Indian J Pcdiatr 1992; 59 : 523-530
Intersex Disorders : An Approach to Surgical Management M. Rohatgi Department of Pediatric Surger); All India h~stitute of Medical Sciences, New Delhi lntcrscx (I.S.) disorders are rare anomalies. Majority of these patient present with ambiguous genitalia with hypospadiac meatus. The urologist and paediatric surgeon who are committed to correct hypospadias often see these disorders, and it is important for them to understand the basic etiopathology in order that they can timely investigate, diagnose and plan surgical correction and assign appropriate sex of rearing t-3. Developmentally, genetic sex (i.e. 46 XX or XY) in an individual is determined at fertilization. Sexual differentiation of gonads, internal and external genitalia occurs during the first half of fetal life under the influence of genetic and/or endocrine factors. lntersex disorders may result from abnormality in genetic sex (sex chromosomal abnormalities), gonadal sex (ovotcstis or streak gonad), and phcnotypic sex (abnormality of external genitalia). In this paper we will limit our discussion to only those disorders which present with ambiguity of external genitalia. The common interscx disorders that present with ambiguous genitalia are (i) Male Pseudohermophroditism (MPH) (i/) Reprint requests : Dr. M. Rohatgi, Professor and I/cad, Department of Pediatric Surgery,All India Institute of Medical Sciences, New Delhi110 029.
Female Pseudohermaphroditism (FPH) (iii) True Hermaphroditism (TH) (iv) Mixed Gonadal Dysgcnesis (MGD) and (v) Dysgenetic Male Pscudohermaphroditism (DMP). The first two have only ambiguous external genitalia whereas the last three have ambiguity of both internal and external genitalia. MANAGEMENT The management of intersex disorders is best undertaken by a team comprising of pediatric surgeon, urologist, pediatric genetist, pediatric endocrinologist and clinical psychologist. The role of the surgeon is to participate in team management and surgically correct the ambiguity. The aim of surgery is to (i) establish the diagnosis by preoperative investigations, laparotomy and gonadal biopsy (//) assign sex of rearing (//i) correct ambiguity and restore function and cosmetic appearance (iv) protect the individual from malignancy of gonad cspccially when Y cell line is present. Each patient should undergo the following investigations to establish the diagnosis: 1. Detailed history including maternal antenatal history, history of drug intake, family history e.g. early death or similar disorder in sibling. 2. Complete general and local physical
l'his article is based on the presentation in the "International Workshop on Recent Advances in Neonatal Surgery and Intcrscx Disorders" held at All India Institute of Medical Sciences, New Delhi from March 1-4,
1989.It was acceptedfor publicationin 1991.
524
THE INDIAN JOURNAl. OF PEDIATRICS
examination. Local examination should include size of phallus, size of meatus, presence of urogenital sinus, size and site of gonad, scrotal size, presence of prostate, uterus, vagina and hernia. Secondary sex characters if present should also be noted
Vol. 59, No. 4
D Y ~ .T ,','F.~I.~
Dv~3.r~rrls
STIT.A.K
13A'IO.TltSTI$ DIIIP
down.
3. Chromosomal studies comprising of (i) Buccal smear for sex chromatin (ii) karyotype (i//) Y chromosome (iv) HY antigen.
Tigris
4. Biochemical tests to determine (i) urinary steroid excretion paitern e.g. 17 KS (ii) plasma steroid level of testosterone (T), Leutinizing hormone (LH) and Follicle stimulaling hormone (FSH), both basal and post IqCG levels of above. 5. Radiological studies (i) retrograde gcnitourcthrogram (RGU) to identify urogenital sinus (UGS), presence of vagina, uterus and ducts (ii) ultrasound/CT scan when available to delineate upper urinary tract anomalies, presence of adrenals uterus and gonads. (iii) endoscopy and contrast studies to define UGS and cervix. 6. Laparoscopy or laparotomy and gonadal biopsy. 7. Assessment of androgen action on cultured fibroblasts. Laparotomy is indicated when RGU shows contradictory internal genitalia & karyotyping reveals mosaicism or contradictory genetic..sex. Four out of five common I.S. disorders enumerated above have presence of mullcrian ducts structures i.e. uterus, vagina and fallopian tubes. The distribution of gonads vary giving it a definitive diagnosis (Figure I). Once the investigations are completed, the diagnosis can be established by matching the findings with those identified for each disorder (Table 1) and sex may be as-
OVMIY
ovtlty
Fig. 1. Internal genitalia in intersex disorder signed. Ideally, sex assignment should be done as early as the first 3 months. Delay is likely to produce psychological consequences. Studies indicate close relationship between sex of rearing and gender role; latter is independent of gonadal chromosomal and anatomical criteria of sex. True Hermaphroditism True hermaphroditism (TH) is defined as any patient whose gonads contain both ovarian and testicular tissue. This is a relatively rare disorder and to date over 400 cases have been reported in the world literature. These patients have ambiguity of both internal and external genitalia. External genitalia is grossly ambiguous with large phallus in 3/4 of patients. Almost all of them have hypospadiac meatus with persistence of UGS. Only 12% of patients have been reported to have normal penile urethra.4 Scrotum is usually bifid and poorly developed when gonad is absent. In 63% of
