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SENESCENCE AND CHROMOSOMAL CHANGES
114 TRISOMY-18 SYNDROME DUE TO DE-NOVO
the
same
translocation chromosome plus
a
much smaller
TRANSLOCATION SIR, The first cases of trisomy-18 were reported simultaneously by Edwards et al. and Patau et al.2 in 1960. Since then over thirty such cases have been recorded, and it has become apparent that trisomy of chromosome number 18 results in quite a uniform syndrome. We have been investigating a child with the classical features of trisomy 18.
fragment.
Our patient, a 3-month-old girl, was born at term weighing about 4 lb. 6 oz. The placenta and cord were tiny. She did not breathe on her own for 15 minutes. She has loose skin, a prominent occiput, a third fontanelle, low-set ears, a high arched palate, small chin, short sternum, severe and incompletely diagnosed congenital heart-disease, left upper lobe emphysema, small diastasis recti, small pelvis, clenched fists with the index finger overriding the third, and the fifth finger overriding the fourth, a simian line on the right only, and rocker bottom feet with short big toes. Her clitoris is enlarged to 1.25 cm., but her external genitalia are unambiguously female, and her nuclear sex-chromatin pattern on buccalmucosa smear is normal female. The child’s mother, aged 17, and father, aged 21, are both normal. Neither have had therapeutic or extensive diagnostic X-ray. The mother’s one previous pregnancy resulted in a normal baby girl weighing 6 lb. 4 oz. The table summarises chromosomal studies on the peripheralblood leucocytes.
hallucal area of the sole where her parents and her normal sibling have a distally opening large loop. The repeated demonstration of dermatoglyphic abnormalities in the autosomal trisomies (mongolism, trisomy
Dermatoglyphic studies were prompted by Uchida’s report* of a high number of digital arches in this syndrome. Neither the parents nor the unaffected sister of our patient have any digital arches. Our patient has 8 digital arches with low ridgecount ulnar loops on both fifth fingers. Her sole-prints suggest that these, too, may be diagnostically helpful in the trisomy-18 syndrome, especially in the presence of an atypical karyotype. Our patient shows the unusual arch fibular in the
18, and trisomy 13-15) leads us to wonder whether each autosomal trisomy syndrome will prove to be dermatoglyphically distinctive. If so, dermal pattern analysis should be helpful both in confirming the clinical diagnosis of autosomal trisomy syndrome and in interpreting the unusual karyotype. Dermatoglyphics might occupy the same place in respect to the autosomal trisomies as nuclear sexing does to abnormalities of the X chromosome. F. HECHT J. BRYANT D. ARAKAKI Departments of Medicine, Pediatrics, and Genetics, University of Washington, E. KAPLAN and Children’s Orthopedic Hospital, G. GENTILE. Seattle, Washington, U.S.A. SENESCENCE AND CHROMOSOMAL CHANGES
Both parents have 46 chromosomes with a normal chromocomplement. ’The patient also has 46 chromosomes (see figure). However, she is missing one chromosome in the
SIR,-Since so many reports on chromosomal aberrations have appeared in your journal, I should like to bring to the attention -of your readers a recently proposed hypothesis relating senescence to chromosomal
some
Karyotype in trisomy-18 syndrome, showing 46 chromosomes with D/E translocation. 13-15 group (the D group) ahd possesses instead a large chromosome which we have labelled D/E. It appears to be composed of a translocation of the long arms of chromosome 18 (one of E group) on to one of the D-group chromosomes. This is analogous to mongolism resulting from translocation of the long arms of chromosome 21 on to one of the other acrocentric chromosomes. Our findings also incriminate triplication of the long arms of chromosome 18 as responsible for the
trisomy-18 syndrome. Another case with the clinical signs of trisomy-18 syndrome due to a translocation has recently been reported3 from Montreal. This translocation differed from ours in that the D/E translocation resulted in an unusually long acrocentric chromosome associated with a sizeable acentric fragment. The normal mother in the Montreal case was found to be carrying 1. 2. 3.
