PROF.DR.G.SUNDARAMURTHY’S UNITBHARGAVI.K.

17 yr old female came to the op with chief c/o

coarse voice…

h/o loss of appetite+

h/o lethargy +

No h/o fever

No h/o recurrent cough with expectoration

No h/o post nasal drip

No h/o hemoptysis

No h/o dysphagia

No h/o intolerance to cold

No h/o constipation

No h/o alopecia

No h/o galactorrhoea

No h/o hot flushes

No h/o palpitations

No h/o visual disturbances

PAST H/O

NO SIGNIFICANT MEDICAL ILLNESSES IN THE PAST OR SURGICAL INTERVENTION IN THE PAST.

NOT A K/C/O HYPOTHYROIDISM No h/o psychiatric disorders

DEVELOPMENTAL H/O: normal

PERSONAL H/O

takes mixed diet No h/s/o of eating disorders NO h/s/o substance abuse Not an athlete- subject to strenuous exerciseMENSTRUAL H/O

NOT ATTAINED MENARCHE.. NOT EVALUATED PRIOR.

FAMILY H/O

Born of non consanguinous marriage.

Parents healthy.

1 sibling –male 21 yrs. Healthy.

A CASE OF PRIMARY AMENORRHOEA

WITH COARSE VOICE

IN THE LINES OF…

CONSTITUTIONAL DELAYHYPOTHYROIDISMHYPERPROLACTINEMIAPREMATURE OVARIAN FAILUREDSD

Gc fairAfebrileHydration fairNo

pallor/icterus/cyanosis/clubbingNo significant lymphadenopathy

Ht,wt- appropriate for age.Hirsute features+No digital anomaliesNo ext markers for congenital

heart disease.

Pulse -88/minBP- 120/70 mm hg CVS

s1s2+ no murmurs.

RESPIRATORY SYSTEM-

nvbs+: no additional sounds.

CNS

Nfnd .

EXMN OF EAR,NOSE , THROAT- normal.

EXMN OF ORAL CAVITY -normal.

PER ABDOMEN- soft, no organomegaly, no free fluid.

BREASTS- TANNER STAGE I

PUBIC HAIR- TANNER STAGE III

AXILLARY HAIR- SPARSE

PER VAGINAL

AMBIGUOUS EXTERNAL GENITALIA

PENIOSCROTAL HYPOSPADIAS

A CASE OF DISORDER OF SEX

AND DEVELOPMENT

DISORDERS OF SEX AND

DEVELOPMENT

46 XX OVOTESTICULAR 46 XY

CAH

BLOOD SUGAR -88 mgs

RFT :urea -18 creatinine- 0.8 mgs

S.electrolytes:Na-140, K- 4,Cl- 98,HCO3-28mEq/L

CBC : TC-6800,DC-P48 L52 E2

HB:11.2 GMS, ESR-5/12 PLATELETS-1.0

URINE ANALYSIS -normal

ECG- NSR

C-XRAY -normal

THYROID FUNCTION TESTS

Thyroid function tests

LH : 12.85 mIU/ml

NORMAL VALUES

FOLLICULAR PHASE:1.9 -12.5

MIDCYCLE PHASE:8.7-76.3

LUTEAL PHASE:0.5-16.9MENOPAUSAL:>50

FSH: 7.60 mIU/ml

NORMAL VALUES

FOLLICULAR PHASE:1.9 -10.2

MIDCYCLE PHASE:3.4-33.4

LUTEAL PHASE:1.5-9.1MENOPAUSAL:23-116

TESTOSTERONE : 3.37 pg/ml.

NORMAL VALUES

MALE: 8.9-42.5 FEMALE:0.2-3.09

PROGESTERONE: 0.88 ng/ml.

NORMAL VALUES

FOLLICULAR PHASE:0.11-1.08

LUTEAL PHASE:0.95-5.0

Estradiol levels :55 pg/ml.

Normal valuesFollicular phase:30-60 pg/mlPreovulatory phase:110-410Luteal phase:19-160

High testosteroneHigh LH

High Estradiol Normal FSH

ULTRASOUND ABDOMEN AND PELVIS

USG PELVIS

BIOPSY OF INGUINAL STRUCTURES

CONFIRMED THE PRESENCE OF SEMINIFEROUS TUBULES,LOBULI TESTIS AND RETE TESTIS.

COARSE VOICE,PRIMARY AMENNORRHOEA

HORMONE PROFILETESTOSTERONE,LH

USG PELVISABSENT UTERUS,OVARIES

BIOPSY OF INGUINAL STRUCTURES-TESTIS

?

