XY Mosaicism

XY Mosaicism


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From the Departments of Urology and Pediatrics, Kaiser-Permanente Medical Center, Oakland, California


The mosaic karyotype XO/XY is expressed by a spectrum of genital phenotypes, ranging from normal male through ambiguous genitalia to normal female. The urologist may see some of these patients because of the following clinical presentations: 1) ambiguous genitalia with a chromatinnegative buccal smear, 2) hypospadias with cryptorchidism or 3) cryptorchidism with mullerian remnants, discovered unexpectedly during inguinal operations. Reliable karyotyping is mandatory for diagnosis of XO/XY patients. Management should include laparotomy with excision of any intra-abdominal gonads (testis and/or streak gonad) because these are prone to develop malignancies that may occur before puberty. Female sex assignment and a reconstructive operation are advised in cases with severely deficient virilization of the genitalia. The mosaic karyotype XO/XY presents clinically in a variety of ways for which urologic consultation or treatment may be sought. Most cases are seen during the neonatal evaluation of ambiguous genitalia. These patients have mixed gonadal dysgenesis, 1- 3 with a unilateral testis that may be intraabdominal, a contralateral streak and persistent mullerian derivatives. The buccal smear is chromatin-negative, which excludes these ncin,c,n,c: from the most common etiology of ambiguity, congenital virilizing adrenal hyperplasia, that is the adrenogenital syndrome in the female subject. The diagnosis is established by a chromosome analysis demonstrating a mosaic pattern containing a 45 XO and a 46 XY stem line. After the common presentation of mixed gonadal dysgenesis the clinical expressions of XO/XY m_osaicism are depending upon the degree of fetal testicular insufficiency." Some of these patients will seek urologic attention for ently common conditions, such as cryptorchidism or spadias associated with cryptorchidism. Such patients can distinguished from XY male subjects only by Because a predilection to gonadal ''""'"'',u".. XY patients, 1' 2 , 5-, laparotomy and gonaaectcnny in addition to reconstruction of the genitalia. XO/XY mosaicism was diagnosed in 6 pacn,u""'' cm,u,,ccu vvith urologic manifestations. sented with ambiguous and a buccal smear, The 4 children were --··u.-~u· anomalies (see table), CASE REPORTS uw,,u,,uu

2 viere conside:red (with unilat-

meatus at tip of the eral and 1 bilateral cryptorchidism. because mullerian structures were discovered at time of the inguinal operation. The management of 1 of these children is presented. Case l, M. S., a 2-year-old black boy, was born at another hospital after 32 weeks of gestation. The penis was normal and had been circumcised. During the neonatal period left cryptorchidism and a right hernia/hydrocele were noted. When the patient was 2 months old herniorrhaphy was done. During entry into the hernia sac an intra-abdominal gonad and mullerian remnants were seen. Exploratory laparotomy

with gonadal biopsy proceeded immediately and the inguinal gonad was placed intra-abdominally. Histologically, both gonads were prepubertal testes. The buccal smear was negative. When the patient subsequently sought continued care at our hospital karyotyping demonstrated XO/XY mosaicism (fig. 1, A). Because the risk of prepuberal gonadal malignancy exists in XO/XY patients laparotomy was done. Postoperative scarring had caused dense fusion of the testes so that ori:t1i,op,exy was not Therefore, bilateral orchiectomy and hysterectomy were done. The operative specimen demonstrated the fused testes, epididymides, vasa deferentia, and infantile uterus and tubes (fig. 1, B). At an appropriate chronologic age puberty will be induced and maintained with testosterone and prosthetic testes will be placed. associated with cryptorchidism. Tvvo other presented with hypospadias and cryptorchidism, 1 unilateral and 1 bilateral. The buccal smear was chromatinnegative and karyotyping showed an XO/XY pattern. The inadequacy of reliance upon buccal smear only is demonstrated. Case 2. G. R., a 9-month-old white child, was born at another hospital. At birth a small, scrotal hypospadiac phallus, bifid scrotum. and a descended right testis 2, .A and B). A smear was chromatinthat the anomalous male but that the child XY mosaicism, Because of deficient size with severe ,JvuIJ•~u.mu the usual absence of in XO/ on ,.,,;-""':rr~"-." contrast of the fernale phenotype was believed to be crn,met11ca11 appropriate, Also, the child was young enough to allow a psychosexually successful change in sex. After a thorough, careful discussion with the parents right orchiectomy, clitoral recession, vaginoplasty and laparotomy were done (fig. 2, C and D), Mullerian remnants were represented by a diminutive uterus and fallopian tube, which were excised, along with a streak gonad. Female hormonal replacement will be used at an appropriate age to induce puberty and to maintain secondary sexual characteristics. DISCUSSION

