Presenter: Dr Avinash KumarModerator: Dr Harish ChellaniDr soumya tiwari
Definition When the external genitalia do not have the typical anatomicappearance of normal male or female genitalia Most cases present in newborn period Social and medical emergency
When to suspect Micropenis: Stretched penile length<2.5cm in a term newborn Asymmetry of labioscrotal folds B/L cryptorchidism U/L cryptorchidism with hypospadias B/L testes with perineoscrotal or penoscrotal hypospadias Female external genitalia with clitoromegaly or inguinal hernia Overtly abnormal genitals like cloacal exstrophy
Disorder of Sexual Differentiation(DSD) Also known as disorder of sexual determination (Nelson) Preferred over older terminology such as ambiguous genitalia,pseudohermaphroditism and intersex Atypical development of genetic, gonadal and phenotypic sex Includes disorders grouped under 4 major headings 46,XX virilized female 46,XY undervirilized male Gonadal differentiation and chromosomal disorders Syndromes associated with ambiguous genitalia
Incidence The exact data on the incidence and prevalence ofconditions causing ambiguous genitalia are limited Congenital adrenal hyperplasia accounts for most of thecases Incidence of CAH 1 in 15000, AIS 1 in 20,000 (Avery’sdisease of newborn 9th ed)
Incidence-IndiaEtiology and clinical profile of ambiguous genitalia studied (n=109)1) Genetic females with virilisation or FPH –27.5 %(n=30) Congenital adrenal hyperplasia (CAH) was the underlying cause in all cases ofFPHSalt wasting form - 23/30Simple virilising form – 7/302) Genetic males undervirilised or MPH –52.3 %(n=57)Androgen insensitivity syndrome - 28% (16/57)5- alpha reductase deficiency - 23%(13/57) .3) Disorder of gonadal differentiation- 10.1%(n=11)Gonadal dysgenesis – 9/11True hermaphrodite – 2/114) Syndromic form of ambiguous genitalia- 1.8% (n=2)Rajesh R. Joshi, Sudha Rao, Meena Desai. Etiology and clinical profile of ambiguousgenitalia-an overview of 10 years experience. Indian Pediatrics, 2006;43:974-979.
Embryology Sexual differentiation-3 stages1. Determination of chromosomal sex (at conception)2. Gonadal differentiation (at 6-7 wks of gestation)3. Phenotypic sex determination (at 8-12 wks of gestation) Stage 1 depends upon sex chromosome complement offertilizing sperm Stage 2 depends upon SRY gene of Y chromosome Stage 3 depends upon testosterone and Mullerian InhibitingFactor (MIF)
Gonad develops from Somatic cells (arise from mesonrphric cells and coelomicepithelium)- sertoli cells/granulosa cells Germ cells (arise from yolk sac and migrate to genital ridge)-Leydig cell/theca cell
Embryology Testicular development is guided by TDF which is encodedby the SRY gene on the short arm of the Y chromosome. Under the influence of the TDF ,germ cells in the genital ridgedifferentiate into Sertoli cells which secrete MIS (causesregression of the mullerian ducts) and Leydig cells whichproduce testosterone (promotes maturation of spermatogoniaand regulates male phenotype).
EmbryologyWolffian duct develops into the following: Epididymis Vas deferens Ejaculatory duct and seminal vesicles
Embryology In the absence of the Y chromosome , gonads differentiateinto ovaries at around 11-13 weeks gestation. Absence of MIS leads to persistence of mullerianstructures which develop into:Fallopian tubesUterus Cervix Vagina
Embryology Undifferentiated external genitalia includes the following: Urogenital tubercle Urogenital swelling Urogenital folds
Embryology In males DHT leads to development of these three structuresinto : Glans penis Scrotum Penile shaft In absence of DHT, these structures develop into Clitoris Labia majora Labia minora
Embryology True hermaphroditism have both testicular and ovarian tissuein the gonads. In patients with pure gonadal dysgenesis,both gonads arestreak gonads. Patients with mixed gonadal dysgenesis have a testis on oneside and a streak gonad on the other
History Maternal drug ingestion esp. in 1st trimester (virilization in agonadal female) H/O virilization in mother may suggest androgen producingtumour (arrhenoblastoma) Past h/o early death of infants may suggest a previously missedandrogenital deficiency Family h/o affected sibling or family member (CAH, testicularfeminization)
External genitalia Examination Note the size and degreeof differentiation of thephallus, since variationsmay representclitoromegaly orhypospadias Note the position of theurethral meatus -hypospadiasis CAH with ambiguous genitalia
External genitalia Examination Labioscrotal folds may beseparated or folds may befused at the midline,giving an appearance of ascrotum Labioscrotal folds withincreased pigmentationsuggest the possibility ofincreased corticotropinlevels as part ofadrenogenital syndromeMicropenis with hypospadiasis, bifidscrotumAmbiguous genitalia in CAH