KARYOTYPING

46 XY

DIAGNOSIS

A CASE OF INCOMPLETE ANDROGEN INSENSITIVITY

SYNDROME

REFEINSTEIN’S SYNDROME

COMPLETE AIS

PARTIAL AIS

Inheritance  X-linked recessive X-linked recessive

External genitalia 

Female Broad spectrum from female with mild clitoromegaly to male with micropenis and/or hypospadias

Müllerian duct derivatives 

Absent Absent

Wolfian duct Absent Broad spectrum from absent or male

Testes  Inguinal or intraabdominal,

Ectopic, inguinal or intraabdominal,

Puberty  Gynecomastia Gynecomastia

Hormonal diagnosis 

High or normal serum LH and T levels, normal or slightly elevated FSH levels

High or normal serum LH and T levels, normal or slightly elevated FSH levels

Molecular defect 

Mutations or deletions in androgen receptor gene

Mutations in AR gene

? PARTIAL AIS

Penioscrotal hypospadiasAmbiguous external genitaliaHypoplastic wolfian duct derivativesAbsent mullerian duct derivativesUndescended testicular gonadsPresence of pubic n axillary hair- but

scanty Increased LH AND TESTOSTERONE,

normal FSH.

MANAGEMENT

PSYCHOLOGICAL COUNSELLING OF THE PATIENT AND PARENTS

TO CONTINUE SEX OF REARING AS FEMALE

DEPT OF PLASTIC SURGERY, GSH

b/l orchidectomy, herniorrhaphy and clitoroplasty.

Planned next for vaginal reconstuction

Planned breast enhancement- silicone implantation

Now placed under estrogen supplements-on follow up .

PRIMARY AMENNORRHOEA WITH DELAYED PUBERTY

BONE AGE- CONSTITUTIONAL DELAY

THYROID PROFILE

LH, FSH, PROLACTIN

INCREASED LH,FSH NORMAL LH,FSH

INCREASED LH,FSH

KARYOTYPING

45 X( turner’s)

46 XX(pure gonadal dysgenesis)

46 XY(swyer’s)

NORMAL LH, FSHPROLACTIN HIGH

IMAGING MRI

ABNORMAL-PITUITARY CAUSES NORMAL MRI

EATING DISORDERS STRESS

AMENNORHOEA WITH

NORMAL PUBERTY

ULTRASONOGRAM

UTERUS PRESENT

HYPOTHYROIDISMHYPERPROLACTINEMIA FSH LEVELS

LOW- MRIHIGH FSH-

PREMATURE OVARIAN FAILURE

GENITAL TRACT

ABNORMALITIES

ULTRA

SONOGRAm

ABSENT UTERUS FORESHORTENED

VAGINA

KARYOTYPe

46 XX

MULLERIAN AGENESIS-ROKITANSKY

46 XY

TESTOSTERONE

HIGH LOW

ANDROGEN INSENSITIVITY OR

5 A RED DEFICIENCY

TESTICULAR REGRESSION

CAH

21 OH DEFICIENCYMASCULINISATION

SALT WASTINGINCREASED 17 OH P

11 OH DEFICIENCYINCREASED DOCSALT RETENTIONHYPERTENSION

3 B HSD DEFICIENCYLESS VIRILIZ, SALT

LOSING^DHEA

ONLY FORM CAUSING AMB.

GENIT IN MALES

Ovotesticular disorders of sexual development

Appearance of the genitalia varies widely in this condition. While ambiguity is the rule, the tendency is toward masculinization.

The most common karyotype is 46,XX, although mosaicism is common

46 XY DSD

ISOLATED DEFICIENCY

OF MIS

PHENOTYPIC MALE WITH AN

INGUINAL HERNIA ON ONE SIDE

AND AN IMPALPABLE CONTRALATERAL GONAD

DEFICIENT TESTOSTERONE BIOSYNTHESIS

ENZYME DEFECTS OR

LEYDIG CELL DEFECTS

5 ALPHA REDUCTASE DEFICIENCY

EXTREME VIRILISATION AT PUBERTY

HIGH T/DHT RATIO

PARTIAL GONADAL

DYSGENESIS46 XY OR

MOSAICISMONE GONAD IS DYSGENETIC

PURE GONADAL

DYSGENESISB/L STREAK

GONADS

AIS

ANOMALOUS SEXUAL

DEVELOPMENT

I.DISORDERS OF GONADAL DIFFERENTIATION

II.FEMALE PSEUDOHERMAPHRODITISM

III.MALE PSEUDOHERMAPHRODITISM

IV.UNCLASSIFIED FORMS

.TESTICULAR UNRESPONSIVENESS -LEYDIG CELL HYPOPLASIA

.INBORN ERRORS OF TESTOSTERONE BIOSYNTHESIS

.DEFECTS IN ANDROGEN DEPENDENT TARGET TISSUES

DYSGENETIC MALE PSEUDOHERMAPHRODITISM

.DEFECTS IN ANTI MULLERIAN HORMONE RESPONSE

.MATERNAL INGESTION OF PROGESTAGENS

.ENVIRONMENTAL CHEMICALS

I.END ORGAN RESISTANCE TO ANDROGENIC HORMONES

A. syndrome of complete androgen resistanceB. syndrome of incomplete androgen resistanceC. androgen resistance in phenotypically normal males

