female with 1ry amenorrhea 2% of female with hernia

• Unequivocal female gender identity androgen resistance of brain tissue

• Serum Testos N/raised, LH increased, FSH normal, Estrogen raised, DHT decreased

• T/t- Hormone therapy, Vaginoplasty, Gonadectomy after puberty (16-18 yrs)

• Low (5-10%) risk of seminoma or gonadoblastoma before puberty

• Testis produces estradiol helps feminization

Incomplete Androgen Insensitivity

• Reduced number of normally functioning androgen receptors

• Normal receptor number but decreased binding affinity

ReifensteinSyndrome

Infertile Male

• Mildly under masculinized & infertile

• Normal Ext & Int G, normal testes, some gynecomastia

• 10% men with azoospermia / severe oligospermia have Partial AIS

• Decreased androgen receptor binding to DHT in genital skin fibroblasts

Diagnosis of AIS- Most reliable method- sequence AR gene

5α-reductase Complete Incomplete Reifenstein Infertile

Inheritence Autosomalrecessive

X-linked recessive

X-linked recessive

X-linked recessive

X-linked recessive

Spermatogenesis

Decreased Absent Absent Absent Decreased

Mullerian Absent Absent Absent Absent Absent

Wolffian Male Absent Underdevp Male Male

External Female Female Female clitoromegaly

Male hypospadias

Male

Breasts Male Female Female Gynecomastia M (Gynecomastia)

MANAGEMENT OF INCOMPLETE AIS

• Appropriate gender assignment- Size of phallus & feasibility of constructing male urethra

• Hormone therapy- Estrogen therapy for female after puberty.

Female Children- consider growth percentile, velocity, bone age, target

height & predicted adult height.

Boys- with Reifenstein syndrome – High dose testosterone

Adult men- Might improve masculinization

• Psychological support- early disclosure

• Gonadectomy- Earlier to prevent virilization at puberty (F) & maximisefunction(M)

• Reconstructive surgeries

• Gynecomastia in men – mastectomy (Risk of breast ca raised in Reifenstein)

LH Receptor Defects

• AR

• Inactivating mutation in LH/hCG receptor gene Leydig cell hypoplasia decrease testosterone production

• Mullerian – Absent (Normal AMH)

• Wollfian – Impaired (Decreased Testos)

• Testes – Undescended (require IGF3 & Testos, both by Leydig)

• Phenotype – Completely N female to nearly N Male

• At puberty - Females present with 1ry amenorrhea, sexual infantalism, Pubic hair & Breast Absent

• LH raised & testosterone decreased

Disorders of AMH & its Receptor

• Hernia uterine inguinale syndrome

• AR

• AMH receptor gene defect mullerian persists

• AMH gene 45%, AMHR2 receptor gene 39%, No mutation detected 15%

• Normal male Int & Ext Genitalia ,

• Cryptorchid testes &

• Inguinal hernia containing Mullerian structures during hernia repair

• M/M- Require orchidopexy

• Vas deferens are in close proximity to the uterus and proximal vagina not to remove to preserve fertility

• Malignancy of retained müllerian structures has not been reported

THANK YOU…to be continued

TRUE HERMAPHRODITISM

• Gonads :

- ovary one side and testis on the other or

- bilateral ovotestis

• Karyotype :

46,XX most common(57%); XY(13%) and XX/XY(30%)

• Internal genitalia :

Both mullerian and wolffian derivates

• Phenotype is variable

•

XX XY

XX O X Y

XXX XO XXY YO

OVUM SPERMATOZOON

NON-DISJUNCTION

Turner’s Syndrome (45,XO)

1 in 2500 live births

60% are 45,XO and 40% are mosaics

No oocytes remain in the ovaries, which become streaks

Ovum donation for those with bilateral streaks

33% - 60% have structural or positional abnormalities of the kidney

horseshoe kidney = 10%,

duplication or renal agenesis= 20%

malrotation= 15%

multiple renal arteries = 90%

Four classic features:

female phenotype

short stature

lack of secondary sexual characteristics

a variety of somatic abnormalities:

Cubitus valgus

Wide spaced nipples

Broad chest (shield)

Webbed neck

Short stature

peripheral edema at birth, short 4th metacarpal, hypoplastic nails, multiple pigmented nevi, coarctation of the aorta, and renal anomalies

Characteristics

1. Short slender female less than 5 ft.

2. Secondary sexual ratio altered

3. Breast B0 or B1

4. Body hairs absent

5. Shield chest,webbing of neck,cubitus

valgus

6. CVS abnormalities (aortic

stenosis,coarctation of aorta)

7. Urinary abnormalities

8. Mental retardation

9. External genitalia poorly developed.

10. Uterus and tubes –hypoplastic

11. Internal gonads-agenetic or

dysgenetic

12. Primary ovarian failure

13. Colour blindness and multiple navi

on skin

14. Hashimoto’s thyroiditis,Addison’s

disease and vitiligo are common.