Algorithm for evaluation of 46,XX DSDAmbiguous genitalia46 XX KaryotypeUterus present17 Hydroxy progesteroneIncreasedNormal NormalOvotestis on USGBiopsy:Ovarian folicles &testicular tubulesCAHMatrnal virilization/Exogenous androgen exposureHermaphroditism(Bisexual gonads)Maternal virilizing disorders:Medications: ProgestinsTumors (adrenal/ovarian)Luteomas of pregnancyAromatase deficiency
Algorithm for evaluation of 46,XY DSDAmbiguous genitaliaKaryotype 46 XYUterus presentGonadal biopsy:•True hermaphordite•Persistent mullerian ductsyndromeNo uterushCG stimulation testN/ T & DHT:AIS(Ar mutationanalysis)/IdiopathicNormal T & DHT: 5 alpha reductasedeficiencyT and DHT:LH/FSH :partial gonadal dysgenesis,leydig cell hypoplasiaPrecursor steroids : T-biosynthesisdefectlvisUSG Pelvis
Ultrasonography Identify müllerian structures- uterus, ovaries, fallopian tubesand upper half of vagina Allows visualization of a neonates adrenal glands - enlarged ininfants with congenital adrenal hyperplasia (CAH) - have acribriform appearance. Normal ultrasonographic findings of the adrenal glands do notexclude a diagnosis of CAH.
Genitography Helps to determine ductal anatomy. In a neonate with ambiguous genitalia, a catheter can beinserted into the urethra - Contrast is injected to outline theinternal ductal anatomy. Findings - normal urethral anatomy, a müllerian remnant in amale, a common urogenital sinus, or normal female internalgenitalia CT and MRI - may help identify internal anatomy
Genetic Evaluation KARYOTYPE FISH Presence of SRY X and Y probes for gonadal biopsies Specialized molecular genetic tests Mutation analysis of 21-hydroxylase gene Androgen receptor sequencing Y chromosome microdeletions
hCG stimulation test Evaluation of gonadal axis in children Dynamic & reliable test for leydig cell evaluation in boys Assess testosterone secretion by testes 500 IU of hCG given i/m daily for 3 days Serum testosterone, DHT, DHEA, androsteedione, LH & FSHare measured at baseline and then 24 hr after 3rd day Collection of 24 hr urine before & after three doses of hCGused in analysis of steroid profile to detect testosteronebiosynthesis defect
Interpretation 2 to 20 times rise in testosterone1)adequate rise indicates presence of functioning testes2)if rise is blunted –enzymatic defect in testosterone synthesis,gestational loss of testicular tissue, LH receptor mutation3) ↑ T:DHT ratio(>20:1)- 5 alpha reductase def Raised LH,FSH denotes anorchia or primary gonadal failure Increased precursor steroid denotes biosynthesis defect
GnRH stimulation test Assess the pituitary function and degree of pubertal maturationin DSD Evaluation of B/L cryptorchidism (along with hCG stimulationtest)Method: Serum LH, FSH, estradiol, testosterone and SHBGcollected, followed by 2.5mcgm/kg GnRH iv is given, thenabove samples collected at 30 and 60 min.
Interpretation In normal cases FSH&LH values rise at 30 min and laterdecline at 60 min Initially there is predominant FSH response with progressiveincrease in LH response with pubertal maturation In primary gonadal failure the basal gonadotropins areelevated with exaggerated response to GnRH
DSD Team Participants Pediatrician Medical Geneticist Pediatric Urologist Pediatric Endocrinologist Gynecologist Pediatric Psychologist Cytogeneticist Social Worker
General guidelines for genderassignment Try to match the baby’s sex assignment to the chromosomaland gonadal sex if possible Try to anticipate pubertal development Consider future function when planning surgeries Try to preserve fertility Respect the opinions of well-informed parents
TreatmentTreatment options include : Reconstructive surgery Hormone therapy
Reconstructive surgeryGoalsCosmetic to make a boy’s or a girl’s genitalia look natural restoring sexual function May need repeated surgeries later in life
Reconstructive surgery For girls : sexual function of organs is often not compromiseddespite any ambiguous appearance. Depending on severity options are : Uncovering vagina hidden under skin Removing excess masculine tissue around theclitoris(clitoral reduction) – done once hormone replacementtherapy has begun Testis should be removed soon after birth if female sex ofrearing is decided
Reconstructive surgery For boys : surgery is complicated but often successful. Itincludes : Lengthening of the incomplete penis Undescended testis that is to be retained is best broughtdown into the scrotum at the time of initial gonadal biopsy Correction of chordee and urethroplasty in boys withhypospadias is usually performed between 6 and 18 monthsof age
Hormone therapy Depending on severity of condition, hormone therapy alonemay be enough to correct the initial hormonal imbalance. Ability of the gonads to produce appropriate hormones for sexof rearing is a factor in sex assignment. Advantageous to retain a gonad appropriate to the assigned sexif it is likely to function adequately.
