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of sex-linked inheritance of autoimmune diseases hasbeen obtained from family studies, Burch’s hypothesiscannot be considered more than an interesting sugges-tion. One X-linked gene concerned in gamma-globulinproduction and having a mutant form leading to agam-maglobulinaemia is of course known. Burch feels thatthe data concerning sex-incidence of autoimmunediseases indicate that this gene does not obey the inac-tive-X theory. In fact, in contrast to this supposition,Bach and Hirschhorn have recently shown that thislocus does show X-inactivation. Heterozygotes for

agammaglobulinaemia could be shown by fluorescent

antibody techniques to have two populations of cells,with and without gamma-globulin.At present there is no positive evidence in favour of

the hypothesis of Gartler and Sparkes 8 that the abnor-malities of XO individuals with Turner’s syndrome aredue to the inactivation of the single X in half the cellsof the XO and subsequent death of these cells, leavingan embryo with a normal X-chromosome dosage buthalf the normal number of cells. The attractiveness ofthe idea is that by extending it one would be able to

explain both male Turner’s and female Turner’s with anapparently normal karyotype, neither of which can easilybe fitted into any explanation involving wrong X-chro-mosome dosage. On Gartler and Sparkes’ hypothesisone would postulate that these two types resulted fromembryos which began as a mosaic of cells some with anormal karyotype and others with absence or lethal

deficiency of the X chromosome. The cells with absentor lethal X would die in similar circumstances to thosein the XO individuals, leaving the surviving embryoswith similar malformations. The hypothesis supposesthat most organs and tissues are able to reconstitutethemselves normally after loss of half their cells at suchan early stage; there are just a few developmental processesso disturbed as to result in malformation.Studies of early XO embryos of mice are to be made

in the hope of finding some evidence in favour of Gartlerand Soarkes’ idea.

MARY F. LYON.M.R.C. Radiobiological Research Unit,

Harwell, Didcot, Berkshire.

CHROMOSOME ANALYSIS AND PARENTAL AGEIN THE DEL CASTILLO SYNDROME

SIR,-Dr. Solari and others (Oct. 26) report chromo-some studies in a patient with germinal aplasia (DelCastillo syndrome 9), and suggest that a similar study offurther cases would be valuable. As this diagnosis is a

histological one made on testicular biposy material, casesmust be comparatively rarely recognised.Most cases are probably labelled as chromatin-negative

Klinefelter’s syndrome because they have chromatin-negativenuclear sex and yet share many features in common with

chromatin-positive Klinefelter’s syndrome, the more notable ofthese being azoospermia, small testes, increased urinary gona-dotrophins, and, very occasionally, gynaecomastia.1O-12 Dur-

ing a period of six years, we have made the diagnosis of germinalaplasia without tubular hyalinisation and fibrosis by testicularbiopsy in 24 chromatin-negative patients attending the maleinfertility clinic at this hospital. 11 of these patients wereavailable for recall for chromosome analysis and each, like the7. Bach, F., Hirschhorn, K. Proceedings of 11th International Congress

of Genetics, 1963, p. 312.8. Gartler, S. M., Spearkes, R. S. Lancet, Aug. 24, 1963, p. 411.9. Del Castillo, E. B., Trabucco, A., de la Balze, F. A. J. clin. Endocrin.

1947, 7, 493.10. Stewart, J. S. S., Mack, W. S., Govan, A. D. T., Ferguson-Smith, M. A.,

Lennox, B. Quart. J. Med. 1959, 28, 561.11. Ferguson-Smith, M. A., Lennox, B., Stewart, J. S. S., Mack, W. S.

Mem. Soc. Endocrin. 1960, no. 7, 173.12. Ferguson-Smith, M. A. Proc. Roy. Soc. Med. 1963, 56, 577-578.

patient of Dr. Solari and his colleagues, proved to have anormal male karyotype 12 in peripheral-blood cultures.However, an interesting and unexpected result emerged from

our study. This was’a suggestion that the maternal ages at thebirth of our patients may be higher than in the general popula-tion. The individual maternal ages of our cases are 44, 41, 39,35, 32, 32, 32, 30, 30, 30, and 21 years (mean 33-3 years), andthe paternal ages, in the same order, are 41, 40, 40, 36, 39,34, 29, 37, 31, 30, and 21 years (mean 34-4 years). Comparablefigures for the mean parental ages in a control population aregiven by Penrose 13 as 28-7 years and 32-2 years. The meanmaternal and paternal ages for 45 cases of chromatin-positiveKlinefelter’s syndrome seen at the same hospital are 32-5 and33-8 years.14 A high maternal age is considered a possible factorpredisposing to chromosomal non-disjunction and is an

understandable finding in chromatin-positive Klinefelter’s

syndrome. It is strange that the same maternal age effect mayoccur in germinal aplasia-a condition often indistinguishable byclinical features alone, and yet without recognisable chromosomeaberration. Admittedly our sample is small, and the possibilityof selection bias must be eliminated before speculation can bemade about the implications of this finding.