Edwards, J. H., Harden, D. G., Cameron, A. H., Crosse, V. M., Wolfe, O. H. Lancet, 1960, i, 787. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., Wagner, H. P. ibid. p. 790. Brodie, H. R., Dallaire, L. Canad. med. Ass. J. 1962, 87, 559.
changes.’
.
In
exploring cellular changes associated with human ageing, it has been customary to emphasise the changes in such long-lived well-differentiated cells as neurons, while shortlived cells (like lymphocytes) have been regarded as young cells and, therefore, unsuitable for studies of ageing. This is a reasonable approach if the age of a cell is dated from the last mitotic division of its precursor. On the other hand, if we consider the number of generations by which a given cell is separated from the original zygote, then we might call the nerve-cell young and the lymphocyte old. To avoid semantic confusion, let us simply refer to cells as long-lived or shortlived. Since long-lived cells are the products of relatively few mitotic divisions, and short-lived ones represent the results of many, the chances for the occurrence and propagation of mitotic errors are much higher in short-lived than in long-lived cells. Senescence in short-lived cells would thus be reflected in an increased frequency of chromosomal aberrations, with an eventual net loss, rather than the usual histological changes characteristic of ageing long-lived cells. Emphasis upon the mitotic aspects of ageing would serve to resolve the apparent paradoxical relation between ageing and cancer. By and large, the frequency of cancer rises as the individual ages, and yet it is rare in what have been considered old cells, like nerve-cells. If we make the distinction of short-lived and long-lived, however, then the short-lived cells with a long mitotic history are more likely to undergo neoplastic change as the age of the organism increases. Similarly, a mitotic hypothesis of ageing would account for the relatively uniform changes observed in ageing individuals, particularly in one-egg twins. Contrary to the infinitesimally small probability that out of twenty thousand genes or so the same one will mutate repeatedly in two separate individuals (be it spontaneously or due to cosmic radiations), the chances are fairly high that duplication of errors will occur for any 1 of only 46 chromosomes. Uchida, I. A., Patau, K., Smith, D. W. Amer. J. Dis. Child. 1961, 102, 588. 5. Jarvik,L.F. Conference on Ageing and Biological Organisation. A.I.B.S., Princeton, 1962. 4.
115
Assuming that one important mechanism of ageing consists of the gradual accumulation of aberrant cells-with a net loss of chromosomal material and functional capacity--one may expect that a level would ultimately be reached where homoeostatic methanisms could no longer cope with primary and secondary metabolic dysfunctions, a level incompatible with survival. In contrast to unicellular organisms where karyotypic anomalies are subject to natural selection, a complicated multicellular organism may be compared to a civilised community which not only protects its deviant members but may even encourage their propagation. If there is some truth in the old concept that ageing and death are the penalties exacted for differentiation and complex organisation, then all of us would probably be glad to pay the price, given a choice between human frailty and amoebic immortality.
Experimental testing of these theoretical speculations is, of course, highly desirable. The prediction, for example, of an increased variability in chromosome number with age might be subjected to investigation. At the moment, the only chromosome data analysed with respect to age are those of Court Brown. According to his findings, which were interpreted somewhat differently,6 there was a definite tendency toward decline in chromosome number with advancing age. Perhaps some of your readers may be able to furnish data useful in the evaluation of the proposed working hypothesis. Department of Medical Genetics, New York State Psychiatric Institute, Columbia-Presbyterian Medical Center, New York.
LISSY F. JARVIK.
FIFTY YEARS OF RAMSTEDT’S OPERATION
SIR,-Iwas hoping that a surgeon would comment during 1962 that 50 years have now passed since Ramstedt devised his operation for congenital pyloric stenosis. It is doubtful if any operation has saved so many lives and the technique has remained virtually unchanged. The surgical mortality in this condition is now almost nil and this has been brought about in the last 20 years or so by earlier diagnosis and better preoperative managementthe surgery has remained the same. This is a wonderful achievement and babies can nowadays be safely discharged home the day after operation. For an operation to have stood the test of time in this way has won the gratitude of many thousands of children all over the world-this jubilee should not pass unmentioned. Department of Child Health, Llandough Hospital, Penarth, Glamorgan.