ROHATGI : SURGICAL MANAGEMENt' OF INTERSEX DISORDERS T~ lntersex disorder FPH MPH TH
1. Diagnostic Criteria for Common lntersex-Disorders
Buccal Smear Barr. B F. body + _+80%
525
+ _+
MGD
+
DMP
+
Karyotype
HY antigen
46 XX 46 XY 46XX 46 XX/46 XY 46 XY 46 XY/47 XXY 45 XO/46 XY 46 XY & mosaic 46 XY
+ +
Phenotype F to M Mto F M 75%
Mul duct +
Gonads
17-Ks
+
0/0 T/T T/O
t N N
N
N
+
F60%
+
OVOT/O OVOT/OVOT T/St
+
+
+
DygT/DygT
O =-Ovary; T = Testis; OVOT- Ovotestis; St = Streak; Dygt = Dysgenetic Testis FPH = Female Pseudohermaphroditism; MPH = Male Pseudohermaphroditism; TH =True Hermaphroditism; MGD =Mixed Gonadal Dysgenesis; DMP = Dysgenetic Male Pseudohermaphroditism cases, unilateral undescended gonad is present. The descended gonad is either testis or ovotestis and is usually seen in right scrotum. When ovotestis is present it will have dual consistency (firm ovary and soft testis) and may be of dumbell shape. In 3 of the 10 cases of T H seen in our department, the diagnosis was made on the basis of dumbcll shape of gonad with dual consistcncy. The most common gonad in these patients is ovotestis (44%) followed by ovary (34%) and then testis (22%). The disposition of gonads occurs in the following frequcncy:4 Ovary/testis Ovotestis/ovary Ovotestis/ovotestis Ovo:estis/testis Ovotestis/tumor or no gonad Others
30% 30% 20% 10% 4% 6%
Ovotestis and testis is more often located in the scrotum on the right side, whereas ovary is most often located on the left side at the ovarian position and rarely in the scrotum. It is observed that more the ovarian tissue, more likely it is to lie in ovarian position, whereas more the tcsticular tissue more chances of its being in the inguinal or scrotal position. Histopathological examination of ovotestis has revealed that in 80% cases ovarian and testicular tissue are arranged at each pole, whereas in 20% patients testicular tissue is located in hilar area. On naked eye examination, there is a distinct line of demarcation between the ovarian and testicular tissue. The ovarian portion is convoluted, pale and firm in consistency, whereas the testicular portion is smooth, yellow and soft. It has been reported that ovarian tissue has ndrmal histology in 77% gonads4; also, fertility has been reported in these patients. Whereas the testicular tissue is usually abnormal, sperma-
526
THE INDIAN JOURNAl. OF PEDIATRICS
togonia or spermatogenesis is never observed. However, when the testis alone is present in scrotum, spermatogenesis has been reportcd in 12% patients. Investigations have revealed that in 80% of patients, sex-chromatin is positive and most common karyotype is 46 XX (58%) followcd by 46 XY/46 XX (13%), 46 XY (12%), other mosaicism (17%). II-Y antigen is positive in these patients. Thc primary consideration in the managemcnt of thcse patients should be gender assignmcnt and decision is made as follows: 1. If phallus is small - rear as female, irrespective of the type of gonads. Laparotomy and male gonadectomy is done whcn the child has grown older. 2. If phallus is large and vagina is also well dcvelopcd, decision should be made on laparotomy findings; (i) If one normal ovary, utcrus and fallopian tube prcscnt-rcar as female, as fertility has been reportcd. (ii) If phallus largc and one normal testis in scrotum - rear as male. (iii) If ovotestis is located in the abdomen - remove the gonad. If B/L ovotestis located in inguinoscrotal region, excise the ovarian portion and fix the testicular portion to scrotal wall so that T may become available at puberty. (iv) If Y cell line is present, remove ovotestis to avoid late malignancy and rear as fcmale. Uterus should be removed only if there is no connection with vagina. Give substitution hormone therapy where necessary after puberty.
Mixed Gonadal Dysgenesis & Dysgenetie Male Pseudohermaphroditism Mixed gonadal dysgcncsis (MGD) and Dysgenetic Male Pseudohcrmaphroditism
Vol. 59, No. 4 (DMP) are inter-related intersex disorders resulting from impropcr testicular differentiation in utero.
Mixed gonadal dysgenesis (MGD) It is defined as an intersex patient who has a streak gonad on one side and dysgenetic testis on the contralaterai side, presencc of mullcrian structures like uterus, vagina and tubes, cryptorchidism and hypospadias. It is said to be second most common cause of intersexuality in neonatcs. Genetic constitution is 45 XO/46 XY or 46 XY; H-Y antigen is positive. Clinically these patients may prcscnt an ambiguous gcnitalia. However 60% are reared as female as the gcnitalia are hypoplastic or female like. All have relatively moderate size phallus, UGS or vagina, hypospadiac meatus and cryptorchidism. Testis is present in scrotum in 13% patient only but in majority it is undescendcd.' 50% have short stature. 1/3 have stigmata of Turner Syndrome e.g. webbed neck with simple short stature with stalky build, broad chest with widely separated nipples, cubitus valgus, mental retardation, coarctation of aorta and horse shoe kidncy. 1/3 have lymphedcma of extremities e.g. dorsum of digits with conspicuous shortening of digits. Pigmented naevi are present RGU-shows UGS, uterus, vagina and tube.