Intersex classifications based upon clinical presentation, 1 gonadal constitution'1 or chromosomal pattern8 may be used in evaluating patients with ambiguous genitalia. Each of these is useful but overlap among these diagnostic entities may

Accepted for publication September 16, 1977. Read at annual meeting of Southeastern Section, American Urological Association, New Orleans, Louisiana, March 27-31, 1977. 103



Urologic manifestations ofXO/XY mosaicism in 5 patients Age at Diagnosis

Clinical Presentation


6 yrs.


2 yrs.



Incarcerated hernia surgically reduced, subsequent orchiopexy attempt showed uterus and tube Hydrocele/hernia operation disclosed uterus and tube, and contralateral testis Anomaly of male genitalia



Anomaly of male genitalia



Ambiguous genitalia


External Genitalia Phallus Scrotum/Testis


Internal Genitalia

Sex of Rearing


Rt. cryptorchidism, It. scrotal testis

Streak Testis

Rt. unilat. tube



Bilat. cryptorchidism

Testis Testis

Uterus and miillerian remnants


Hypospadias and scrotal opening Coronal hypospadias

Bifid scrotum, It. cryptorchidism Bilat. cryptorchidism Lt. cryptorchidism

Testis Streak

Diminutive uterus and tube


Penoscrotal hypospadias

Male Testis Streak

Uterus and It. tube


* Laparotomy recommended but transferred out of area.

Fm. 1. Case 1. A, appearance of external genitalia at age 2 years. B, operative specimen demonstrates postoperatively fused testes Forceps is grasping left epididymis and vasa deferentia are noted to lead toward uterus.

create confusion. Varying nomenclature may be applied to a single individual, for example the same patient could be diagnosed as having hernia uteri inguinale, mixed gonadal dysgenesis, an X chromatin-negative variant of the syndrome of gonadal dysgenesis or XO/XY mosaicism. A great reliance has been placed upon the buccal smear when evaluating patients with anomalous genitalia. 1· 3· 9 In XO/XY patients the buccal smear is always chromatin-negative because each stem line has only 1 X. We recommend karyotyping in any patient with sexual ambiguity and a chromatin-negative buccal smear to distinguish XO/XY patients from XY male pseudohermaphrodites. Although the differential diagnostic investigation of patients with ambiguous genitalia should lead to karyotyping and early cytogenetic diagnosis patients with XO/XY mosaicism may mimic phenotypically common urologic conditions1--a, 10 that are not associated with any genotypic or gonadal abnormality. Hypospadias occurs in 0.6 to 0.8 per cent of live births 11 and cryptorchidism in 0. 7 per cent. 12 Although intersexuality is uncommon in these individual disorders when hypospadias and cryptorchidism occur simultaneously the incidence of intersexuality ranges from 27 to 53 per cent. 13 The presence of such apparently minor genital anomalies as coronal hypospadias and unilateral cryptorchidism does not exclude the possibility of XO/XY mosaicism. Patients with any degree of hypospadias when associated with cryptorchidism should be karyotyped to make a precise diagnosis that may alter management before any reconstructive genital operation. Some patients with XO/XY mosaicism may mimic those with hernia uteri inguinale. Patients with this entity are phenotypic male subjects with a hernia, ipsilateral scrotal testis and contralateral cryptorchidism, in whom a uterus and fallopian tube (often associated with the contralateral testis) are discovered at operation. Probably this is the result of an

