W. M. Court Brown

Lymphocyte survival in men treated with x-rays for ankylosing spondylitis.

Lymphocytes with radiation-induced chromosome aberrations, examined in patients treated with X-rays for ankylosing spondylitis, are estimated to have a mean life span of about 1,600 days.

Leukaemia in Childhood and Young Adult Life.

rhere is good reason to believe that the different clinical and cytological types of leukaemia represent distinct diseases. Thus there are major differences between the age and sex distributions of chronic lymnphatic, chronic myeloid, and acute leukaemia (MacMahon and Clark, 1956). Furthermore, ionizing radiations have been shown to cause chronic myeloid and acute leukaemia. but they have not been sho-wn to cause chronic lymphatic leukaemia, and the geographical distribution of the first two types differs from that of the last in that chronic lymphatic leukaemia is relatively rare in the Far East (Wells and Lau, 1960). Finally, recent cytogenetic data have demonstrated the existence of a Epecific chromosomal abnormality in many cases of chronic myeloid leukaemia, but, so far, not in any other type of leukaemia (Nowell and Hungerford, 1960; Baikie, Court Brown, Buckton, Harnden, Jacobs, and Tough, 1960). Clearly, therefore, the various types of leukaemia should be separated in any study of its aetiology. Until recently this has been possible only in studies based on hospital data. Insufficient details have been published in the national vital statistics for mortality of the various types to be examined separately; moreover, many of the deaths attributed to leukaemia have b-een certified as due to leukaemia without further specification. An opportunity to make a more detailed examination of the trends in mortality was provided by the British Registrars-General when they extracted information from the records of all persons certified as dying from leukaemia since 1945 and made it available to the Medical Research Council. This information can be used to re-classify the causes of death in any desired way. The results obtained for adults aged 15 years and o.ver in England and Wales have been published previously (Court Brown and Doll, 1959). The present paper contains similar data for children and for young adults under the age of 30 years. Data for young adults have been included becaus2 the mortality from leukaemia is at a minimum between the ages of 20 and 29 years, and this age period provides a natural break between the childhood and adult forms of the disease. Moreover, Lee (1961) has shown that there is a small peak in the mor-tality from leukaemia at ages 15-19 years, and this is missed if the break is made earlier. The total leukaemia mortality at these ages in England and Wales has also been examined over a longer period, and some of the data are compared with similar data from other countries.

Sex chromosome aneuploidy and parental age

Most investigations of parental age and the attendant risk of the conception of an aneuploid zygote have related to maternal age and to zygotes trisomic for chromosome 21, although more recently interest has been aroused in other types of autosomal trisomy. The study of mongolism and parental age extends back for more than 30 years to the work of Jenkins (1933) and the early studies by Penrose (1933, 1934a, b). Recently Penrose (1966) has published the analysis of the distribution of maternal age for 2605 mongols, the mean maternal age being 35.1 years as compared with 28.3 years for a control population of mothers. He showed from an examination of the distribution of maternal ages that the mongols could be partitioned into two classes. Class A contained about one-third of the total and was made up of mongols whose abnormal chromosome complement was considered due to causes independent of maternal age, such as secondary non-disjunction, structural heterozygosity involving a no. 21 in one or other parent, or an abnormality of meiosis or mitosis due to a specific gene, or possibly some environmental factor such as ionizing radiations (Sigler et al. 1965). The distribution of maternal age for mongols in class A was indistinguishable from that for the controls. By contrast class B contained mongols, about two-thirds of the total, for whom it is assumed that their abnormal complement followed an age-dependent error in maternal gametogenesis. The mean maternal age in this group was found to be 3 8 4 years, about 10 years greater than that for the controls, and the evidence was in keeping with the incidence of mongolism among the children of these older mothers increasing approximately with the tenth power of the age of the mother. Lenz, Pfeiffer & Tunte (1966) and more recently Magenis, Hecht &Milham (1968), have shown that the distribution of maternal age in trisomy D and trisomy E shows a general similarity to that for mongols, and that there is evidence for an increased mean maternal age for spontaneous abortions where the abortus has been shown to be an autosomal trisomic, and these include types of trisomy not yet found in post-natal life (Kerr & Rashad, 1966; Carr, 1967). It seems, therefore, reasonable to assume that the same model used to analyse the distribution of maternal age in mongolism may well also be applicable to the other forms of autosomal trisomy. It may be anticipated that a single general model will be insufficient to account for the various forms of sex chromosome aneuploidy, for the range of viable individuals extends from monosomy (45,X females) to males and females with respectively 49,XXXX Y and 49,XXXXX complements, and includes males with two or more Y chromosomes. Furthermore, sex chromosome mosaicism is identified much more often than autosomal mosaicism and detectable mosaics form an appreciable proportion of males and females recognized to have sex chromosome aneuploidy. Any discussion, therefore, of parental age and the risk of the conception of aneuploid zygotes would not be complete without some reference to sex chromosome mosaicism. There is also a third class of individuals worth considering and these are those with double