Dysgenetic testis. This has characteristically high incidence of malignancy specially when located in the abdomen or has mullerian structures adherent to it) A testis located in
ROHATGL : SURGICAL MANAGEMEN'I" OF INrI'EI~EX DISORDERS
the scrotum has not been reported to have malignant change. Histologically, it is often difficult to differentiate MGD testis from cryptorchid testis. However, when carefully examined, histopathological section may show focal areas of dysgenetic tissues adjacent to normal looking testicular tissue, interstitial fibrosis and hyalinization of basement membrane. Fertility is not known to occur and thcre is abscnce of spermatid and spermatozoa cven in scrotal testis, s
Streak gonad. It is a small gonad like tissue located at the ovarian site which on microscopic examination reveals primitive gonadal tissue with ovarian like stroma without primordial follicles.
bztemal ducts. In these the : uterus and one fallopian tube is always present vas and epididymis may be present on the opposite side. Fertility is not a major consideration in gender assignment. Ideally, these patients should be reared as female because (i) 60% have female like genitalia (it) 50% are short stature (iii) thcre is always presence of uterus and vagina (iv) fertility is unknown (v) gonads have high incidence of malignancy more often in dysgenetic testis than streak. Early B/L gonadectomy and clitoroplasty is advocated for these patients. Rarely, patients may be reared as male if testis is located in the scrotum. Dysgenetic male pseudohermaphroditism (DMP) It is a disorder of intcrsexuality in which patients present with bilateral dysgenetic testis, persistent Muilerlan duct structures,
527
crypto-orchidism, and inadequate external virilization with hypospadiasY Characteristic features. The main features of DMP are : -
bilateral dysgenetic testis (histologically) persistcnt Mullerian duct structures i.e. uterus, vagina and tubes cryptorchidism and hypospadias inadequate external virilization karyotype-mostly 46 XY; less oftcn mosaicism 45 XO/46 XY HY antigen is ~,.,sitive RGU-shows vagina, cervix and uterus high incidence of gonadoblastoma tumour (30%) often associated with breast enlargcment5.
Diagnosis. This is based on histology of the testis which reveals combination of immature hypoplastic testicular tubules and persistent stromal tissue, characteristic of ovarian stroma, but lacking primary ovarian fi)llicles (i.e. presence of primitive dysgenetic stromal tissue within thc gonad).5
Etiology It is caused by defect in the sex chromosome that subsequcntly resulted in abnormal testicular differentiation during the early phases of embryogenesis. Dysgenetic testis falls between two extremes i.e. normal testis and streak gonad?
Management. This is done by : (i) early gonadectomy becausc of high incidence of malignancy, (it) gender assignment and surgical correction of external genitalia. It is bcst to bring them up as females, as they have vagina and uterus with small phallus. Surgery comprises of- clitoroplasty and bilateral gonadectomy and vaginoplasty. Male Pseudohermaphroditism (MPii) Male pseudohermaphroditism is defined as
528
"1"IIE INDIAN J O U R N A l . OF PEDIATRICS
genetic male (46 XY) having ambiguous genitalia in the presence of bilateral testes? In majority of patients the external genitalia has an ambiguous appearance, though some may have complete female appearance, e.g. Tcsticular Fcminization syndrome, whereas others may have normal male external genitalia c.g. Rose water syndrome, persistent Mullcrian duct syndrome. The ambiguous look is because of small phallus, severe chordee, hypospadiac meatus, persistence of UGS, bifid scrotum, partial pcnoscrotal transposition and webbing of pcnis? The testis may be undescended or dcscended of variable size depending on the type of MPH. Patients with testicular fcminization syndrome may present with inguinal hernia in prcpubcrtal age and amenorrhoea with cnlargcmcnl of breast after puberty.
Development of male genitalia. At 6 weeks of intrauterine life, testis is developed from primitivc gonad in the presence of HY antigcn. It secretes two hormones (i) testosterone (it) mullcrian inhibiting substance. The former stabilises the development of wolffian duct structures e.g. epididymis, vas defercns and seminal vesicles, whereas the latter causes disappearance of Mullerian duct structures e.g. uterus, fallopian tubes and upper 1/3 vagina. Development of male external genitalia i.e. elongation of phallus, formation of penile urcthra, formation of scrotum and descent of testis occurs from 9th wcck of gestation onward under the influence of dihydrotestosterone (DHT). The latter is metabolised lrom T in the presence of 5 o~ reductase enzyme which is available in plenty in the region of UGS, prostate phallus and scrotum. For DHT to be effective as masculinizing hormone, it has to be taken up by the androgen cell receptor located in the cxtcrnal genitalia.