A. G. WATKINS.
ELECTROCARDIOGRAPHIC CHANGES ASSOCIATED WITH PHENOTHIAZINE SIR,-We have seen within the past year a number of patients of different ages, transferred to us from other hospitals where they had received treatment with phenothiazine for different periods of time. In approximately 30% we found characteristic features in the E.c.G. which we do not think have been described before. The most striking changes were: low voltage in the standard leads with widening of QRS complexes and flat or isoelectric T especially in AVL and inverted T in the right precordial leads. After treatment was stopped, the E.c.G. returned to normal. No known reason for this pattern, such as myocardial damage, myocarditis, electrolyte dis-
turbances, myxoedema, amyloidosis, pleural effusion, pneumothorax, emphysema, or deformities of thorax, could be found. Malben Hospital,
Shaar-Menashe,
I. TEITELBAUM.
Israel. 6. Court
Brown,
W. M. ibid.
ARTIFICIAL PACING FOR HEART-BLOCK SiR,—The fascinating paper of Dr. Leatham and his colleagues (Dec. 29) raises a small semantic side-issue. As they and others have observed, the electrocardiograms of patients with complete heart-block show a disproportionate frequency of apparent bundle-branch-block patterns. Are these better described as complete heartblock with a ventricular focus below the bifurcation of the bundle ? This postulates one lesion instead of two. St. Helier
Hospital, Carshalton, Surrey.
C. P. PETCH.
POISONOUS PAINTS have SIR,-We recently treated a young child who had eaten some emerald green artist’s water colour which she had squeezed out of a tube. The severity of the vomiting associated with the small amount of colour eaten suggested that the pigment was of high toxicity. Preliminary inquiries from the local art school suggested that the pigment was an arsenical compound of copper, and this was confirmed by analysis. Those of your readers who have to deal with the emergency treatment of poisoning may be interested to know that the manufacturers of artists’ colours issue a caution about the poisonous qualities of the following paints: (a) Cobalt violet (contains arsenate of cobalt). (b) Emerald green (contains aceto-arsenite of copper). (c) Mauve (prepared from an unspecified organic pigment). (d) Purple lake (prepared from synthetic alizarin lakes). The makers issue a booklet of notes on the Composition and Permanence of Artists Colours. This seems to be a further reference book which should be available in every
poisons
centre.
Emergency and Accident Department, Royal Infirmary, Preston.
M. H. HALL.
CONVULSANT EFFECT OF PENICILLIN ON THE CEREBRAL CORTEX SIR,-Ican find no published reference to the con-
vulsant effect of crystalline penicillin when applied to the cerebral cortex. I have inserted this substance after removing bone in open fractures of the skull, sometimes when the dura was torn, without ill effects, and I am therefore prompted to record the following case. An African, aged about 35, was admitted on July 9, 1962, with a swelling over the right parietal bone for 5 months, which had arisen spontaneously without any previous injury. The tumour was round, moderately hard, connected with the skin though not intimately adherent to it, and attached to the underlying bone. There were no localising signs of brain disease. An X-ray of the skull showed a defect in the right parietal bone 11/2 x 11/4 in. with an ill-defined, ragged edge. A leucocyte-count revealed 4300 cells per c.mm. (polymorphs 43%, lymphocytes 51%, and eosinophils 6%). Haemoglobin was 98%. A tentative diagnosis of secondary carcinoma of bone was made. Since the patient complained of severe pain, an operation After was performed under local anxsthesia on July 27. in of a burr-hole was 1 down a made in. scalp, flap turning front of the tumour and enlarged backwards to the edge of the defect through which the growth was protruding from the dura mater. The edge of the body defect was removed round the tumour, and a small incision was made into the dura, through which a probe could easily be passed beneath the tumour. The tumour was removed by snipping through the dura round it and dividing its attachments to the skin. 5,000,000 units of crystalline penicillin was sprinkled into the wound, and the scalp was closed without drainage. On the patient’s return to the ward, unconsciousness set in ’
the
same
translocation chromosome plus
a
much smaller
TRANSLOCATION SIR, The first cases of trisomy-18 were reported simultaneously by Edwards et al. and Patau et al.2 in 1960. Since then over thirty such cases have been recorded, and it has become apparent that trisomy of chromosome number 18 results in quite a uniform syndrome. We have been investigating a child with the classical features of trisomy 18.
fragment.
