The Journal of Obstetrics and Gynaecology of the British Commonwealth May 1971. Vol. 78. pp. 448-457.

STREAK GONADS AND THE Y CHROMOSOME BY

JOAN ANDREW, Senior Lecturer The Department of Obstetrics and Gynaecology, The University of Liverpool

Summary Seven cases in which streak gonads were found in association with a Y chromosome in the karyotype are presented. The varied clinical features are discussed. The high incidence of gonadal tumours in individuals who have streak gonads and a Y chromosome in the karyotype is emphasized.

THE association between the somatic manifesta- tions of Turner’s syndrome, streak gonads and an XO chromosome constitution was recognized by Ford and his colleagues in 1959. Since then there have been cases reported of patients who, whilst having streak gonads, show none, or only some, of the manifestations of Turner’s syndrome and who have varied chromosomal patterns.

The possible variations were classified by Teter (1969) as follows:

Chromosome constitution 45 XO or 45 X0/46 XX mosaic

45 X0/46 XY

1. Turner’s syndrome

2. Turner’s syndrome with or without some degree of masculinization mosaic

3. Gonadal dysgenesis without somatic abnormalities and with normal stature 46 XX

4. Gonadal dysgenesis without somatic abnormalities, with or without masculinization 46 XY The following cases illustrate some of the

possible variants seen when streak gonads are found in association with a Y chromosome.

Case 1 . Gonadal Dysgenesis with Masculinization and XOl X Y Karyotype

The patient first presented at the age of 21 years with the complaint of primary amenor- rhoea and a four-year history of increasing

generalized hirsutes and deepening of her voice. She was of moderate height (163 cm.) and had virtually no development of the breasts or nipples. Examination revealed the external genitalia to be female in type except that the phallus was enlarged to a length of 2 cm. A vagina was present. Buccal smears were negative for sex chromatin. Chromosome analysis of the leucocytes showed that 49 per cent of nuclei contained 46 chromosomes with an XY karyo- type, and the remainder 45 chromosomes with an XO karyotype.

Laparoscopy was undertaken to establish the nature of the internal genitalia. A fold of peritoneum was found across the pelvis and this contained an infantile uterus and tubes. The right gonad, lying on the pelvic wall, measured 3 * 5 x 2 x 2 cm. ; the left gonad was represented only by a streak of connective tissue. In view of the doubtful nature of the right gonad, laparo- tomy was performed and both gonads removed. The enlarged phallus was also excised.

Microscopically the right gonad was shown to consist of Leydig cells and well-formed semi- niferous tubules with no evidence of sperma- togenesis. A skin biopsy was taken at the time of laparotomy and chromosomal studies of the epithelial cells showed that only 15 per cent of nuclei had an XY karyotype. The chromosomal make-up of the gonadal tissue was not investi- gated. Prior to operation the levels of 17-cortico- steroids and 17-oxosteroids in the urine were 28.3 and 22.8 mg. per 24 hours respectively. These fell to 13.2 and 12.6 mg. per 24 hours in the immediate postoperative period.

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STREAK GONADS AND THE Y CHROMOSOME 449

Oestrogen therapy was given after operation and during the first year resulted in moderate development of the breasts and monthly episodes of uterine bleeding. The hirsutism remained unaffected.

Case 2. Gonadal Dysgenesis with Masculinization and XO/ X Y Y Karyotype ( ? X O / X Y / X Y Y )

This case was described previously by Jeffcoate ( 1967).

This patient, aged 15 years, complained of increasing hirsutism of the legs and buttocks and deepening of the voice for one year. She had not menstruated and her height was only 126 cm. The breasts had not developed. The axillae were free from hair although there was a normal growth of pubic hair. The phallus was enlarged but the external genitalia were otherwise female in type. The vagina was normal but unstimulated. Intravenous pyelography showed the presence of a single horseshoe kidney. Buccal smears contained chromatin negative cells. At laparo- tomy the uterus and tubes were seen to be infantile. There was a streak gonad (1 - 5 x0-25 cm.) on the right side and a small gonad measur-

ing 2.5 cm. in length on the left. Both gonads and the large phallus were removed.