15. Anormality of lymphatic system

may sometimes cause gross swelling

of thelegs in the child or adult.

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

After birth tubules are aplastic and functionless so sterility is the rule.

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

Klinefelter's syndrome

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 teratomahave also been reported

Management removal of both streak gonads and proper cyclic hormone replacement with estrogen and progesterone

Mixed gonadal dysgenesis (MGD)

Characterized by a unilateral testis, often intra-abdominal

Contralateral streak gonad

Persistent müllerian structures with varying inadequate masculinization

Most are 45,XO/46,XY, the most common form of Y chromosome mosaicism

Second most common cause of ambiguous genitalia after CAH

Dysgenetic or streak gonad is associated with ipsilateral mullerian derivatives (uterus, fallopian tube)

Well-differentiated testis with functional Sertoli and Leydig cells will have ipsilateralwolffian but no mullerian ducts

no germ cells so infertility is the rule

Increased risk of developing gonadoblastoma or dysgerminoma of 15% to 20%

Also increased risk for Wilm’s tumor .

Endocrine function of testis is normal post-pubertally

fetal testis dysfunction may account for ambiguous genitalia

90% to 95% of 45,X/46,XY mosaicism have normal-appearing male genitalia

Bilateral dysgenesis of testes( Swyer

Syndrome)

XY karyotype with mutation in SRY gene.

Fibrous bands in place of gonads.

Female internal and external genitalia

presents with primary amenorrhea and lack of

secondary development at puberty.

To prevent neoplasia removal of band areas is

advocated as diagnosis is made.

Anorchia

XY individual with infantile umambiguous

male external genitalia and male wolffian

ducts and lack mullerian ducts.

No detectable testes, early testes did occur

but was not sustained in sufficient amount or

duration to develop normal size phallus.

Also known as “disappearing testis

syndrome”.

Noonan syndrome

Inheritence autosomal dominant

Both affected male and females have normal chromosome complements and normal gonadalfunction.

The phenotypic appearance is that of a patient with turner syndrome. The cardiac lesions are different, pulmonic stenosis as opposed to aortic coarctation.

These are fertile.

AMBIGUOUS GENITALIA AT

BIRTH

The external genital organs look

unusual, making it impossible to

identify the sex of the newborn

from its outward appearance.

Any one of the following :

A small, hypospadiac phallus

and unilaterally

undescended gonad.

An enlarged phallus with

bilaterally impalpable

gonads.

An enlarged phallus and a

vagina in the same infant.

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.

MANAGEMENT OF NEWBORN WITH

AMBIGUOUS GENITALIA

DIAGNOSIS

History : pregnancy; family

Detailed examination : abdomen; pelvis; external genitalia; urethral and anal openings.

Federman’s rule: a palpable gonad below the inguinal ligament is testes until proven otherwise

MANAGEMENT OF NEWBORN WITH

AMBIGUOUS GENITALIAInvestigations

• Rule out cong. Adrenal hyperplasia: Serum electrolytes; 17-OHP level and urinary levels of 17-ketosteroids

• Karyotype ( buccal smear; blood)

• Pelvic US and sometimes MRI or Genitogram

• Skin biopsy; fibroblast culture to measure 5alpha-reductase activity or dihydrotestosterone binding

• Laparoscopy

• Gonadal biopsy (laparotomy)

Sex assignment1)Phallus length- Male gender assignment :

- stretched phallus > 2.5 cm

- erectile tissue

- lack of severe hypospadias

Female gender assignment :

- clitoris < 1cm

- cervix and uterus present.

2) Degree of labioscrotal fold fusion

In difficult cases; sex assignment should be

to the sex which can be surgically made to be

adequate for coitus

DDx Algorithm

SURGICAL CONSIDERATIONS

Phallic / clitoral reduction if the assigned sex is female, before 3 years of age

Removal of intra-abdominal gonads / streaks in newborns carrying Y chromosome

Vaginal construction / repair is better performed around puberty

Before surgery After surgery

GONADECTOMY

VAGINAL CREATION

Vaginal dilatation

McIndoe Vaginoplasty

William’s vulvo-vaginoplasty

Colovaginoplasty

Transsexualism

Transsexualism occurs when a person strongly

believes that he or she belong to the opposite sex.

This is typically a lifelong feeling and results in

varied degrees of physical/external changes

These patients should be referred to the psychiatrist

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