Vol. 59, No. 4
Hence the cause of MPH may be because of : (i) defect in androgen biosynthesis or,
(it) defect in androgen metabolism from T to DHT or, (iii) defect in androgen action on cell receptors responsible for masculinization or, (iv) defect in Mullerian regression. All the above 3 types present with ambiguous external genitalia except the 4th type called persistent Mullerian Duct Syndrome (PMDS), which presents with normal phallus with bilateral undescended testis. The defect in androgen action is usually hcriditary and x-linked. There are two main types in this group : (i) Complete Testicular Feminization Syndrome (CTFS) (it) Incomplete Testicular Feminization Syndrome (ITFS). The former patients have completely normal female like external genitalia, whereas the latter have partial virilization, but both of thcm develop breasts after puberty. The ITFS includes conditions like Lubs, Gilbert Dreyfus, Riefenstein and Rose Water syndromes. In patients with 5~ rcductase enzyme deficiency, the T takes over the virilizing function of DHT at puberty and there is sudden masculinization in these patients from female to male phenotype. However, breasts do not develop at puberty in this type of MPH. Diagnosis of type of MPH can be made on the basis of family history, complete clinical examination and the investigation suggested by Prader 6. 1. demonstration of Y chromosome and HY antigen 2. response of T (in plasma and urine) to HCG. a. when there is nil or subnormal re-
R O H A T G i : S U R G I C A L MANAGI:.M|:JNq" O F I N I E R S E X I)ISORDEILS
529
sponsc of T, and T precursors are absent, sequent management depends on phenothe diagnosis of anorchia or dysgenetic ru- tyoe. dimentary testicles or LH deficiency can be Those MPH, reared as female, should undergo bilateral orchiectomy and clitoromade. b. when the T response is subnormal but plasty (where necessary) before puberty. thcre is marked increase in precursors, di- Vaginoplasty can be done later. Oestrogen agnosis of hcrditary defect in T biosynthesis replacement therapy should be initiated after puberty to allow development of breast is made. 3. Increase in ratio of Etiocholanone/ in all the patients of MPH who are assigned androstcnidione or plasma T/DHT is in- female sex. dicative of 5 oc reductase deficiency. Whereas those reared as males should 4. Decrease in nitrogen retention follow- undergo masculinizing gcnitoplasty e.g. ing T therapy indicates receptor defect. chordee correction and urethroplasty. Also, this defect can be identified in fibrob- Where necessary surgical elongation of last culture with T. phallus, correction of webbing and peno5. Response of LH & FSH allows differ- scrotal transposition and orchiopcxy may be entiation between primary pituitary defi- done. Androgens should be given after puciency from primary testicular deficiency berty to allow secondary sexual characters i.e. hypogonadotrophic conditions from hy- to develop. pergonadotrophic conditions. Female Pseudohermaphroditism (FPH) 6. Gonadal biopsy is indicated only when above findings arc inconclusive. These patients are genetically female (46 XX with HY antigen) with variable degree A precise diagnosis is helpful to predict of masculinization of external genitalia only. course of puberty and for genetic counThe common disorders producing FPH selling. are : Sex assignment depends on phenotypc as well as on the type of MPH. The patients of (i) congenital adrenal hyperplasia MPH due to testosterone biosynthesis fail- (CAH), (ii) non-adrenal virilization, (iii) ure should be reared according to the phe- progestagen induced virilization, (iv) andronotype, as fertility is not known to occur. gen secreting maternal tumor The patients of MPH due to 5~ reductase Diag~osis. It is diagnoscd by : deficiency should be rearcd as female. Also, MPH duc to complete androgen inscnsivity (i) raised urinary 17 ketoster- 1 (CTFS) should be reared as female and the old and pregnantriol .~ in CAH testis should be rctained till puberty, as the raised serum - 17 OH progesandrogen precursors are converted into oe- terone strogen in the peripheral tissues causing (ii) history of maternal virilizing tumour feminization and development of breast. (iii) history of maternal drug intake The testis in these patients should be exe.g. progestin. cised after the age of 14 years, as malig- (it,) sex chromosome -+ve; karyotype 46 nancy is known to occur in these gonads. In XX; HY antigen -ve patients with ITFS, sex assignment and sub- (v) RGU - urethra, UGS, vagina, tubes
530
TI IE INDIAN JOURaNAL OF PEDIATRICS
Management. This can be done by : 1. 2.
Treat metabolic disorders in C A H Corrective surgery 7.~ (i) Reduction of size of phallus a. clitoroplasty for m o d e r a t e clitoromegaly b. c l i t o r o d e c t o m y for large phallus c. clitoral recession for mild clitoromegaly (if) Perincoplasty (iii) Vaginoplasty simple vaginoplasty - if vagina is close to urethral orifice flap vaginoplasty - U G S and vagina deeply located pull through vaginoplasty when no communication between vagina and U G S or vaginal pouch opens high up at verumontanum. -
In the last 10 years we have seen 200 cases of intersex disorders in children at the Pediatric lntersex Clinic, AIIMS. Majority of these were M P H , 10-TH, 6-DMP, 15M G D and 5 7 - F P H . T h e diagnosis was made on the basis of criteria laid down in this paper and the credit goes to team approach in the management. REFERENCES 1. Rohatgi M, Menon PSN, Verma IC, Iyen-
Vol. 59, No. 4 gar JK. The presence ot" intersexuality in patients with advanced hypospadias and undescended gondas. J Urol 1987; 137 : 263-267. 2. Iyengar JK, Rohatgi M, Menon PSN et al. Clinical, cytogenetic & hormonal profile in extreme hypospadias with bilaterally descended testes, h, dian J Med Res 1986; 83 : 604-609. 3. Aarskog D. lntersex conditions masquerading as hypospadias. Birth Defects 1971; 7 : 122-130. 4. Van Niekerk WA. True hermaphroditism. In : Josso N, ed. The b~tersex Child. Pediatric and Adolescent Endocrinology. New York : S. Karger, 1981; Volume 8; 80-90. 5. Rajfer Walsh PC. Mixed gonadal dysgenesis-dysgenetic male pseudohermaphroditism. In : Josso N, ed. The Intersex Child. Pediatric and Adolescent F'tdocrinolog)~. New York : S. Karger, 1981; Vol. 8; 1o3115. 6. Prader A. Male P~udohermaphroditism: A Review. In : Ghai OP, cd. Developments hi Pediatric Rexecurh. Vol. III : pp. 1111. New Delhi. Presented at XV International Congress of Pediatrics, New Delhi; 1977. 7. Cendron J. Plasty of the genitals in case of female pseudohermaphroditism. Birth Defects 1977; 13 : 261-263. 8. F6k6t6 CN. Feminizing genitoplasty in the intersex child. In : Josso N, ed. The lntersex Child. Pediatric and Adolescent Endocrinology New York; S. Karger, 1981; Vol. 8 : 247-260.