On histological examination the left gonad showed the typical appearance of an undescended testis with Leydig cells and seminiferous tubules, but there was no evidence of spermatogenesis (Figs. 1 and 2). The right gonad showed only fibrous tissue (Fig. 3). Chromosome studies of the leucocytes carried out preoperatively indicated a genotype of 44fXO in the majorityof cells, but in 16 per cent of cells the count was 47 with a probable genotype 44+XYY. Chromosome studies of skin removed at the time of laparotomy revealed a varied picture of 44+XYY in 27 per cent of cells, 44+XY in 10 per cent and 44+XO in 54 per cent, suggesting a triple mosaicism of XO/XY /XYY.

Cyclical oestrogen therapy given after opera- tion resulted in satisfactory breast development and monthly episodes of uterine bleeding.

Case 3 . Gonadal Dysgenesis with Slight Masculinization and XO/ X Y Karyotype. Gonadoblastoma of the Right Gonad

The patient, who was 20 years old, complained of primary amenorrhoea although withdrawal

FIG. 1 Left gonad from Case 2. Showing undeveloped test is with well-formed seminiferous tubules

and Leydig cells. ( x 80.)

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FIG. 2 Left gonad from Case 2. ( x 500.)

FIG. 3 Right gonad from Case 2. Showing gonadal streak. ( x 80.)

STREAK GONADS A N D THE Y CHROMOSOME 451

uterine bleeding had previously been induced twice by means of norethynodrel and mestranol. She was only 126 cm. in height. There was evidence of some glandular development of the breasts. Axillary and pubic hair were present and there was slight facial hirsutes. The cells in a buccal smear were chromatin negative. Chromo- some studies of leucocyte nuclei revealed a mosaic picture of 44fXY in 77 per cent cells and 44+X in 18 per cent cells. The level of 17-oxosteroids in the urine was 10.7 mg. per 24 hours.

At laparotomy the uterus and tubes were seen to be infantile. The left gonad was represented by a streak of apparent fibrous tissue. The right gonad, lying on the pelvic wall, was spherical (diameter 2.5 cm.), white and hard. The surface of the gonad was roughened by spicules of calcium. The right gonad was removed and, on subsequent histological examination, was found to consist of connective tissue such as is found in the ovarian cortex with small and large clusters of what looked like granulosa cells with dark staining nuclei scattered in the sub-stroma (Figs. 4 and 5). In places these cells were arranged in follicles, some of which contained larger pale cells; in others the follicular groups coalesced. There were small psammoma bodies or calcified areas in the cell clusters and, scattered throughout the stroma were larger nodules of calcification. Also in the connective tissue were small groups of cells of the Leydig type. The microscopic features of the tumour are typical of those of a “gonadoblastoma” as described by Scully (1953). There was no histological evidence of malignancy. The left gonad showed only fibrous tissue on microscopic examination.

Chromosomal study of the cells from the right gonad again showed a mosaic picture with 79 per cent of the nuclei having a 44+Y karyotype and 9 per cent having a G + X Y karyotype.

Following the operation cyclical treatment of the patient with oestrogen resulted in further breast development and withdrawal uterine bleeding.

Case 4. Gonadal Dysgenesis with X Y Karyotype The patient attended at the age of 17 years

complaining of primary amenorrhoea. She was a tall girl, 170 cm. in height with an arm span

of 173 cm. There was little evidence of develop- ment of either nipple or glandular tissue of the breast. There was only a scanty growth of pubic hair and axillary hair and the external genitalia appeared female in type. Intravenous pyelo- graphy showed no abnormality of the renal tract.