Red cell glucose‐6‐phosphate dehydrogenase activity in individuals with abnormal numbers of X‐chromosomes

Red cell glucose‐6‐phosphate dehydrogenase (G‐6‐PD) activity was measured in fourteen XXX, eleven XX Y, three XO individuals, four individuals who were 17 but had testicular feminization, and in appropriate male and female controls. No evidence for any quantitative relationship between the number of X‐chromosomes present and the level of red‐cell G‐6‐PD activity was observed. Since G‐6‐PD is known to be determined by at least one gene locus in the X‐chromosome, these results in agreement with others imply complete dosage compensation.

Radiation Sickness in Man following the Administration of Therapeutic Radioiodine

(i) Radiation sickness occurring after therapeutic radioiodine administration as 131I has been observed on 28 out of 44 occasions. The symptoms have been described and their resemblance to the symptoms occurring after a single X-ray dose has been noted. (ii) The latent period prior to the onset of symptoms after radioiodine administration varied between four and 13 hours with a mean of eight hours. This finding has been contrasted with the latent periods of two to five hours after medium voltage X rays. (iii) The correlations between integral dose at eight hours per square metre and mean dose-rate per hour to symptom onset per square metre and latent period have been noted. (iv) It is suggested that dose-rate may be an important factor involved in the production of the symptoms of radiation sickness.

Chromosome Studies on Women formerly employed as Luminous-Dial Painters.

In man the study of the harmful effects in bone of internally deposited radioactive material has been made either on subjects who have been given radium compounds internally for medicinal purposes, a practice now discontinued, or on subjects who have accidentally ingestedradium, and sometimes mesothorium, while working as luminous-dial painters. The use of self-luminous paints for watch dials developed in Germany and Switzerland before the first world war and followed the discovery that scintillations of light were produced by individual alpha-particles impinging on a screen of zinc sulphide. Self-luminous paints were made by mixing radium sulphate with zinc sulphide, and sometimes mesothorium was added to the mixture. During and immediately after the first world war increasing use was made of luminous paints, and from about 1925 reports based on the experience of early American dial-painters led to the recognition of the serious consequences that could follow the accidental ingestion of these compounds. There have also been a number of reports of the hazards associated with the internal use of radium compounds for medicinal purposes. It is clear that the accumulation in the body -over a short period of time of large amounts of radium or mesothorium leads to the early production of extensive bone damage with pathological fractures, to septic necrosis of the mandible and maxilla, and in many instances to the later development of bone tumours. Severe anaemia and leucopenia are also features of the acute and subacute forms of poisoning with radium or mesothorium,

Fertility in an XY/XXY Male Married to a Translocation Heterozygote

The question has arisen of whether subjects showing the features of seminiferous tubular dysgenesis (Kiinefelters syndrome) may sometimes be fertile. Fr0land and Ullrich (I962, personal communication) studied one such subject, who had an XY/XXY sex chromosome complement and who claimed to have had 2 children. Blood group studies on the propositus, his wife, and his surviving son, showed that the probability of the propositus being the father of the son was 6 times that of a male from the general population. Kaplan, Aspillaga, Shelley, and Gardner (I963) published data on another male with the features of seminiferous tubular dysgenesis who claimed to have had 7 children by 3 wives. The sex chromosome complement of cells from a blood culture was XXY. As blood group studies could not be done the claim to paternity could not be substantiated. Lennox (I963) quotes 4 subjects with seminiferous tubular dysgenesis who claimed to have had children, but on investigation none of these claims was shown to be valid. We have now had the opportunity of studying altogether I40 males with an abnormal sex chromosome complement, a number of whom have been children or adolescents and a number who have been unmarried adults. Of 42 adults known to have been married, 5 have been said to have had children. In only i instance, however, has investigation supported the claim to paternity. This subject, who with his wife and family is the subject of this report, has an XYIXXY sex chromosome complement. There is considerable added interest, however, because not only did the propositus have one unusually large autosome i6, but his wife was found to be a translocation heterozygote.