Intersex Disorders : An Approach to Surgical Management M. Rohatgi Department of Pediatric Surger); All India h~stitute of Medical Sciences, New Delhi lntcrscx (I.S.) disorders are rare anomalies. Majority of these patient present with ambiguous genitalia with hypospadiac meatus. The urologist and paediatric surgeon who are committed to correct hypospadias often see these disorders, and it is important for them to understand the basic etiopathology in order that they can timely investigate, diagnose and plan surgical correction and assign appropriate sex of rearing t-3. Developmentally, genetic sex (i.e. 46 XX or XY) in an individual is determined at fertilization. Sexual differentiation of gonads, internal and external genitalia occurs during the first half of fetal life under the influence of genetic and/or endocrine factors. lntersex disorders may result from abnormality in genetic sex (sex chromosomal abnormalities), gonadal sex (ovotcstis or streak gonad), and phcnotypic sex (abnormality of external genitalia). In this paper we will limit our discussion to only those disorders which present with ambiguity of external genitalia. The common interscx disorders that present with ambiguous genitalia are (i) Male Pseudohermophroditism (MPH) (i/) Reprint requests : Dr. M. Rohatgi, Professor and I/cad, Department of Pediatric Surgery,All India Institute of Medical Sciences, New Delhi110 029.
Female Pseudohermaphroditism (FPH) (iii) True Hermaphroditism (TH) (iv) Mixed Gonadal Dysgcnesis (MGD) and (v) Dysgenetic Male Pscudohermaphroditism (DMP). The first two have only ambiguous external genitalia whereas the last three have ambiguity of both internal and external genitalia. MANAGEMENT The management of intersex disorders is best undertaken by a team comprising of pediatric surgeon, urologist, pediatric genetist, pediatric endocrinologist and clinical psychologist. The role of the surgeon is to participate in team management and surgically correct the ambiguity. The aim of surgery is to (i) establish the diagnosis by preoperative investigations, laparotomy and gonadal biopsy (//) assign sex of rearing (//i) correct ambiguity and restore function and cosmetic appearance (iv) protect the individual from malignancy of gonad cspccially when Y cell line is present. Each patient should undergo the following investigations to establish the diagnosis: 1. Detailed history including maternal antenatal history, history of drug intake, family history e.g. early death or similar disorder in sibling. 2. Complete general and local physical
l'his article is based on the presentation in the "International Workshop on Recent Advances in Neonatal Surgery and Intcrscx Disorders" held at All India Institute of Medical Sciences, New Delhi from March 1-4,
1989.It was acceptedfor publicationin 1991.
524
THE INDIAN JOURNAl. OF PEDIATRICS
examination. Local examination should include size of phallus, size of meatus, presence of urogenital sinus, size and site of gonad, scrotal size, presence of prostate, uterus, vagina and hernia. Secondary sex characters if present should also be noted
Vol. 59, No. 4
D Y ~ .T ,','F.~I.~
Dv~3.r~rrls
STIT.A.K
13A'IO.TltSTI$ DIIIP
down.
3. Chromosomal studies comprising of (i) Buccal smear for sex chromatin (ii) karyotype (i//) Y chromosome (iv) HY antigen.
Tigris
4. Biochemical tests to determine (i) urinary steroid excretion paitern e.g. 17 KS (ii) plasma steroid level of testosterone (T), Leutinizing hormone (LH) and Follicle stimulaling hormone (FSH), both basal and post IqCG levels of above. 5. Radiological studies (i) retrograde gcnitourcthrogram (RGU) to identify urogenital sinus (UGS), presence of vagina, uterus and ducts (ii) ultrasound/CT scan when available to delineate upper urinary tract anomalies, presence of adrenals uterus and gonads. (iii) endoscopy and contrast studies to define UGS and cervix. 6. Laparoscopy or laparotomy and gonadal biopsy. 7. Assessment of androgen action on cultured fibroblasts. Laparotomy is indicated when RGU shows contradictory internal genitalia & karyotyping reveals mosaicism or contradictory genetic..sex. Four out of five common I.S. disorders enumerated above have presence of mullcrian ducts structures i.e. uterus, vagina and fallopian tubes. The distribution of gonads vary giving it a definitive diagnosis (Figure I). Once the investigations are completed, the diagnosis can be established by matching the findings with those identified for each disorder (Table 1) and sex may be as-
OVMIY
ovtlty
Fig. 1. Internal genitalia in intersex disorder signed. Ideally, sex assignment should be done as early as the first 3 months. Delay is likely to produce psychological consequences. Studies indicate close relationship between sex of rearing and gender role; latter is independent of gonadal chromosomal and anatomical criteria of sex. True Hermaphroditism True hermaphroditism (TH) is defined as any patient whose gonads contain both ovarian and testicular tissue. This is a relatively rare disorder and to date over 400 cases have been reported in the world literature. These patients have ambiguity of both internal and external genitalia. External genitalia is grossly ambiguous with large phallus in 3/4 of patients. Almost all of them have hypospadiac meatus with persistence of UGS. Only 12% of patients have been reported to have normal penile urethra.4 Scrotum is usually bifid and poorly developed when gonad is absent. In 63% of