Our patient, a 3-month-old girl, was born at term weighing about 4 lb. 6 oz. The placenta and cord were tiny. She did not breathe on her own for 15 minutes. She has loose skin, a prominent occiput, a third fontanelle, low-set ears, a high arched palate, small chin, short sternum, severe and incompletely diagnosed congenital heart-disease, left upper lobe emphysema, small diastasis recti, small pelvis, clenched fists with the index finger overriding the third, and the fifth finger overriding the fourth, a simian line on the right only, and rocker bottom feet with short big toes. Her clitoris is enlarged to 1.25 cm., but her external genitalia are unambiguously female, and her nuclear sex-chromatin pattern on buccalmucosa smear is normal female. The child’s mother, aged 17, and father, aged 21, are both normal. Neither have had therapeutic or extensive diagnostic X-ray. The mother’s one previous pregnancy resulted in a normal baby girl weighing 6 lb. 4 oz. The table summarises chromosomal studies on the peripheralblood leucocytes.
hallucal area of the sole where her parents and her normal sibling have a distally opening large loop. The repeated demonstration of dermatoglyphic abnormalities in the autosomal trisomies (mongolism, trisomy
Dermatoglyphic studies were prompted by Uchida’s report* of a high number of digital arches in this syndrome. Neither the parents nor the unaffected sister of our patient have any digital arches. Our patient has 8 digital arches with low ridgecount ulnar loops on both fifth fingers. Her sole-prints suggest that these, too, may be diagnostically helpful in the trisomy-18 syndrome, especially in the presence of an atypical karyotype. Our patient shows the unusual arch fibular in the
18, and trisomy 13-15) leads us to wonder whether each autosomal trisomy syndrome will prove to be dermatoglyphically distinctive. If so, dermal pattern analysis should be helpful both in confirming the clinical diagnosis of autosomal trisomy syndrome and in interpreting the unusual karyotype. Dermatoglyphics might occupy the same place in respect to the autosomal trisomies as nuclear sexing does to abnormalities of the X chromosome. F. HECHT J. BRYANT D. ARAKAKI Departments of Medicine, Pediatrics, and Genetics, University of Washington, E. KAPLAN and Children’s Orthopedic Hospital, G. GENTILE. Seattle, Washington, U.S.A. SENESCENCE AND CHROMOSOMAL CHANGES
Both parents have 46 chromosomes with a normal chromocomplement. ’The patient also has 46 chromosomes (see figure). However, she is missing one chromosome in the
SIR,-Since so many reports on chromosomal aberrations have appeared in your journal, I should like to bring to the attention -of your readers a recently proposed hypothesis relating senescence to chromosomal
some
Karyotype in trisomy-18 syndrome, showing 46 chromosomes with D/E translocation. 13-15 group (the D group) ahd possesses instead a large chromosome which we have labelled D/E. It appears to be composed of a translocation of the long arms of chromosome 18 (one of E group) on to one of the D-group chromosomes. This is analogous to mongolism resulting from translocation of the long arms of chromosome 21 on to one of the other acrocentric chromosomes. Our findings also incriminate triplication of the long arms of chromosome 18 as responsible for the
trisomy-18 syndrome. Another case with the clinical signs of trisomy-18 syndrome due to a translocation has recently been reported3 from Montreal. This translocation differed from ours in that the D/E translocation resulted in an unusually long acrocentric chromosome associated with a sizeable acentric fragment. The normal mother in the Montreal case was found to be carrying 1. 2. 3.