The effect of a single dose of x-rays on the peripheral blood count of man.

16 13 3 I 43 26-59 I A NUMBER of accounts have been given of the effects of a single dose of X-rays on the peripheral blood count of a variety of animals but little attention has been paid to those produced by a single dose of X-rays on the blood count of human beings (Prosser, 1947; Brecher et al. 1948; Jacobson et aE. 1954; Eldred and Eldred, 1953; Loutit, 1953; Gershon-Cohen and Hermel, 1954). In particular the changes that occur in association with the development of radiation sickness have not been the subject of a detailed analysis. The increasing use of radioactive materials both in research and industry, together with the possible effects of the explosion of nuclear weapons, make it desirable that the changes following a single X-ray exposure to the whole body be investigated. In practice, within the limits of therapeutic irradiation, this information is not easy to obtain, but it is llkely that the study of the effects of the irradiation of large volumes of tissue, particularly in the trunk, will give a useful indication of the changes that whole-body exposure may induce. The data to be presented have been obtained from patients suffering from ankylosing spondylitis to whom a single X-ray exposure has been given to the sacro-iliac joints and the whole length of the spine (Table I).

The relationship of x-ray dose to the time of development of radiation sickness following exposure to a single dose of x rays.

1. The influence of body size and X-ray dose have been discussed in relationship to the time of development of symptoms following a single X-ray exposure to either the whole length of the spine or the pelvis. 2. Evidence has been brought forward to indicate that the total body integral dose cannot be correlated with the severity of radiation sickness. 3. It is suggested that certainly as regards radiation sickness the expression of dose ought to be qualified by the level of dose received in specified organs and tissues of known radiosensitivity.

A CLASSIFICATION OF PATIENTS WITH PRIMARY AMENORRHOEA ON A CYTOGENETIC BASIS

THE recent publication by Jacobs and her colleagues (1961) has emphasized the importance of cytogenetic studies in the investigation of patients with primary amenorrhoea. It was found from a study of 68 women, referred with a presumptive diagnosis of primary amenorrhoea, that in at least 28 per cent of these there was evidence of either an abnormal sex chromosome complement or a normal male complement. Furthermore these authors noted that, if those women were excluded who had only a delayed menarche or in whom there was an adequate explanation for their condition such as chronic inflammatory disease, then the proportion with an anomalous sex chromosome complement rose to over 40 per cent. It is clear, therefore, that cytogenetic studies have much to contribute, not only to the understanding of the aetiology of primary amenorrhoea but also to the general management of the patients. For example the early recognition of an abnormal chromosome status may spare the patient unnecessary investigation, and will also provide a sound basis for her future management. This communication attempts to provide a classification of cases of primary amenorrhoea in relation to sex chromosome constitution, which has the merit of being a working guide to the investigation of these patients. Primarily this classification is based on the height of the patient and the results of the examination of buccal smear cells for sex chromatin. Within each subgroup formed from the consideration of these two parameters, the various abnormal sex chromosome states are noted that have so far been reported. No attempt has been made to fit in a number of theoretically possible abnormal states yet to be identified; it is felt, however, that the classification is sufficiently flexible to accommodate these should they be discovered. Before describing the classification, some attention must be paid to the two basic parameters-height and sex chromatin. Characteristically cases of gonadal dysgenesis (Turner’s syndrome) are short in stature. Thus Jacobs et al. (1959) found 13/14 women of 4 feet 10 inches or less with primary amenorrhoea to have a sex chromosome abnormality. None of their patients was between 4 feet 10 inches and 5 feet 1 inch but only 3/18 of those of 5 feet 1 inch or more had an abnormality. Two were cases of testicular feminization and the third one of a deletion of the long arm of an X chromosome. It seems reasonable for present purposes to adopt a height of 5 feet as being critical, and to postulate that the majority under this height will have a sex chromosome abnormality, but only the minority among those who are 5 feet or more. Sex chromatin studies done on suitably stained smears of buccal cells are preferred to the examination of polymorphonuclear leucocytes for “drum-sticks”. Buccal smears are more informative, and also they are less tedious to examine than blood films. It is essential to note the frequency of cells with sex chromatin, for which purpose 100 cells should be examined. In our hands the range in normal women is from 36 per cent to 76 per cent (mean 49 per cent). In cases of primary amenorrhoea the frequency will range from 0 per cent, for example in those with an XO or XY complement, to over 90 per cent. Two classes of case may be found in the