isolated deficiency of miillerian inhibiting factor, the nonsteroidal fetal testicular hormone responsible for involution of the miillerian structures, 1. 3 These patients are otherwise normal, fertile XY male subjects. Of our patients 2 had miillerian elements discovered during the inguinal operation but they were distinguished from hernia uteri inguinale by chromosomal studies that revealed XO/XY mosaicism. The size of the phallus is the single most important factor in planning the genital operation. If the phallus is deficient in size the presence of a scrotal testis should not preclude female sex assignment and an appropriate reconstructive operation. 9 Reconstruction of the external genitalia should be attempted primarily to obtain a surgical result that is functional. The gonads of patients with XO/XY mosaicism may undergo malignant degeneration to gonadoblastomas in 25 per cent. 1· 2' 5-s, 10 These are tumors that develop almost exclusively in abnormal gonads, most of which are intra-abdominal. Of patients with gonadoblastomas 89 per cent are chromatin-negative and virtually all have a stem line with a Y chromosome. 5 Scully reported that 10 of 30 karyotyped patients with gonadoblastoma had XO/XY patterns. 5 Although gonadoblastomas are considered benign they are commonly associated with malignant dysgerminoma/seminoma. Because of this removal of all intra-abdominal gonads of patients with XO/XY mosaicism is recommended. 8 Uniquely, these tumors may occur even before puberty and prophylactic gonadectomy should proceed soon after diagnosis. In XO/XY patients being reared as male subjects with normal-appearing testes orchiopexy may be possible. Also, an occasional patient with XO/ XY karyotype has a testis that is already scrotal. In neither of these situations is removal recommended. CONCLUSION

Because there is a strong predilection for gonadal malignancy in XO/XY mosaicism reliable karyotyping is mandatory




FIG. 2. Case 2. A and B, genitalia show small phallus, severe hypospadias and unilaterally descended right testis. C and D, appearance of genitalia after female reconstruction.

in 1) chromatin-negative patients with ambiguous genitalia, 2) patients with any degree of hypospadias associated with cryptorchidism or 3) patients with cryptorchidism who are found to have mullerian elements at operation. After the cytogenetic diagnosis of XO/XY mosaicism is made management depends upon the phenotypic appearance of the genitalia and the sex of rearing. Because of a liability toward prepuberal gonadal malignancies laparotomy should be done at an early age, with removal of any intra-abdominal streak gonad and/or testis. Simultaneous removal of mullerian remnants also should be done in patients being reared as male subjects. A normal-appearing inguinal testis may be in the scrotum or the scrotal testis may be position Female sex assignment and a reconstructive - are advised for patients with severely deficient of the genitalia. Karyotypes for these patients were performed in the genetics Laboratory of Ronald Bachman. REFERENCES 1. Federman, D. D.: Abnormal Sexual Development. A Genetic

and Endocrine Approach to Differential Diagnosis. Philadelphia: W. B. Saunders Co., 1967. 2. Sohval, A. R.: "Mixed" gonadal dysgenesis: a variety of hermaphroditism. Amer. J. Hum. Genet., 15: 155, 1963. 3. Allen, T. D.: Disorders of sexual differentiation. Urology, suppl., 7, p. 1, 1976. 4. Morishima, A. and Grumbach, M. M.: The interrelationship of

sex chromosome constitution and phenotype in the syndrome of gonadal dysgenesis and its variants. Ann. N. Y. Acad. Sci., 155: 695, 1968. 5. Scully, R. E.: Gonad.oblastoma. A review of 74 cases. Cancer, 25: 1340, 1970. 6. Mostofi, F. K. and Price, E. B., Jr.: Tumors of the male genital system. In: Atlas of Tumor Pathology. Washington, D. C.: Armed Forces Institute of Pathology, series 2, fasc. 8, pp. 114120, 1973.

7. Moshang, T., Jr., Vallet, H. L., Cintron, C., Bongiovanni, A. M. and Eberlein, W. R.: Gonadal function in mosaic XO/XY or XX/XY Turner's syndrome. J. Ped., 80: 460, 1972. 8. Grumbach, M. M. and Van Wyk, J. J.: Disorders of sex differentiation. In: Textbook of Endocrinology, 5th ed. Edited by R. H. Williams. Philadelphia: W. B. Saunders Co., pp. 423-501, 1974.

9. Walsh, P. Intersex states. In: Urologic Surgery, 2nd ed. Edited F. Glenn. N·ew York: Harper & Row, Publishers, Inc., pp. 1975. 10. Aarskog, D.: Clinical and cytogenetic studies in hypospadias. Acta Paediat. Scand., suppl. 203, p. 44, 1970. 11. Sweet, R. A., Schrott, H. G., Kurland, R. and Culp, 0. S.: Study of the incidence ofhypospadias in Rochester, Minnesota, 19401970, and a case-control comparison of possible etiologic factors. Mayo Clin. Proc., 49: 52, 1974. 12. Scorer, G. C. and Farrington, G. H.: Congenital Deformities of the Testis and Epididymis. New York: Appleton-CenturyCrofts, p. 19, 1972. 13. Rajfer, J. and Walsh, P. C.: The incidence of intersexuality in patients with hypospadias and cryptorchidism. J. Urol., 116: 769, 1976.