Edwards, J. H., Harden, D. G., Cameron, A. H., Crosse, V. M., Wolfe, O. H. Lancet, 1960, i, 787. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., Wagner, H. P. ibid. p. 790. Brodie, H. R., Dallaire, L. Canad. med. Ass. J. 1962, 87, 559.
changes.’
.
In
exploring cellular changes associated with human ageing, it has been customary to emphasise the changes in such long-lived well-differentiated cells as neurons, while shortlived cells (like lymphocytes) have been regarded as young cells and, therefore, unsuitable for studies of ageing. This is a reasonable approach if the age of a cell is dated from the last mitotic division of its precursor. On the other hand, if we consider the number of generations by which a given cell is separated from the original zygote, then we might call the nerve-cell young and the lymphocyte old. To avoid semantic confusion, let us simply refer to cells as long-lived or shortlived. Since long-lived cells are the products of relatively few mitotic divisions, and short-lived ones represent the results of many, the chances for the occurrence and propagation of mitotic errors are much higher in short-lived than in long-lived cells. Senescence in short-lived cells would thus be reflected in an increased frequency of chromosomal aberrations, with an eventual net loss, rather than the usual histological changes characteristic of ageing long-lived cells. Emphasis upon the mitotic aspects of ageing would serve to resolve the apparent paradoxical relation between ageing and cancer. By and large, the frequency of cancer rises as the individual ages, and yet it is rare in what have been considered old cells, like nerve-cells. If we make the distinction of short-lived and long-lived, however, then the short-lived cells with a long mitotic history are more likely to undergo neoplastic change as the age of the organism increases. Similarly, a mitotic hypothesis of ageing would account for the relatively uniform changes observed in ageing individuals, particularly in one-egg twins. Contrary to the infinitesimally small probability that out of twenty thousand genes or so the same one will mutate repeatedly in two separate individuals (be it spontaneously or due to cosmic radiations), the chances are fairly high that duplication of errors will occur for any 1 of only 46 chromosomes. Uchida, I. A., Patau, K., Smith, D. W. Amer. J. Dis. Child. 1961, 102, 588. 5. Jarvik,L.F. Conference on Ageing and Biological Organisation. A.I.B.S., Princeton, 1962. 4.
115
Assuming that one important mechanism of ageing consists of the gradual accumulation of aberrant cells-with a net loss of chromosomal material and functional capacity--one may expect that a level would ultimately be reached where homoeostatic methanisms could no longer cope with primary and secondary metabolic dysfunctions, a level incompatible with survival. In contrast to unicellular organisms where karyotypic anomalies are subject to natural selection, a complicated multicellular organism may be compared to a civilised community which not only protects its deviant members but may even encourage their propagation. If there is some truth in the old concept that ageing and death are the penalties exacted for differentiation and complex organisation, then all of us would probably be glad to pay the price, given a choice between human frailty and amoebic immortality.
Experimental testing of these theoretical speculations is, of course, highly desirable. The prediction, for example, of an increased variability in chromosome number with age might be subjected to investigation. At the moment, the only chromosome data analysed with respect to age are those of Court Brown. According to his findings, which were interpreted somewhat differently,6 there was a definite tendency toward decline in chromosome number with advancing age. Perhaps some of your readers may be able to furnish data useful in the evaluation of the proposed working hypothesis. Department of Medical Genetics, New York State Psychiatric Institute, Columbia-Presbyterian Medical Center, New York.
LISSY F. JARVIK.
FIFTY YEARS OF RAMSTEDT’S OPERATION
SIR,-Iwas hoping that a surgeon would comment during 1962 that 50 years have now passed since Ramstedt devised his operation for congenital pyloric stenosis. It is doubtful if any operation has saved so many lives and the technique has remained virtually unchanged. The surgical mortality in this condition is now almost nil and this has been brought about in the last 20 years or so by earlier diagnosis and better preoperative managementthe surgery has remained the same. This is a wonderful achievement and babies can nowadays be safely discharged home the day after operation. For an operation to have stood the test of time in this way has won the gratitude of many thousands of children all over the world-this jubilee should not pass unmentioned. Department of Child Health, Llandough Hospital, Penarth, Glamorgan.