MALCOLM A. FERGUSON-SMITHW. S. MACKPATRICIA M. ELLISMARION DICKSON.

Department of Genetics,The University, Glasgow,

and Department of Urology,Western Infirmary, Glasgow.

NON-DISJUNCTION AND XXY MENSiR,ŃThe recent recognition 15 of a blood-group

antigen, Xga, determined by a dominant gene Xga, placedon the X chromosome, has furnished a useful tool for thestudy of non-disjunction of sex chromosomes in man.Lindsten et al.16 used the Xg groups in a study of femaleswith sex-chromosome disorders : we have found the

groups informative in a study of XXY men.A 62-year-old chromatin-positive male with Klinefelter’s

syndrome and of the karyotype XXY is Xg(a+); his 79-year-old mother is Xg(a-), and his sister Xg(a+). The XXY manmust have received his father’s X chromosome carrying anXga gene, as the mother must be homozygous for the recessiveallele’Xg). This, we believe, is the first demonstration in manthat XXY can result from non-disjunction at spermatogenesis.An example of XXY with a maternal and a paternal X chromo-some has been described in the mouse.17

In three families the Xg groups have made it clear that XXYpeople may have received both their X chromosomes from theirmother-a finding that had already been demonstrated bycolour-vision studies: Nowakowski et al.18 reported that threecolour-blind chromatin-positive men all had fathers withnormal colour-vision.

In the first of the families, a 30-year-old chromatin-positivemale with Klinefelter’s syndrome and of the karyotype XXYis Xg(a-): his father is Xg(a+), his 71-year-old motherXg(a-), and his sister Xg(a+). He cannot have received hisfather’s X chromosome.

In the second family, a 31-year-old chromatin-positive malewith Klinefelter’s syndrome and of the karyotype XXY isXg(a-): his father is Xg(a+). He cannot have received hisfather’s X chromosome.

In the third family, a pair of apparently monozygoticchromatin-positive male twins, aged 33, with Klinefelter’ssyndrome and of the karyotype XXY are Xg(a-): their fatheris Xg(a+), their brother Xg(a-), and their sister Xg(a+). Thetwins cannot have received their father’s X.

13. Penrose, L. S. Recent Advances in Human Genetics; p. 14. London,1961.

14. Ferguson-Smith, M. A. Unpublished data.15. Mann, J. D., Cahan, A., Gelb, A. G., Fisher, N., Hamper, J., Tippett,

P., Sanger, R., Race, R. R. Lancet, 1962, i, 8.16. Lindsten, J., Bowen, P., Lee, C. S. N., McKusick, V. A., Polani, P. E.,

Wingate, M., Edwards, J. H., Hamper, J., Tippett, P., Sanger, R.,Race, R. R. ibid. 1963, i, 558.

17. Russell, L. B., Chu, E. H. Y. Proc. nat. Acad. Sci., Wash. 1961, 47,571.

18. Nowakowski, H., Lenz, W., Parada, J. Acta endocrinol, Copenhagen,1959, 30, 296.

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The last three families do not disclose whether the non-disjunction of the maternal Xs was prezygotic or postzygotic.We are greatly indebted to Dr. Klaus Henningsen, Copenhagen,

who carried out blood-grouping on the twins; to Dr" H. Moltrup,Silkeborg, and Dr. S. Hauschildt, Skive, for collecting some of theblood-samples; and to Dr. Amos Cahan, New York, for the anti-Xgaplasma.

ANDERS FRØLAND.

SVEND G. JOHNSEN.PAUL ANDRESEN.

ERLING DEIN.

RUTH SANGERR. R. RACE.

Institute of Human Genetics,Copenhagen N.

Male Hypogonadism Study SectionUniversity Hospital, Copenhagen.

Medical Department.County Hospital of Ribe, Denmark.

Sct. Hans’ Hospital,Roskilde, Denmark.

M.R.C. Blood Group Research Unit,The Lister Institute, London.

ENCEPHALOPATHY AND FATTY DEGENERATION

OF THE VISCERA

SIR,-Since 1954 I have seen six, possibly eight, fatalcases in children which conform to the clinicopathologicalsyndrome described by Reye et al. (Oct. 12). The oldestchild was 14 years, and in all except one the illness wasof a few days’ duration, neurological symptoms pre-

dominating. Swelling of the brain and fatty changes inthe liver were the chief pathological findings. The neuro-pathological changes were inconclusive and did not

indicate the presence of any of the well-recognised formsof encephalitis.