Buccal smears contained only chromatin negative cells and chromosome studies of leucocytes indicated a 44+XY karyotype. Examination of the urine indicated an output of hormones as follows:

Oestriol 4-5 pg. per 24 hours, total pituitary gonadotrophins 45 mouse units per 24 hours, 17-corticosteroids 11 - 5 mg. per 24 hours and 17-oxosteroids 7.6 mg. per 24 hours. The state of the genitalia was studied in more

detail by examination under general anaesthesia and laparoscopy. The external genitalia, vagina, uterus and tubes were infantile, and both gonads were represented by streaks of tissue lying on the back of the broad ligaments.

After completion of the investigations oestro- gen therapy was given cyclically and produced withdrawal uterine bleeding and some develop- ment of the glandular tissue of the breasts but, even after two years’ treatment, the bust measurement remained small and this worried the patient. Mammoplasty was therefore carried out with a good result.

Case 5. Gonadal Dysgenesis with X Y Karyotype This patient, aged 21 years, complained of

primary amenorrhoea and lack of breast development. She appeared to be a good-looking but tall girl, 174 cm. in height (pubis-ground measurement 93 cm.) and with an arm span of 183 cm. The pubic hair development was normal but axillary hair was scanty. The breasts were infantile.

The clitoris was hypertrophied but the external genitalia were otherwise feminine in appearance. The blood pressure measured 1701 120 mm. Hg and examination of the urine showed gross albuminuria. Initially tests of renal function gave normal results and intravenous pyelography showed only minimal clubbing of the renal calyces. However, isotopic radio- graphy performed later suggested that the function of the left kidney was impaired.

The cells in the buccal smears were chromatin

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FIG. 4 Right gonad from Case 3. Showing gonadoblastoma. (x40.)

FIG. 5 Right gonad from Case 3. ( x400.)

STREAK GONADS AND THE Y CHROMOSOME 453

negative. The chromosomal pattern was shown to be 44+XY in both the leucocytes and skin cells.

Hormone assays carried out on the urine gave the following results: total pituitary gonado- trophins 20 mouse units per 24 hours; 17- corticosteroids 6 . 1 mg. per 24 hours; 17- oxosteroids 3 - 3 mg. per 24 hours; and oestriol 10.4 pg. per 24 hours. Pelvic examination under anaesthesia, together with laparoscopy, revealed normal but unstimulated vagina, uterus and tubes. The left gonad was represented by a streak of tissue and the right gonad by only a few small patches of pale connective tissue.

Following the investigations the patient was treated with cyclical norethisterone acetate and ethinyl oestradiol. This resulted in the occur- rence of cyclical withdrawal uterine bleeding but no breast development.

Case 6. Gonadal Dysgenesis with X Y Karyotype. Disgerminoma of the Right Gonad, and Gonadoblastoma of the Left Gonad

This patient, aged 20 years, presented with a complaint of primary amenorrhoea. She was of tall stature (169 cm.) and showed little evidence of development of the nipples and glandular tissue of the breast. Axillary and pubic hair were present although scanty in amount. The external genitalia and vagina appeared normal, but on pelvic examination a right-sided pelvic mass was felt separate from a very small uterus. Intra- venous pyelography revealed no abnormality. The chromosome make-up of the nuclei of the leucocytes was 44fXY. Laparotomy was performed and confirmed the presence of an infantile uterus and tubes. The right gonad was replaced by a solid buff-coloured tumour (5 x 3 x 2 cm.) whilst on the left side there was a streak gonad. Frozen sections taken from the tumour showed features suggestive of a dis- germinoma with large cells arranged in cords and nests and nuclear pleomorphism and numerous mitoses. These cells were surrounded by abun- dant connective tissue containing some lympho- cytes and giant cells. Both tubes and gonadal structures were removed. Subsequent microscopic examination of the right gonad confirmed the findings in the frozen sections. The left gonad, however, was not the typical undifferentiated streak of tissue in that it contained groups of cells arranged in alveolar pattern, with both

psammoma bodies and larger areas of calcifica- tion in the surrounding stroma (Figs. 6 and 7). Surrounding these was a rim of what looked like ovarian stroma.

Because some histological features of the tumour suggested that it had malignant char- acteristics the pelvis was irradiated. A total dose of 3000 rads was given by linear accelerator.