II.DEFECTS IN TESTOSTERONE METABOLISM BY PERIPHERAL TISSUES

5 alpha reductase deficiency

o Grade 1: PAISMale genitals, infertile

o Grade 2: PAISMale genitals but mildly ‘under-masculinized’

o Grade 3: PAISMale genitals more severely ‘under-masculinized’

o Grade 4: PAISAmbiguous genitals

o Grade 5: PAISEssentially female genitalia, with enlarged clitoris

o Grade 6: PAISFemale genitalia with pubic/underarm hair

o Grade 7: CAISFemale genitalia with little to no

pubic/underarm hair

Exists along continuum depending on degree of mutation in AR gene

Androgen Receptor GeneAndrogen 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.

Mutations include complete or partial gene deletions, point mutations and small insertions or deletions.

Mullerian duct inhibitor suppresses the mullerian ducts and 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 and genitals to be unable to respond to the androgens testosterone and dihydrotestosterone.

-testicular feminizationSyndrome of MorrisPrevelance about 1 in 44,000-60,000

live male births

KARYOTYPE 46 XY

INHERITANCE X-LINKED RECESSIVE,MUTATIONS IN AR GENE

GENITALIA FEMALE WITH BLIND VAGINALPOUCH

WOLFIAN DUCT DERIVATIVES:

USUALLY ABSENT

MULLERIAN DUCT DERIVATIVES:

ABSENT OR VESTIGIAL

GONADS TESTIS

HABITUS: ABSENT PUBIC AND AXILLARY HAIR,BREAST DEVELOPMENT AND FEMALE HABITUS AT PUBERTY, PRIMARY AMENNORHOEA”HAIRLESS WOMEN”

HORMONE AND METABOLIC PROFILE:

INCREASED PLASMA LH AND TESTOSTERONE CONCENTRATION,INCREASED ESTRADIOL, FSH LEVELS OFTEN NORMALRESISTANCE TO ANDROGENIC N METABOLIC EFFECTS OF TESTOSTERONE

ANDROGEN RECEPTOR STUDIES

GENETIC HETEROGENEITY: RECEPTOR NEGATIVE, UNSTABLE OR RECEPTOR POSITIVE FORM

REIFENSTEIN SYNDORME

Incidence- 1 in 1, 30,000 LIVE BIRTHSSynonyms:Gilbert-Dreyfus Syndrome Incomplete Testicular Feminization Lubs Syndrome Rosewater Syndrome Type I Familial Incomplete Male

Pseudohermaphroditism

KARYOTYPE 46 XY

INHERITANCE X-LINKED RECESSIVE,MUTATIONS IN AR GENE

GENITALIA AMBIGUOUS WITH BLIND VAGINAL POUCH-PERINEOSCROTAL OR PENILE HYPOSPADIAS, ASMALL VAGINAL POUCH, A HOODED PHALLUS, UNFUSED PREPUTIAL FOLDS, BIFID SCROTUM, OCCASIONALLY GONADS.

WOLFIAN DUCT DERIVATIVES:

RUDIMENTARY-HYPOPLASTIC-NORMAL

MULLERIAN DUCT DERIVATIVES:

ABSENT

GONADS TESTIS- USUALLY UNDESCENDED

HABITUS: decreased to normal axillary and pubic hair, beard growth and body hair, gynaecomastia

HORMONE AND METABOLIC PROFILE:

increased plasma lh n testosterone, increased estradiol, fsh levels normal or slightly increasedPartial resistance to androgenic and metabolic effects of testosterone

ANDROGEN RECEPTOR STUDIES

genetic heterogeneity, partial deficiency of normal receptor, mutations lead to qualitatively abnormal receptor.

DURING PREGNANCY Chorionic villus

sampling, ultrasound and amniocentesis

AFTER BIRTH

Hormone profile Usg pelvis karyotyping

Special dynamic endocrine tests

HCG STIMULATION TEST

ADMINISTRATION OF STEROIDS – DECREASED RESPONSE IN SEX HORMONE BINDING GLOBULIN

EVIDENCE OF ABNORMAL ANDROGEN BINDING IN A GENITAL SKIN FIBROBLAST

SURGERIES

Orchidectomy or gonadectomy

Vaginal lengthening

Genital plastic surgery

Phalloplasty

Vaginoplasty

clitoroplasty

HORMONE REPLACEMENT THERAPY

ESTROGENProgesterone

Route-oral,transdermal or vaginal

Prevention of osteoporosis

EMOTIONAL AND PSYCHOLOGICAL SUPPORT

WHEN AND HOW TO DISCLOSE THE NEWS TO THE PATIENT

FAMILY: GUIDANCE IF THEY ARE CARRIERS AND DECISION ON FURTHER CHILD BIRTHS

ANDROGEN INSENSITIVITY SUPPORT GROUPS

PSYCHOLOGICAL ISSUES