Hormone therapyOvaries of true hermaphrodites may also produceadequate levels of estrogen.However, the testes of true hermaphrodites and mixedgonadal dysgenesis may initially show good function thatdeclines during childhood Testosterone supplements may be necessary for theestablishment of puberty or in adult life.
Ovotesticular DSD Pts who are highly virilised have a good testicular function,have no uterus and therefore are usually raised as males If uterus exists, virilisation is mild, testicular function isminimal, and female sex is usually assigned
Prediction of fertility Ovaries are generally functional but testicular tissue isgenerally dysgenetic XX patients with CAH have a reasonably high probability ofbeing fertile since they have a uterus and 2 normal ovaries Women with 46,XX ovotesticular DSD are occasionally fertile
Pts with gonadal dysgenesis, partial AIS, 17-OHD are infertileeither because testis are abnormal or there is no uterus If child has no chance of fertility and genitalia are sufficientlywell developed to function as male, male sex of rearing isadvised Pts with ovotesticular DSD should be raised as female afterremoving the testicular tissue and leaving the ovary in place
Congenital Adrenal Hyperplasia Incidence – 1 in 12000 Most common cause of ambiguous genitalia in female newborn Autosomal recessive inheritance No sex prediliction 21-hydroxylase deficiency - common cause of CAH Young women may present with symptoms of polycysticovarian syndrome
PresentationMales - classic CAH-no signs of CAH at birth Hyperpigmentation and possible penile enlargementFemales – Virilisation at birth May present as salt-wasting disease Non-salt-wasting disease - present later with signs ofvirilization
Management Medical –Stablisation of general conditionCorrection of electrolyte abnormalitiesAfter stabilisation – replacement of glucocorticoid and / ormineralocorticoids depending on the general condition Glucocorticoid replacement : Hydrocortisone – 10-15mg/m2/d Prednisolone – 2.5-6mg/m2/d Mineralocorticoid replacement : 9 fluorohydrocortisone – 0.1-0.2mg/d
Management Surgical –Females with severe virilisation – early recession of clitorisfollowed by vaginoplastyMild virilisation – medical treatment is adequate
5 alpha reductase deficiency Autosomal recessive Clinical features - Normal male external genitalia, ambiguousgenitalia or normal female genitaliaCapable of producing viable spermFeminized or ambiguous genitalia - macroclitoris ormicropenisPrimary amenorrhoea and may experience virilization
Treatment Medical management –Males – testosterone enanthenate 25 mg i.m. monthly X 3mthsmay increase penile lengthFemales - estrogen replacement therapy should be initiated at abone age of 12 years or once an increase in gonadotropins isobservedDose is tailored to reach adult replacement levels over a 3-4year range
Surgical treatment FemalesFeminizing genitoplasty - gonadectomy, restructuring of thelabioscrotal folds into labia, and reduction or recession of thephallus MalesUrethroplasty (Perineoscrotal hypospadias repair is typically amultistage procedure.)Repair of bifid scrotumChordee repairOrchiopexy
Androgen insensitivity syndrome(AIS) Also known as Androgen receptor defects M/c form of male DSD Frequency 1/20,000 genetic males X linked recessive disorder Two typescomplete AISPartial AIS(k/a Reifenstein syndrome)
Clinical presentation Extreme failure of virilization Genetic male invariably reared as female since birth Testes may be intra-abdominal/inguinal Normal breast (due to peripheral aromatization of testosterone) Primary amenorrhoea Absent pubic hair
Investigation Serum GonadotropinsLH & FSH hCG stimulation test (Twofold or greater increase intestosterone level in response to HCG suggests normalfunctioning testicular tissue and helps rule out a defect intestosterone biosynthesis)
Treatment Remove inguinal hernias Gonadectomy before or immediately after completion ofpuberty (increased risk of gonadoblastoma) Estrogen replacement Vaginal reconstruction or vaginoplasty may be needed Supportive counseling for infertility Genetic counseling for family members
Conclusion The controversy revolves around the issues of genderreassignment Physician and family may not correlate with the genderpreference by the patient in adulthood Adequate counseling and support for parents is vital. The most important sex organ is the brain, which may undergohormonal imprinting in utero.