A. F. J. MALONEY.

Neuropathology Laboratory,University of Edinburgh,and Royal Infirmary,

Edinburgh.

THEATRE TROLLEY FORUROLOGICAL INSTRUMENTS

ASHTON MILLER

J. P. MITCHELLN. SLADE.

Department of Urology,United Hospitals,

Bristol.

SIR,-May we comment on Mr. Graves’ design for atheatre trolley (Sept. 14) ?A vertical cylinder for sterilising endoscopic instruments has

been used in some centres for many years. If a tube lies

horizontally in sterilising fluid bubbles of air will be trapped inthe tube and will prevent the sterilising fluid from coming intocontact with that part of the instrument. This was confirmedby simple bacteriological tests.1The position of the valve diathermy machine on the lower

shelf seems unsatisfactory: in endoscopic surgery it is muchsafer for the indicator panel to be conveniently placed where thesurgeon can glance at the dials to ensure that their setting iscorrect. Furthermore, there is always the risk that the sterilisingfluid may be spilt from the trays above on to the terminals anddials and cause corrosion.On the lower shelf, there is a formalin oven, which is used to

store sterile bougies. Although formalin vapour is a satisfactorymethod of sterilisation it is difficult to be sure that the instru-ments do not have any of the irritant formalin still on theirsurface when they are used. Wiping a bougie with a sterile,moist swab or rinsing the bougie in water is not sufficient toremove the smell of formalin from the instrument, and there-fore some must remain on its surface. When the bougie is

passed to dilate a stricture, a small quantity of the irritantformalin is wiped off the surface of the bougie on to the stric-ture, with the obvious risk of aggravating the fibrosis of thestricture.

We heartily support Mr. Graves in drawing attention tothe need for a depot trolley for urological instruments, butwe believe that the diathermy should be on a separatestand.

1. Miller, A., Gillespie, W. A., Linton, K. B., Slade, N., Mitchell, J. P.Lancet, 1958, ii, 608.

LEUKÆMIA CLUSTERS

SiR,-Dr. Swan (Oct. 12) asks whether others haveseen a tendency toward " focal distribution " of casesof acute leukaemia, as opposed to a random scatteringgeographically of chronic lymphatic leukaemia. I haveno information about the chronic leukaemias, but I haverecently looked for time-space aggregates of acute

childhood leukaemia in upstate New York (the entire

state, excluding New York City).Punch cards containing death-certificate information of

children under 10 resident in upstate New York, dying in theyears 1948-60 of leukaemia, were counted by county of resi-dence within year of death (there are 57 counties in upstateNew York). Incidence rates by county by year of death werecomputed, using appropriate 1950 and 1960 census populationsas denominators. Statistical significance levels were computed,using a Poisson model (see table).

In upstate New York in 1950, 54 children under 10 died ofleukaemia and had the event reported on a certificate of death.8 of the 54 cases listed an Oneida county, New York, residence.In the following year (1951) another 4 such cases were reported.Since all cases were ascertained through death certificates only,incidences by area should be comparable. No other countyin the State had as high an incidence in the years studied.

2 additional cases of childhood leukaemia were identifiedin the years 1950-51 in Oneida county. These cases were notcounted in determining incidence, since 1 was over study age(10 years) and 1 died out of the scudy period (1950-51) buthad onset in 1951.

Hospital records were reviewed in an attempt to verify thediagnosis in each case. All but 1 of the 14 cases had recordsof blood examinations available. None of the initial whitecounts were in the normal range. All showed immature or" blast " cells in peripheral-blood smears. 6 had records ofbone-marrow studies and 2 cases came to postmortem examina-tion. All cases were seen by at least one consultant.With the exception of a child who died suddenly, all had

characteristic rapid downhill courses with fever, severe

anaemia, and hxmorrhagic manifestations. No case survivedfor more than a year after onset. 7 of the 14 cases had their

INCIDENCE RATES FOR DEATH-CERTIFICATE-REPORTED LEUKAEMIA

UNDER AGE 10, UPSTATE NEW YORK, ONEIDA COUNTY, AND SELECTEDAREAS WITHIN ONEIDA COUNTY

* Significance levels are based on a Poisson model.

onset in the six months from July to December, 1950. 5 ofthe 7 died in the same period.

Next-of-kin of all but 1 case were questioned in September,1963, especially about contact with other cases. No commonfactor or characteristic was discovered ifi the cases or theirfamilies. Residences (1950) were not clustered; none of thecases or their sibs attended the same school; none of theparents were employed similarly; national origins and religionswere varied; none of the families attended the same church;none of the families were more than remotely acquainted.The mother of one of the cases died of acute leukaemia at 28,a year after her son’s death.

Admittedly, the thirteen years which have elapsedsince these cases occurred may have obscured a commonfactor shared by some or most of them. It may also bethat the critical questions were not asked. But this