Pleno kelompok 3A

PLENARY DISCUSSION (PRESENTED BY GROUP 3)

MODUL 1

TERMINOLOGIES
Sex of rearing : pattern of how-to-raise an individual according to sex. Phallus : the primordium of penis or clitoris that develops from genital tubercle. Chordee : downward bbowing of the penis as a result of congenital hypospadias or a urethral gonorrhoea infection. Hypospadias : a developmental anomaly in which the external urethra orificium opens inferior to its usual location. Penoscrotal hypospadias : hypospadias in the male with the urethral orifice at the junction of the penis and scrotum, sometimes associated with congenital chordee Gonad : a gamete-producing gland; an ovary, testis, or ovotestis. Genitography : radiography of the urogenital sinus and internal duct structures after injection of a contrast medium through the opening of the sinus. Bifid scrotum : a separation of the two halves of the scrotum, as in penoscrotal transposition

 DSD : Disorders of Sex Development; a congenital condition in which development of chromosomal, gonadal, or phenotype sex is atypical. 46 XY DSD : male pseudohermaphroditism, in which has 46 XY karyotype and genital ambiguicity (undervirilization) with penoscrotal hypospadia, with or without chordee. 46 XX DSD : female pseudohermaphroditism, in which has 46 XX karyotype and genital ambiguicity (virilization).

PROBLEMS IDENTIFICATION (BRAINSTORMING)

1. 2. 3. 4. Why Putra urinate in squat position? How to diagnose this defect earlier after birth? How is the referral did by the doctor? What is the interpretation of general-to-genitaliaregion examination? Why Putra is working diagnosed as 46 XY DSD? What is the next upcoming examination needed by Putra? What is the management of Putra and why it has to be multidiscipline team needed in managing Putra? What is the differences between 46XX DSD and 46 XY DSD? What is the prognosis of Putras conditions?

5. 6.
7. 8. 9.

1. Chordee and hypospadia posterio (including penoscrotal hypospadias) emmision of urin while urinate spreading widely squatting to shortened the distance between OUE and urination place

2. It can be detected after birth, as if in 46XY DSD with its hypospadias and 46XX DSD with its clitoromegaly 3. Referral was did as soon as possible in order to diagnosing, maintaining, and correcting the defect/disorders

4. General examination: - No physical abnormality - No others congenital anomaly Genitalia region examination: - No pubic hair = no puberty - Phallus 2 cm = abnormal size ; small (N= 7cm) - Chordee & Penoscrotal hypospadias = Congenital anomaly - No gonad in left scrotum = undescendsus testis or agenesis testis

5. 46 XY DSD - kariotype 46 XY - Genital ambiguicity with penoscrotal hypospadia (mild to severe), with or without chordee - Defect in gonad differentiation with testicular elements (- Sperm production can be reduced to none - Can be followed by Mullerian structures - Can be raised in to male - Autosomal resessive - Et causa gene defect; SRY-gene, SF1-gene, DHH-gene, NROB1gene, WNT4-gene, etc.)

6. Hormone test : LH, FSH, testosteron, androgen Chromosome analysis Abdominal USG HCG test ACTH stimulating test

5. 46 XY DSD - kariotype 46 XY - Genital ambiguicity with penoscrotal hypospadia (mild to severe), with or without chordee - Defect in gonad differentiation with testicular elements (- Sperm production can be reduced to none - Can be followed by Mullerian structures - Can be raised in to male - Autosomal resessive - Et causa gene defect; SRY-gene, SF1-gene, DHH-gene, NROB1gene, WNT4-gene, etc.)

6. Hormone test : LH, FSH, testosteron, androgen Chromosome analysis Abdominal USG HCG test ACTH stimulating test

7. The management of Putra has to multidiscipline due to aspects affected in Putras life medically or non-medically relevant. - Psychosocial = making peer group, consultation; due to mental stressor and making him not depressed etc. - Spritual consellor - Surgeon, Gynecoplasty, = in reposition and reconstruction the anomaly congenital while make sure that patient has a normal erection due to coitus and fertility - Endocrinology, Paramedics, etc.