ROHATGI : SURGICAL MANAGEMENt' OF INTERSEX DISORDERS T~ lntersex disorder FPH MPH TH
1. Diagnostic Criteria for Common lntersex-Disorders
Buccal Smear Barr. B F. body + _+80%
525
+ _+
MGD
+
DMP
+
Karyotype
HY antigen
46 XX 46 XY 46XX 46 XX/46 XY 46 XY 46 XY/47 XXY 45 XO/46 XY 46 XY & mosaic 46 XY
+ +
Phenotype F to M Mto F M 75%
Mul duct +
Gonads
17-Ks
+
0/0 T/T T/O
t N N
N
N
+
F60%
+
OVOT/O OVOT/OVOT T/St
+
+
+
DygT/DygT
O =-Ovary; T = Testis; OVOT- Ovotestis; St = Streak; Dygt = Dysgenetic Testis FPH = Female Pseudohermaphroditism; MPH = Male Pseudohermaphroditism; TH =True Hermaphroditism; MGD =Mixed Gonadal Dysgenesis; DMP = Dysgenetic Male Pseudohermaphroditism cases, unilateral undescended gonad is present. The descended gonad is either testis or ovotestis and is usually seen in right scrotum. When ovotestis is present it will have dual consistency (firm ovary and soft testis) and may be of dumbell shape. In 3 of the 10 cases of T H seen in our department, the diagnosis was made on the basis of dumbcll shape of gonad with dual consistcncy. The most common gonad in these patients is ovotestis (44%) followed by ovary (34%) and then testis (22%). The disposition of gonads occurs in the following frequcncy:4 Ovary/testis Ovotestis/ovary Ovotestis/ovotestis Ovo:estis/testis Ovotestis/tumor or no gonad Others
30% 30% 20% 10% 4% 6%
Ovotestis and testis is more often located in the scrotum on the right side, whereas ovary is most often located on the left side at the ovarian position and rarely in the scrotum. It is observed that more the ovarian tissue, more likely it is to lie in ovarian position, whereas more the tcsticular tissue more chances of its being in the inguinal or scrotal position. Histopathological examination of ovotestis has revealed that in 80% cases ovarian and testicular tissue are arranged at each pole, whereas in 20% patients testicular tissue is located in hilar area. On naked eye examination, there is a distinct line of demarcation between the ovarian and testicular tissue. The ovarian portion is convoluted, pale and firm in consistency, whereas the testicular portion is smooth, yellow and soft. It has been reported that ovarian tissue has ndrmal histology in 77% gonads4; also, fertility has been reported in these patients. Whereas the testicular tissue is usually abnormal, sperma-
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THE INDIAN JOURNAl. OF PEDIATRICS
togonia or spermatogenesis is never observed. However, when the testis alone is present in scrotum, spermatogenesis has been reportcd in 12% patients. Investigations have revealed that in 80% of patients, sex-chromatin is positive and most common karyotype is 46 XX (58%) followcd by 46 XY/46 XX (13%), 46 XY (12%), other mosaicism (17%). II-Y antigen is positive in these patients. Thc primary consideration in the managemcnt of thcse patients should be gender assignmcnt and decision is made as follows: 1. If phallus is small - rear as female, irrespective of the type of gonads. Laparotomy and male gonadectomy is done whcn the child has grown older. 2. If phallus is large and vagina is also well dcvelopcd, decision should be made on laparotomy findings; (i) If one normal ovary, utcrus and fallopian tube prcscnt-rcar as female, as fertility has been reportcd. (ii) If phallus largc and one normal testis in scrotum - rear as male. (iii) If ovotestis is located in the abdomen - remove the gonad. If B/L ovotestis located in inguinoscrotal region, excise the ovarian portion and fix the testicular portion to scrotal wall so that T may become available at puberty. (iv) If Y cell line is present, remove ovotestis to avoid late malignancy and rear as fcmale. Uterus should be removed only if there is no connection with vagina. Give substitution hormone therapy where necessary after puberty.
Mixed Gonadal Dysgenesis & Dysgenetie Male Pseudohermaphroditism Mixed gonadal dysgcncsis (MGD) and Dysgenetic Male Pseudohcrmaphroditism
Vol. 59, No. 4 (DMP) are inter-related intersex disorders resulting from impropcr testicular differentiation in utero.
Mixed gonadal dysgenesis (MGD) It is defined as an intersex patient who has a streak gonad on one side and dysgenetic testis on the contralaterai side, presencc of mullcrian structures like uterus, vagina and tubes, cryptorchidism and hypospadias. It is said to be second most common cause of intersexuality in neonatcs. Genetic constitution is 45 XO/46 XY or 46 XY; H-Y antigen is positive. Clinically these patients may prcscnt an ambiguous gcnitalia. However 60% are reared as female as the gcnitalia are hypoplastic or female like. All have relatively moderate size phallus, UGS or vagina, hypospadiac meatus and cryptorchidism. Testis is present in scrotum in 13% patient only but in majority it is undescendcd.' 50% have short stature. 1/3 have stigmata of Turner Syndrome e.g. webbed neck with simple short stature with stalky build, broad chest with widely separated nipples, cubitus valgus, mental retardation, coarctation of aorta and horse shoe kidncy. 1/3 have lymphedcma of extremities e.g. dorsum of digits with conspicuous shortening of digits. Pigmented naevi are present RGU-shows UGS, uterus, vagina and tube.