Three months later, examination of the patient suggested the possibility of a swelling lying above the right fornix, so laparotomy was repeated. This, however, did not reveal any abnormality. The uterus was removed and intensive histologi- cal examination of the specimen did not reveal any evidence of tumour cells. Two years later the patient remains well.

Case 7. Gonadal Dysgenesis with X Y Karyotype and Disgerminoma

The patient, who was 19 years old, complained of primary amenorrhoea. She was a tall girl (183 cm., in height) and wore size 94 shoes. There was little evidence of breast development. Axillary hair was absent and pubic hair scanty in amount. The patient had a history of femoral herniorrhaphy at the age of 8 and of appendicec- tomy at the age of 9 years.

Cells obtained by buccal smear were chromatin negative. Chromosome studies of leucocyte nuclei showed the karyotype to be 44fXY.

Pelvic examination under anaesthesia revealed normal but unstimulated vagina, cervix and uterus. A mass was felt lying behind and to the right of the uterus. Laparotomy was therefore performed and an infantile uterus and tubes were identified. There were multiple intra- peritoneal adhesions presumably dating from the appendicectomy operation, and a gonad was not found on the left side. The right gonad was replaced by a solid tumour measuring 10 x 6 x 5 cm. Both kidneys were present and of normal size. The tumour which was lobulated was removed and when sectioned proved to have a homogenous pale yellow cut surface.

The histological picture was that of a dis- germinoma with lobules of cells separated by fine fibrous trabeculae infiltrated with lympho- cytes.

Further chromosome studies carried out on skin and on tumour tissue confirmed the karyo- type as 44fXY.

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FIG. 6 Left gonad from Case 6. Showing gonadoblastoma. ( X 40.)

FIG. 7 Left gonad from Case 6. ( x 80.)

Cyclical oestrogen therapy (ethinyl oestradiol 0.05 mg. three times daily) was given to the patient after operation and resulted in some breast and nipple development and monthly episodes of uterine bleeding. phenotype.

DISCUSSION Various mechanisms have been suggested to

explain the occurrence of streak gonads in association with a Y chromosome and a female

STREAK GONADS AND THE Y CHROMOSOME 455

For the development of a functioning gonad, either testis or ovary, two sex chromosomes appear to be essential and the complete or partial absence of one sex chromosome results in germ cell degeneration. The commonest sex chromo- some pattern associated with streak gonads is 44tXO.

Mosaicbn In the human with an XO/XY mosaic

karyotype the gonadal development is dependent on the relative proportion of XO/XY cells and may result in bilateral streak gonads, a streak gonad with a testis, or two testes (Ferguson- Smith, 1965).

It is suggested that chromosome studies of the gonadal tissue from patients with an XO/XY karyotype may reveal histological and karyotype differences between the two sides; e.g. XO karyotype in cells from a streak gonad and XY in a differentiated testis. Studies of the karyotype in such patients reported by Starkman and Jaffe (1967) and by Russell er al. (1966) did not substantiate this idea. However, in a patient described by Turner et al. (1970), tissue culture of primitive ridge material associated with bilateral streak gonads showed 44fXX chromo- somes on one side and 44+XO on the other.

The complete absence of a functioning gonad always, and irrespective of chromosomal pattern, results in the development of the Mullerian duct system. This was shown by the experimental work of Jost (1953). By removing the fetal gonads of mice at an early stage in intrauterine life, Jost produced animals with female genitalia regardless of the gonadal sex.

In the human, in the absence of a functional testis, a female duct system develops regardless of chromosomal sex, whereas normal functional testis are responsible for the organization of the Wolffian duct system.

Where the XO/XY karyotype exists, the development of any masculine characteristics is dependent on the degree of differentiation of the gonads and the number of active Leydig cells present. Individuals with this chomosomal pattern can have a genital tract intermediate in development between the complete Mullerian duct system of the XO female and the complete Wolffian duct system of the normal XY male.