8. 46 XY DSD ; male pseudohermaphroditism, hypospadia, which can be reconstructed in children, disorders of anti-Mullerian hormone, CAI, AISS, etc. Genetically determined as male but has some female genitalia external structure. 46 XX DSD ; female pseudohermaphroditism, ovarian development disorders, CAH, atresia vagina, etc. Genetically determined as female but has been remarkable as male due to the appearance.

9. Process of urination has to be corrected +/- in 8 months old by chordee removing, penis straightening, and making a new external urethral meatus. There are 2 possibilities; - Accomplished normal urination process - Failed Stricture abnormal urination Fertil or not? Hypospadia posterior (include penoscrotal) sperm emission abnormal the amount of sperm needed in penetrating are less than the needed If it is followed by undescend testis, which now Putra is 9year-old-boy, it is too late to save the testis due to overheat temperature in body makes Sertoli cells, Leydig cells damaged. less s \permagenesis. Ergo, it can narrows to fertility.

SCHEME

LEARNING OBJECTIVE
Students are able to explain about : Embriology of Urogenitalia System Disorders of Sex Differentiation Congenital anomaly of Urogenitalia System classification, epidemiology, etiology, risk factor, pathogenesis, pathophysiology, clinical manifestations, working diagnosis, differential diagnosis, lab examination, comprehensive management, prognosis, referral.

Embryology urogenital system

Embryology urogenital system system urogenitalia a.urogenital derived from mesoderm bridge (intermediate mesoderm) along the posterior abdominal wall b.ekresi pair entered into a terminal cloaca,primordium bladder, rectum, genital

system urinarium a.Sistem kidney 1.Pronefros formed early week 4 is located in the cervical region 2.Mesonefros arises when pronefros began in pars thoracic regression - L3 formed tubules + elongated and twisted rice glomerular capillaries korpuskulum renale tubules in lateral pars into longitudinal koligentes ductus ductus aka wolfii a.k.a duct mesonefrikus

Tubules into wolfii mid-month2mesonefros ovaid formed on both sides of the center line (in the medial gonad) urogenital ridge caudal tubules continue to differentiate women: gone men: caudal tubules settled dc.mesonefrikus form genital tract

3.Metanefros Appears in week 5 dc.koligentes formed ureteric bud jar.metanefrospenetrate the distal tip of his hat like a wide pelvis renalis primitif menjadi kranial dan kaudal kaliks mayor forming buds and continue to divide The end result: the ureter, renal pelvis, major Calix, Calix minor, pyramid renal tubules 0.1 to 3 million koligentes

system ekskretorik From the end of the tubular koligentes had no network covermetanephric tissue caporm small vesicles, small vesicles, kidneyshaped tubules S capillaries grow at one end of the tubule S Glomerulus +tubule nephron

Nefron terus memanjang tub.kontortus prox,ansa henle,tub.kontortus distalis Nefron terus terbentung 1juta nefron/ginjal ketika lahir Nefrondi ujung proximal nya membentuk kapsula bwman ujung distal:membentuk hub.dengan tub.koligentes

Kidney position: his early panggul.naik region to new cranial abdomen Renal function: Renal definitive (from mesonephros) start functioning before week 12.

urethra Epithelium of the urethra: endoderm Connective tissue and smooth muscle derived from mesoderm splanknik Late last month to 3, the epithelium proliferates Formatting prostatic urethra bud, growing out into the mesenchyme lk:prostat wanita :glomerulus

bladder 4-7 weeks cloaca is divided into a.sistem urogenital (anterior) bladder pelvis: prostatic urethra and pars membranasea phallus

b.Septum urorectal edges form a corpus perineale c.Kanalis analyst (posterior)

system genitalia
In the genes: SRY gene on chromosome Y.gen SRY testis determining factor would issue gonad Recently formed in week 7