Dysgenetic testis. This has characteristically high incidence of malignancy specially when located in the abdomen or has mullerian structures adherent to it) A testis located in
ROHATGL : SURGICAL MANAGEMEN'I" OF INrI'EI~EX DISORDERS
the scrotum has not been reported to have malignant change. Histologically, it is often difficult to differentiate MGD testis from cryptorchid testis. However, when carefully examined, histopathological section may show focal areas of dysgenetic tissues adjacent to normal looking testicular tissue, interstitial fibrosis and hyalinization of basement membrane. Fertility is not known to occur and thcre is abscnce of spermatid and spermatozoa cven in scrotal testis, s
Streak gonad. It is a small gonad like tissue located at the ovarian site which on microscopic examination reveals primitive gonadal tissue with ovarian like stroma without primordial follicles.
bztemal ducts. In these the : uterus and one fallopian tube is always present vas and epididymis may be present on the opposite side. Fertility is not a major consideration in gender assignment. Ideally, these patients should be reared as female because (i) 60% have female like genitalia (it) 50% are short stature (iii) thcre is always presence of uterus and vagina (iv) fertility is unknown (v) gonads have high incidence of malignancy more often in dysgenetic testis than streak. Early B/L gonadectomy and clitoroplasty is advocated for these patients. Rarely, patients may be reared as male if testis is located in the scrotum. Dysgenetic male pseudohermaphroditism (DMP) It is a disorder of intcrsexuality in which patients present with bilateral dysgenetic testis, persistent Muilerlan duct structures,
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crypto-orchidism, and inadequate external virilization with hypospadiasY Characteristic features. The main features of DMP are : -
bilateral dysgenetic testis (histologically) persistcnt Mullerian duct structures i.e. uterus, vagina and tubes cryptorchidism and hypospadias inadequate external virilization karyotype-mostly 46 XY; less oftcn mosaicism 45 XO/46 XY HY antigen is ~,.,sitive RGU-shows vagina, cervix and uterus high incidence of gonadoblastoma tumour (30%) often associated with breast enlargcment5.
Diagnosis. This is based on histology of the testis which reveals combination of immature hypoplastic testicular tubules and persistent stromal tissue, characteristic of ovarian stroma, but lacking primary ovarian fi)llicles (i.e. presence of primitive dysgenetic stromal tissue within thc gonad).5
Etiology It is caused by defect in the sex chromosome that subsequcntly resulted in abnormal testicular differentiation during the early phases of embryogenesis. Dysgenetic testis falls between two extremes i.e. normal testis and streak gonad?
Management. This is done by : (i) early gonadectomy becausc of high incidence of malignancy, (it) gender assignment and surgical correction of external genitalia. It is bcst to bring them up as females, as they have vagina and uterus with small phallus. Surgery comprises of- clitoroplasty and bilateral gonadectomy and vaginoplasty. Male Pseudohermaphroditism (MPii) Male pseudohermaphroditism is defined as
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genetic male (46 XY) having ambiguous genitalia in the presence of bilateral testes? In majority of patients the external genitalia has an ambiguous appearance, though some may have complete female appearance, e.g. Tcsticular Fcminization syndrome, whereas others may have normal male external genitalia c.g. Rose water syndrome, persistent Mullcrian duct syndrome. The ambiguous look is because of small phallus, severe chordee, hypospadiac meatus, persistence of UGS, bifid scrotum, partial pcnoscrotal transposition and webbing of pcnis? The testis may be undescended or dcscended of variable size depending on the type of MPH. Patients with testicular fcminization syndrome may present with inguinal hernia in prcpubcrtal age and amenorrhoea with cnlargcmcnl of breast after puberty.
Development of male genitalia. At 6 weeks of intrauterine life, testis is developed from primitivc gonad in the presence of HY antigcn. It secretes two hormones (i) testosterone (it) mullcrian inhibiting substance. The former stabilises the development of wolffian duct structures e.g. epididymis, vas defercns and seminal vesicles, whereas the latter causes disappearance of Mullerian duct structures e.g. uterus, fallopian tubes and upper 1/3 vagina. Development of male external genitalia i.e. elongation of phallus, formation of penile urcthra, formation of scrotum and descent of testis occurs from 9th wcck of gestation onward under the influence of dihydrotestosterone (DHT). The latter is metabolised lrom T in the presence of 5 o~ reductase enzyme which is available in plenty in the region of UGS, prostate phallus and scrotum. For DHT to be effective as masculinizing hormone, it has to be taken up by the androgen cell receptor located in the cxtcrnal genitalia.