In the series of cases described here, patients 1,

2 and 3 were found to have a mosaic chromo- somal pattern, predominantly XO/XY. All three had only one streak gonad. In patients 1 and 2 the other gonad was an underdeveloped testis with seminiferous tubules and Leydig cells without evidence of spermatogenesis. In patient 3, the second gonad was replaced by a tumour. All three patients showed some degree of mascu- linization, as indicated by enlargement of the phallus and absent or minimal breast develop- ment. The genital duct system in each patient was Mullerian, not Wolffian.

Y Chromosome Deletion To explain the association between streak

gonads and an XY karyotype without apparent chromosomal mosaicism, deletion of part of the Y chromosome is postulated. The degree of deletion of the Y chromosome may be large or small and in the latter case the remaining fragmentary Y chromosome may pass unrecog- nized when the karyotype is studied, the patients then being described as having an XO karyotype.

It appears that the short arms of X or Y chromosome determine stature and the long arms of the X chromosome and homologous loci on the Y chromosome govern gonadal develop- ment. Thus an X, individual, with deletion of the short arms of the Y chromosome, is stunted in growth and shows the stigmata of Turner’s syndrome but, if still possessing a fragment of the Y chromosome, may develop some testicular tissue and show a variable degree of masculiniza- tion. On the other hand, absence of the long arm of an X chromosome does not result in short stature and other somatic abnormalities, but leads to the development of streak gonads (Ferguson-Smith, 1965).

X Y Karyotype and Streak Gonads Some alternative explanation is still necessary

to account for the finding of streak gonads occurring in association with what appear to be normal XY chromosomes. In such patients the karyotype is that of a normal male but the gonads are represented only by streaks of fibrous tissue.

Jost (1 953), Hemsworth and Jackson (1963) and Dewhurst (1967) postulated that in these karyotypic and phenotypic males early intra- uterine destruction of the testis occurred,

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with subsequent loss of its organizing effect. That such destruction is possible was shown by Hemsworth and Jackson (1 963) who gave Busulphan to pregnant rats and caused the offspring, whether male or female, to be born with sterile atrophic gonads.

In the human being it may be envisaged that such intrauterine damage to the gonad could be caused by chemical, radiological or bacterio- logical agents. Following complete testicular destruction the absence of germ cells and Leydig cells results in female differentiation of the genital ducts, and failure of all male differentia- tion. Variations in the time and extent of the testicular destruction with or without involve- ment of Leydigcells might then explain variations in the degree of sex differentiation intermediate between male and female. Thus apparent females with an XY karyotype, and with some external signs of masculinization, may have testicular tissue with a uterus, testicular tissue without a uterus, or may be devoid of both uterus and testicular tissue. Dewhurst ( I 967) described a case in which the patient with an XY karyotype had moderate clitoral enlargement, bilateral testes, a blind vagina with fused labia, and no internal genitalia.

Neither mosaicism nor deletion of chromo- somes were recognized when the karyotypes of patients 4, 5, 6 and 7 were examined. Associated with an apparently normal XY karyotype these four women were all of tall stature and complained of primary amenorrhoea and lack of breast development. On the above concept, it might be postulated that in each of these patients complete intrauterine destruction of gonadal tissue occur- red with subsequent development of a female genital duct system with no signs of masculiniza- tion. However, there was no evidence that the mothers of these individuals had been exposed, during early pregnancy, to any agent capable of testicular destruction in the human fetus.

The Somatic Efects of Chromosome Deletion and Mosaicism

Upon the degree of deletion, or mosaicism of the sex chromosomes depends not only the extent of failure of normal gonadal and genital duct development, but also the presence or absence of other stigmata of Turner’s syndrome. When there is complete absence of the second

chromosome (XO karyotype) the affected individuals show, in addition to streak gonads, some or all of the features of Turner’s syndrome such as short stature, neck webbing, genital infantilism and congenital heart disease. In such a case it is the loss of the short arms of one X chromosome which results in the somatic stigmata of Turner’s syndrome and the absence of the long arms of one X chromosome which is responsible for the streak gonads. When only the long arms of an X chromosome are missing in a patient with partial deletion of one of two X chromosomes (Xx) then the result is streak gonads in a woman of apparently normal physical development.

