XO MOSAICISM

XO MOSAICISM

783 such a visit and would be happy to discuss the matter and so get rapidly healed the wounds which have been caused by the article. E. W. FARMER ...

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783

such a visit and would be happy to discuss the matter and so get rapidly healed the wounds which have been caused

by the article. E. W. FARMER

Black Bourton Parish Council, Carterton, Oxford.

Clerk

to the

Council.

XY/XO MOSAICISM SIR,-Recent correspondence in The Lancet on XY/XO mosaicism has raised a number of important points not only in relation to this particular mosaic but also to the general problem of ambiguous development of the genitalia. One of the more important aspects, and one to which insufficient attention has so far been paid, is that of gonadal histology. Hirschorn et al.l described carefully the histological appearances of the gonad in their case; there was dense fibrous stroma such as is found in ovarian tissue ; in the hilar area were nests of cuboidal cells interpreted as rete-like structures ; a careful search showed two structures identified as ovarian follicles, whilst near

the cortex

were

tubular

structures

early seminiferous

tubules.

In Blank et al.’s case2 there

was no

pathologists

as

interpreted by

some

material available for

histological study. Miller et al. found that in their two cases one gonad was absent whilst the other showed abundant seminiferous tubules, aseminoma, and ovarian stroma. Jacobs and her colleagues4 report two cases with " streak " gonads showing in one case ovarian stroma and in the other connective tissue and a cluster of theca-like cells. Willemse et al. describe a case with Leydig cells and seminiferous tubules without spermatogenesis. Judge et al. report that in their case biopsy of the " ovary " showed what appeared to be ovarian stromal tissue without

follicles. The italics (which are mine) in the above paragraphs indicate that these appearances cannot be, considered conclusive and suggest that caution should be exercised in interpreting them. Yet caution is not always evident when one reads of these cases quoted by others. For instance, despite Hirschorn et al.’s qualified appraisal of their case as a possible hermaphrodite, it is now freely quoted as a definite one, whilst Judge et al. even stated that Willemse’s case had an ovotestis-a view quite unjustified from Willemse’s description. With so much attention rightly focused on the chromosomal aspects of these cases it seems to me that there is a danger of our interpreting too certainly the appearances of these gonads on histological examination. Are we justified in assuming that a few theca-like cells or some stroma resembling ovarian stroma really indicates that a gonad is an ovary ?? Can we with certainty distinguish primitive ovarian stroma without follicles from primitive testicular stroma without tubules ? I ask these questions in all humility for I am no pathologist, but they seem to me to be of fundamental importance. If we assume that the most likely starting point for an XY/XO individual is an XY zygote, which then loses Y

a

during mitotic division, the presence of ovarian a surprising finding. It is known from Jost’s s

structures is 1.

Hirschorn, K., Decker,

W. H., Cooper, H. L. New Engl. J. Med. 1960, 263, 1044. 2. Blank, C. E., Bishop, A., Caley, J. P. Lancet, 1960, ii, 1450. 3 Miller, O. J. Quoted by Rappoport, S., Kaplan, W. D. J. Pediat. 1961, 59, 415. 4. Jacobs, P. A., Harnden, D. G., Buckton, K. E., Court Brown, W. M., King, M. J., McBride, J. A., MacGregor, T. N., Maclean, N. Lancet, 1961, i, 1183. 5. Willemse, C. H., Van Brink, J. M., Los, P. L. ibid. 1962, i, 488. 6. Judge, D. L. C., Thompson, J. S., Wilson, D. R., Thompson, M. W. ibid. Aug. 25, 1962, p. 407.

workthat when the testes are removed in the laboratory animal at a very early stage of development the animal develops a female phenotype and the uterus, vagina, &c., persist; there is evidence in support of a similar mechanism in the human where there is very early testicular failure. But would a primitive gonad, destined to be a testis but failing to develop, then assume ovarian characteristics, or is it merely that the primitive gonad more nearly resembles the ovary than the testis ?

Regarding the suggestion that a specific XY/XO synexists, the reported cases do show some points of similarity, but they also show important points of difference, whilst there are other reports of cases,8 which appear similar clinically, of different chromosome complements-XY and probably XO/Xy, the y being partially drome

deleted.9 It may well be that further detailed reports will show that an XY/XO syndrome does exist; we can only wait and see. Meanwhile, perhaps, we may speculate on the support that these cases give to a mechanism in the human similar to that shown by Jost to operate in the laboratory animal. The cases reported by Jacobs et al. and Judge et al. showed no masculinisation, and the gonadal histology showed no dentifiable testicular tissue; Miller’s cases and those of Hirschorn et al., Willemse et al., and Conen et al. showed some testicular elements and some degree of masculinisation. This seems to suggest that if the testis fails to develop from the indifferent gonad or develops to only a minimal degree we may expect a female phenotype, with or without some masculinisation, the clinical features depending more upon the extent of this failure than upon the precise chromosome complement The chromosome abnormality may well give rise to the failure of the indifferent gonad to develop into a testis, but it may be this failure which is important in deciding the clinical features of the case Department of Obstetrics and Gynæcology, Jessop Hospital for Women,

Sheffield.

C. J. DEWHURST.

SIR,-Dr. Judge and his coworkers (Aug. 25) agree with Willemse

al. in thinking that there may be a specific a female phenotype, primary amenorrhoea, with syndrome and rudimentary gonads with possible elements of both male and female origin, together with XY/XO mosaicism. We should like to record a case of XY/XO mosaicism with male phenotype. A

et

unmarried clerk is the seventh of eight childMaternal and paternal age at his birth were 34 and 35. His general health has always been good. At the age of 35, a Denis Browne plastic operation was successfully performed for hypospadias. He now presents with obesity and suspicion of female breast development.