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Hence the cause of MPH may be because of : (i) defect in androgen biosynthesis or,
(it) defect in androgen metabolism from T to DHT or, (iii) defect in androgen action on cell receptors responsible for masculinization or, (iv) defect in Mullerian regression. All the above 3 types present with ambiguous external genitalia except the 4th type called persistent Mullerian Duct Syndrome (PMDS), which presents with normal phallus with bilateral undescended testis. The defect in androgen action is usually hcriditary and x-linked. There are two main types in this group : (i) Complete Testicular Feminization Syndrome (CTFS) (it) Incomplete Testicular Feminization Syndrome (ITFS). The former patients have completely normal female like external genitalia, whereas the latter have partial virilization, but both of thcm develop breasts after puberty. The ITFS includes conditions like Lubs, Gilbert Dreyfus, Riefenstein and Rose Water syndromes. In patients with 5~ rcductase enzyme deficiency, the T takes over the virilizing function of DHT at puberty and there is sudden masculinization in these patients from female to male phenotype. However, breasts do not develop at puberty in this type of MPH. Diagnosis of type of MPH can be made on the basis of family history, complete clinical examination and the investigation suggested by Prader 6. 1. demonstration of Y chromosome and HY antigen 2. response of T (in plasma and urine) to HCG. a. when there is nil or subnormal re-
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sponsc of T, and T precursors are absent, sequent management depends on phenothe diagnosis of anorchia or dysgenetic ru- tyoe. dimentary testicles or LH deficiency can be Those MPH, reared as female, should undergo bilateral orchiectomy and clitoromade. b. when the T response is subnormal but plasty (where necessary) before puberty. thcre is marked increase in precursors, di- Vaginoplasty can be done later. Oestrogen agnosis of hcrditary defect in T biosynthesis replacement therapy should be initiated after puberty to allow development of breast is made. 3. Increase in ratio of Etiocholanone/ in all the patients of MPH who are assigned androstcnidione or plasma T/DHT is in- female sex. dicative of 5 oc reductase deficiency. Whereas those reared as males should 4. Decrease in nitrogen retention follow- undergo masculinizing gcnitoplasty e.g. ing T therapy indicates receptor defect. chordee correction and urethroplasty. Also, this defect can be identified in fibrob- Where necessary surgical elongation of last culture with T. phallus, correction of webbing and peno5. Response of LH & FSH allows differ- scrotal transposition and orchiopcxy may be entiation between primary pituitary defi- done. Androgens should be given after puciency from primary testicular deficiency berty to allow secondary sexual characters i.e. hypogonadotrophic conditions from hy- to develop. pergonadotrophic conditions. Female Pseudohermaphroditism (FPH) 6. Gonadal biopsy is indicated only when above findings arc inconclusive. These patients are genetically female (46 XX with HY antigen) with variable degree A precise diagnosis is helpful to predict of masculinization of external genitalia only. course of puberty and for genetic counThe common disorders producing FPH selling. are : Sex assignment depends on phenotypc as well as on the type of MPH. The patients of (i) congenital adrenal hyperplasia MPH due to testosterone biosynthesis fail- (CAH), (ii) non-adrenal virilization, (iii) ure should be reared according to the phe- progestagen induced virilization, (iv) andronotype, as fertility is not known to occur. gen secreting maternal tumor The patients of MPH due to 5~ reductase Diag~osis. It is diagnoscd by : deficiency should be rearcd as female. Also, MPH duc to complete androgen inscnsivity (i) raised urinary 17 ketoster- 1 (CTFS) should be reared as female and the old and pregnantriol .~ in CAH testis should be rctained till puberty, as the raised serum - 17 OH progesandrogen precursors are converted into oe- terone strogen in the peripheral tissues causing (ii) history of maternal virilizing tumour feminization and development of breast. (iii) history of maternal drug intake The testis in these patients should be exe.g. progestin. cised after the age of 14 years, as malig- (it,) sex chromosome -+ve; karyotype 46 nancy is known to occur in these gonads. In XX; HY antigen -ve patients with ITFS, sex assignment and sub- (v) RGU - urethra, UGS, vagina, tubes
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Management. This can be done by : 1. 2.
Treat metabolic disorders in C A H Corrective surgery 7.~ (i) Reduction of size of phallus a. clitoroplasty for m o d e r a t e clitoromegaly b. c l i t o r o d e c t o m y for large phallus c. clitoral recession for mild clitoromegaly (if) Perincoplasty (iii) Vaginoplasty simple vaginoplasty - if vagina is close to urethral orifice flap vaginoplasty - U G S and vagina deeply located pull through vaginoplasty when no communication between vagina and U G S or vaginal pouch opens high up at verumontanum. -
In the last 10 years we have seen 200 cases of intersex disorders in children at the Pediatric lntersex Clinic, AIIMS. Majority of these were M P H , 10-TH, 6-DMP, 15M G D and 5 7 - F P H . T h e diagnosis was made on the basis of criteria laid down in this paper and the credit goes to team approach in the management. REFERENCES 1. Rohatgi M, Menon PSN, Verma IC, Iyen-
Vol. 59, No. 4 gar JK. The presence ot" intersexuality in patients with advanced hypospadias and undescended gondas. J Urol 1987; 137 : 263-267. 2. Iyengar JK, Rohatgi M, Menon PSN et al. Clinical, cytogenetic & hormonal profile in extreme hypospadias with bilaterally descended testes, h, dian J Med Res 1986; 83 : 604-609. 3. Aarskog D. lntersex conditions masquerading as hypospadias. Birth Defects 1971; 7 : 122-130. 4. Van Niekerk WA. True hermaphroditism. In : Josso N, ed. The b~tersex Child. Pediatric and Adolescent Endocrinology. New York : S. Karger, 1981; Volume 8; 80-90. 5. Rajfer Walsh PC. Mixed gonadal dysgenesis-dysgenetic male pseudohermaphroditism. In : Josso N, ed. The Intersex Child. Pediatric and Adolescent F'tdocrinolog)~. New York : S. Karger, 1981; Vol. 8; 1o3115. 6. Prader A. Male P~udohermaphroditism: A Review. In : Ghai OP, cd. Developments hi Pediatric Rexecurh. Vol. III : pp. 1111. New Delhi. Presented at XV International Congress of Pediatrics, New Delhi; 1977. 7. Cendron J. Plasty of the genitals in case of female pseudohermaphroditism. Birth Defects 1977; 13 : 261-263. 8. F6k6t6 CN. Feminizing genitoplasty in the intersex child. In : Josso N, ed. The lntersex Child. Pediatric and Adolescent Endocrinology New York; S. Karger, 1981; Vol. 8 : 247-260.