Testes in men germinativum primordial cells mya carrying XY SRY increased proliferation of primitive sex cords penetrate into the medulla forming testes Sel leydig : minggu ke 8

Ovarium XX germinativum primitive cell ovarian medulla forge enyap then be replaced by the stromal vascular form of ovarian medulla If the cord of his men will continue berproloferasi in women weeks to 7 epithelial shape to a second generation korda kortikalis months to 4 split around sel germinativum oogonia

genital duct a.Stadium indifference 2 pairs of duct: duct mesonephros (wolfii) ductus paramesonefros (miliary) Molecular regulation SRY: key genes forming testes Sox9: anti gen Mulier

SRY + S0X9 Menginduksi testis FGF9Tubulus dari ductus mesonefros menembus gonadal ridge SRY SF1DIF.sel sertoli dan leydig hormon testosteron wolfii berkembang saluran pria :epididimis,ductus deferen,ejakulatorius vesikaseminalis SF1+S0X9AMH regresi millier Hormon testosteron oleh 5alfa redutase DHTdif genitalia eksterna ;penis skrotum

Congenital abnormalities ON WOMEN

Wnt4: ovarian determinant genes DAX1 inhibit the function of Sox9 estrogen: 1.dif.ductus miliary: uterine tubes, uterus, uterine cervix, upper vagina 2. Working for eks.pada genitalia stage indifference: the labia majora, minora, clitoris and vagina bagi.bawah

Genitalia eksterna
1.HIMEN IMPERTORATUS .Himen yang tidak menunjukan lubang sama sekali .kelainan ini tidak diketahui sebelum menarkhe .miolimina menstrual dialami setiap bulan tetapi darah haid tidak keluar darah terkumpul dalam vaginahimen tampak kebirubiruan dan menonjol keluar hematokolaps apabila dibiarkan uterus terisi darah (hematometra)mengisi tuba ki-kadapat teraba di ki-ka atas simpisis

treatment Himenektomi: thick dark blackish blood should come out after the act of victimization of people laid Fowler 2-3 days

Genitalia interna
1.Septum vagina . Bulkhead sagittal in the vagina can be found at the top of the vagina . was not uncommon to abnormalities in the uterus, which causes disturbances in the fusion / konalisasi both ductal mulleri . on his general do not cause complaints in question, discovered in gynecologic examination . abnormal menstrual blood . in labor spontaneously torn septum can / need to be sliced and tied

TURNER SYNDROM
Turner syndrom is genetic disorder charaterizid by physical of features and complete or parsial absence of the second sex chromosom

 Incident 1:2000-2500 live female birth Clinical features : reduced growth ovarian disgenesis infertilitas

 Karyotipe vs genotip vs venotipe Karyotipe :khromosomal pattern Genotipe : entire genetic constitution Phenotipe : physical and phisicological make up e.g short stature,infertilty,osteoporosis

What is CAH
1.It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance. 2.The defect is expressed as adrenal enzyme deficiency. 3.5 major Enzymes deficiency are clinically important
21-Hydroxylase 11-b-Hydroxylase 17-a-Hydroxylase 3-b-Hsteroid hydrogenese 20,22 Desmolase deficiency

CAH
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.

21-Hydroxylase Deficiency
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.

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

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.

2 forms, classic early virilization type with or without salt-losing crisis and non-classic type with late-onset virilization.

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.

11-b-Hydroxylase Deficiency
Accounts for 5-10% of cases of CAH. Gene is located on the long arm of chromosome 8. It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11deoxycorticosterone. 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.

ESSENTAILS 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 11Deoxycortisol

Diagnosis is confirmed by measurement of ACTH, Cortisol, Aldosterone, 17-OHprogesterone, Testosterone & urinary 17ketosteroids. Needs alertness for the possibility in all babies with Diarrhea & Vomiting, hypoglycemia or BP.