42-year-old

ren.

His height is 157 cm. and he weighs 64 kg. His general appearance is typically male, and he shaves every day. There is slight feminisation of the breasts which, however, contain no glandular tissue. Hair growth is abundant on the body and limbs. The left testis, situated in the scrotum, is the size of a large pea. The right testis is not palpable. The penis is of nearly average size and the orifice of the urethra is situated just under the glans. Biopsy of the left testis revealed absence of spermatogenesis, thickening of the tubular membranes, atypical Sertoli cells, and hyperplastic Leydig cells. Thyroid and adrenal functions are normal. Urography and X-ray pic7. 8. 9.

Jost, A. Rec. Prog. Hormone. Res, 1953, 8, 379. Alexander, D. S., Ferguson-Smith, M. A. Pœdiatrics, 1961, 28, 758. Conen, P. E., Bailey, J. D., Allemang, W. H., Thompson, D. W., Ezrin, C. Lancet, 1961, ii, 294.

784 of the skull are normal, but the bone structure of the lumbar vertebrx is markedly dense. Gonadotrophin excretion is more than 40 mouse uterine units per 24 hours. 17-ketosteroids, 7-1 mg. per 24 hours. The oral mucosa-cell nuclei contain no Barr bodies, and drumsticks are absent. Chromosome preparations made from peripheral leucocytes 10 on two different occasions revealed a 45/XO/46/XY mosaic constitution. The distribution of chromosome counts is as follows: tures

The undescended right gonad of the patient might contain ovarian tissue. Thus, the possibility that he is, in fact, a true hermaphrodite cannot be excluded. But his phenotype is male. We therefore feel justified in claiming that not all cases of XY/XO mosaicism are phenotypic females. Samfundet Folkhälsan ALBERT DE LA CHAPELLE Institute for Genetics, HERMAN HORTLING. Helsinki, Finland. TRANSLOCATION BETWEEN CHROMOSOME 2 AND AN ACROCENTRIC IN GROUP 13-15 SiR-We have recently had an opportunity to study APPARENT

boy who has some no.

a

apparent translocation between chromo2 and one of the acrocentric chromosomes in the an

13-15 group. 10.

Hungerford,

D.

A., Donnelly, A. J., Nowell, P. C., Beck, S. Amer. J.

hum. Genet. 1959, 11, 215.

Fig. 1-Metaphase plate. Giant chromosome

is

readily visible.

The patient is a 12-year-old boy who was brought to the Cleveland Clinic because he was about to fail in his school studies. He is the firstborn of four children. The parents and the siblings are apparently normal and of good intelligence. The pregnancy was reported as normal, except for some bleeding in the first trimester. Delivery was spontaneous at the seventh month of pregnancy by a breech presentation. The birth weight was 4 lb. Because of difficulty with feeding, there was a weight loss of 1/2 lb. during the first week of life. Subsequently, infancy was uneventful. Physical development was somewhat delayed; he walked at 18 months. He is described as being unusually active and immature. He is attending a regular school, but is having great difficulty with reading and with mathematics. On examination he had multiple anomalies that were difficult define. Although he was not mongoloid, the multiplicity of minor abnormalities was similar to those in that syndrome. The height and weight were average for a male of his age. The head was more rounded than usual, but of average circumference. The eyes were deep set with rather striking dark circles about them. The irises and the retinas appeared normal. The external ears were large; the pinnse were deficient in cartilage, and a plastic surgical procedure had been performed to set the pinnx closer to the skull. The mouth appeared normal. The speech was defective with poor articulation, and excessive air escaped through the nose on exhalation as if velar closure were inadequate. The neck was short, and there was only a slight suggestion of webbing. The chest was narrow. His muscles were generally poorly developed with the deltoids particularly weak and small. All joints were hyperextensible. A simian line was not present, and the small fingers were not curved. A deep pilonoidal sinus was present. Both feet were weak, and there was a moderate genu valgum. At rest, the right foot assumed a varus position and the left a valgus position. The trunk was short in proportion to his legs. Genital development seemed average. The testes were normal to palpation, and testes and penis were of a size appropriate for early adolescence. A slight growth of pubic hair was present. to

The blood cells were cultured and were stained with standard techniques. 67 cells were photographed and were counted; 62 demonstrated 45 chromosomes. In 5 cells we could not be certain as to whether there were 44 or 45 chromosomes. We find in our normal series about 10% cells in which we are uncertain of the count or in which there may be a chromosome missing because of technical difficulties. All cells photographed and all seen clearly by microscopy demonstrated an unusually large metacentric chromosome. Karyotypes consistently demonstrated only 5 chromosomes in the 13-15 group, and only 1 member of the no.

2

pair.

The upper arms of the large chromosome were identical to the upper arms of the single no. 2 chromosome. The total length of the large chromosome was approximately that of the combined length of the no. 2 chromosome plus one of the 13-15-group chromosomes. Most of the large chromosomes demonstrated a secondary constriction at the junction of the lower and middle thirds of the long arm.

We are not certain whether the missing chromosome is no. 13,14, or 15. Attempts to determine this point by comparison of satellites have not so far been successful. We believe, however, that this individual clearly demonstrates a translocation between chromosome no. 2 and one of the chromosomes of the 13-15 group. Fig. 2-Karyotype demonstrating giant chromosome in no. 2 position. Note secondary constriction. The missing large acrocentric chromosome is arbitrarily assigned f to the 15 position.

Department of Pediatrics, Cleveland Clinic

Foundation, Cleveland, Ohio.

ROBERT D. MERCER GHAZAR DARAKJIAN.