When there is an XO/XY mosaic pattern of chromosomes, it is the proportion of abnormal XO cells which influence the presence of any somatic stigmata of Turner’s syndrome. Amongst the cases of XO/XY karyotype described here (Cases 1 , 2 and 3) the only apparent defect was the short stature of patients 2 and 3.

Visceral abnormalities additional to the obvious external physical characteristics can occur in association with streak gonads. Two of the four patients reported here who had intra- venous pyelography performed showed some renal malformation, which in one case was associated with hypertension, presumably renal in origin. Amongst a series of 26 patients with gonadoblastoma collected by Boczkowski e f al. (1967) three died from uraemia.

Other somatic abnormalities described in association with Turner’s syndrome and streak gonads can be recessive and linked to an X chromosome. They are seen when the karyotype in XY, XO or Xx and include conditions such as sex-linked diabetes (Stewart, 1960) and red- green colour blindness (Polani et al., 1956). Patients with gonadal dysgenesis are also known to have a high level of thyroid auto-antibodies in their circulation and to develop thyroiditis (Vallalton and Forbes, 1967).

Gonadal Tumours Associated with Streak Gonads

The development of various tumours in streak gonads was described by Neugenauer (1 900) and Scully (1953). Teter (1967) reviewed published reports of 51 patients with dysgenetic gonads of whom 10 had tumours. These were germinal cell

STREAK GONADS AND THE Y CHROMOSOME 457

tumours (8), Brenner tumour (1) and interstitial cell tumour (1). Barr (1967) described cases of XY phenotype females with streak gonads and found 9 tumours among 24 patients (37.5 per cent).

Teter (1967) suggested a classification for germ cell tumours, or gonadocytomas, as follows:

Gonocytoma (&-a hormo nall y inactive tumour identical with a disgerminoma and formed solely of germ cells.

Gonocytoma (11)-a tumour consisting of germ cells and granulosa type cells which has feminizing effects.

Gonocytoma (111)-a tumour of germ cells, granulosa cells and inter- stitial cells which can have e i t h e r f e m i n i z i n g o r masculinizing effects. This commonly has calcium con- cretions in its substance.

Gonocytoma (IV)-a tumour of germ cells and interstitial cells, having mas- culinizing effects.

With regard to malignancy he considered the prognosis best in the small single tumour with differentiated cells and calcification (gonocytoma 111) and worst with the pure dysgerminoma (gonocytoma I).

Gonocytomas only arise with streak gonads when the karyotype is XY, and it is suggested that the presence of a Y chromosome and the potential of a dysgenetic gonad towards differ- entiation into a testis favours tumour develop- ment. A single exception to this apparent im- munity to tumour formation of streak gonads in women who do not have a Y chromosome was reported by Barr et a/. (1967); he described a disgerminoma in a patient with XO sex chromo- some complement.

From the present evidence it would appear that whenever streak gonads are found in an individual with a Y chromosome, laparoscopy or laparotomy is indicated to exclude a tumour in the gonad. Such tumours may be small and in only three out of ten of Teter’s (1967) patients was their presence suspected on clinical examina-

tion alone. In the series reported here, one of the three tumours was only diagnosed as a result of laparotomy .

It might further be argued that all streak gonads associated with a Y chromosome should be removed. This practice was not followed in Cases 4 and 5, and instead it was decided merely to keep the patient under observation. The periods of observation in these cases are so far 4 years and 2 years.

ACKNOWLEDGEMENTS I am grateful to Professor Sir Norman

Jeffcoate and Mr. V. R. Tindall for permission to report these cases.

I also wish to thank Dr. A. S. Woodcock and Dr. F. K. Storring for histological reports and Dr. S. Walker and Dr. M. Lawrence for chromo- some studies.

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