CLINICAL COURSE
The clinical phenotype depends upon the nature and severity of the enzyme deficiency. Approximately 50% of patients with classic congenital adrenal hyperplasia due to 21hydroxylase (CYP21) deficiency have salt wasting due to inadequate aldosterone synthesis. Girls are usually recognized at birth because of ambiguous genitalia.

Non salt losing CAH present late in childhood with precocious pubic hair and/or clitoromegaly, often accompanied by accelerated growth and advanced bone age. Those individuals with mild deficiencies of the enzyme present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirsutism and infertility.

GIRLS WITH CAH

Have ambiguous genitalia at birth: complete fusion of the labioscrotal folds and a phallic urethra. clitoromegaly and partial fusion of the labioscrotal folds In less severe forms, genitalia is normal at birth. Precocious pubic hair & clitoromegaly and excess facial or body hair appear later in childhood, often accompanied by tall stature.

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-ahydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone

Laboratory 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).

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 17a-hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia.

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.

TREATMENT PRINCIPLES
Treatment is life-long Treatment goals are:
to maintain growth velocity & skeletal maturation. to normalize electrolytes & hormone levels using the smallest dose of glucocorticoids that will suppress the ACTH to normal. Mineralocorticoid replacement may be needed to sustain normal electrolyte homeostasis.

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

46XY DSD
Common causes: androgen insensitivity syndrome (AIS) Incident: 1:20000 - 1:64000 The existence of peripheral resistance (target cells) caused by mutations in the androgen receptor gene androgen

Klasifikasi
SIA complete and incomplete a.SIK complete phenotype perfect man diagnosed at puberty: amenorrhoea prepubertal: herniafemoralis san femoral normal or elevated testosterone levels with fixed internal genitalia laki2 because IMH remained secreted by the testes wolfii developing, muller distressed

b.SIAP (partial) ambiguous genital

Alfa Defisiensis reductase 1.bersifat autosomal recessive disorder that conversion of testosterone into DHT DHT is reduced resulting in virilization of the external genitalia is not perfect Clinical 2.clinical would be normal to the man, ambiguous genital virilization during prepubertal great in adolescence to become men

3.Baby or child: chordae small phallus, hypospadias posterior.skrotum bifida with or without kriptokrismus

diagnostic approach
a.Anamnesis 1.riwayat serupa didalam keluarga 2.riwayat kematian neonatal dini yan tidak jelas akibat muntah muntah dengan atau tanpa genital ambigu 3.riwayat virilisasi pada saat pubertas 4.riwayat infertilitas dalam keluarga 5.riwayat kehamilan :paparan androgen obat2 tertentu

b. physical examination General condition: failure to thrive (HAK, turner) mental retardation mikrosefal hipertesi, hyperpigmentation

c. external genitalia 1.Gonad a.two gonand palpable and symmetric men who did not experience adequate virilization mulirent regression dd: prod.testosteron inadekuat, def.5 alpha reductase, minimal testicular dysplasia

b.Asimetris palpable gonad with only one gonad there are at least one of his testicles that may ovary, ovotestis c.gonad no palpable gonads and duct condition unknown

2.Phallus Mikopenis: <2 cm clitoris> 1cm klitoromegali 3.Ofricium urethral offricium urethra and vaginal introitus clearly separated: 46 XX indication if there is one hole in the external genitalia: 46 XY indication

 DIAGNOSIS SUPPORT 1.Analisis chromosome The first step when faced with cases of ambiguous genitalia / DSD using 20% metaphase possible long mosaic hasi examination 3 weeks

imaging Pelvic Ultrasound: strutur duct mulleri testis in the inguinal region adrenal hyperplasia genitogram: detecting internal genitalia urogenital sinus

Procedures Objective: 1.To ensure as much as possible fertility or reproductive 2.ensure maximum functionality sexual 3.ensure compliance outcomes phenotype and the type of psychosocial specified sex