A. G. WATKINS.
ELECTROCARDIOGRAPHIC CHANGES ASSOCIATED WITH PHENOTHIAZINE SIR,-We have seen within the past year a number of patients of different ages, transferred to us from other hospitals where they had received treatment with phenothiazine for different periods of time. In approximately 30% we found characteristic features in the E.c.G. which we do not think have been described before. The most striking changes were: low voltage in the standard leads with widening of QRS complexes and flat or isoelectric T especially in AVL and inverted T in the right precordial leads. After treatment was stopped, the E.c.G. returned to normal. No known reason for this pattern, such as myocardial damage, myocarditis, electrolyte dis-
turbances, myxoedema, amyloidosis, pleural effusion, pneumothorax, emphysema, or deformities of thorax, could be found. Malben Hospital,
Shaar-Menashe,
I. TEITELBAUM.
Israel. 6. Court
Brown,
W. M. ibid.
ARTIFICIAL PACING FOR HEART-BLOCK SiR,—The fascinating paper of Dr. Leatham and his colleagues (Dec. 29) raises a small semantic side-issue. As they and others have observed, the electrocardiograms of patients with complete heart-block show a disproportionate frequency of apparent bundle-branch-block patterns. Are these better described as complete heartblock with a ventricular focus below the bifurcation of the bundle ? This postulates one lesion instead of two. St. Helier
Hospital, Carshalton, Surrey.
C. P. PETCH.
POISONOUS PAINTS have SIR,-We recently treated a young child who had eaten some emerald green artist’s water colour which she had squeezed out of a tube. The severity of the vomiting associated with the small amount of colour eaten suggested that the pigment was of high toxicity. Preliminary inquiries from the local art school suggested that the pigment was an arsenical compound of copper, and this was confirmed by analysis. Those of your readers who have to deal with the emergency treatment of poisoning may be interested to know that the manufacturers of artists’ colours issue a caution about the poisonous qualities of the following paints: (a) Cobalt violet (contains arsenate of cobalt). (b) Emerald green (contains aceto-arsenite of copper). (c) Mauve (prepared from an unspecified organic pigment). (d) Purple lake (prepared from synthetic alizarin lakes). The makers issue a booklet of notes on the Composition and Permanence of Artists Colours. This seems to be a further reference book which should be available in every
poisons
centre.
Emergency and Accident Department, Royal Infirmary, Preston.
M. H. HALL.
CONVULSANT EFFECT OF PENICILLIN ON THE CEREBRAL CORTEX SIR,-Ican find no published reference to the con-
vulsant effect of crystalline penicillin when applied to the cerebral cortex. I have inserted this substance after removing bone in open fractures of the skull, sometimes when the dura was torn, without ill effects, and I am therefore prompted to record the following case. An African, aged about 35, was admitted on July 9, 1962, with a swelling over the right parietal bone for 5 months, which had arisen spontaneously without any previous injury. The tumour was round, moderately hard, connected with the skin though not intimately adherent to it, and attached to the underlying bone. There were no localising signs of brain disease. An X-ray of the skull showed a defect in the right parietal bone 11/2 x 11/4 in. with an ill-defined, ragged edge. A leucocyte-count revealed 4300 cells per c.mm. (polymorphs 43%, lymphocytes 51%, and eosinophils 6%). Haemoglobin was 98%. A tentative diagnosis of secondary carcinoma of bone was made. Since the patient complained of severe pain, an operation After was performed under local anxsthesia on July 27. in of a burr-hole was 1 down a made in. scalp, flap turning front of the tumour and enlarged backwards to the edge of the defect through which the growth was protruding from the dura mater. The edge of the body defect was removed round the tumour, and a small incision was made into the dura, through which a probe could easily be passed beneath the tumour. The tumour was removed by snipping through the dura round it and dividing its attachments to the skin. 5,000,000 units of crystalline penicillin was sprinkled into the wound, and the scalp was closed without drainage. On the patient’s return to the ward, unconsciousness set in ’