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Chromosome 18: A topologic approach
MEDICAL PROGRESS
Chromosome l& A topologic approach Jean de Grouchy PARIS~
FRANCE
loci) controlling leukogenesis is located on the lower half of chromcsome 21. More recently it has been suggested that loci controlling the synthesis of the enzymes, alkaline phosphatase, and galactose-one-phosphate-uridyl transferase might be located on chromosome 21. An excessive activity of these enzymes has indeed been reported in trisomy 21. 7-1~ Although not offering quite as exciting opportunities for study as chromosome 21, various abnormalities of chromosome t8 have been observed which are associated with particular clinical syndromes, Their study offers an opportunity for a tentative discussion of certain loci located on chromosome 18. The trisomic condition for No. 18 first documented by Edwards and associates 11 and then by Patau and co-workers 12 and Smith and his group 13 is now known to be the cause of a well-defined syndrome. :t4.a5 The true identity of the chromosome responsible for this trisomy is still a matter of discussion, however. According to the Denver classification, it was first considered as a No. 1711 and later as a No. 18.12, la, 21, a2-a4 Recent studies with autoradiographic labeling of the chromosomes now suggest that the chromosome involved in the trisomy 17-18 syndrome is indeed chromosome 1876 With this restric-
S I s c e the discovery by Lejeune, Gautier, and Turpin 1 that the trisomic condition for chromosome 21 is the cause of mongolism, this particular chromosome has attracted considerable attention. Some of the loci responsible for m3ngolian features, when in a trisomic state, are now under direct assault by geneticists. This is indeed the case of the locus or loci governing one of the tryptophan metabolism pathways. As first suggested by Jerome and colleagues, 2,a and later by O'Brien and Groshek 4 trisomy for these loci may result in excessive enzyme production and deviation of tryptophan metabolism. The discovery of the relation of partial deletion of chromosome 21 to the Philadelphia chromosome in chronic myeloid leukemia s and the finding by Turpin and Bernyer 6 that there are fewer lobulations of the polymorphonuclear cells in mongolism have led to the hypothesis that a particular locus (or
From the Clinique de Gdndtique M~dicle, Hapital de En[ants Malades, 149, rue de S~vres, Paris X V ~ France. This work was supported by a grant of the United States Public Health Service No. HD 0032004. A lecture sponsored by the Foreign Lectureship Program of the JOCRNALOF PEDIATRICS Educational Foundation.
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tion on the true identity of the chromosome, we shall first discuss trisomy 18. In the second part of this paper we shall discuss partial deletions of chromosome 13. These have been observed as true deletions or as ring chromosomes. It is possible that we see aberrations of chromosome 18 more frequently than of other chromosomes solely because it is not essential that all segments are rigorously disomic. Hence, chromosome mapping, if possible, may concern "unimportant" chromosomes before "important" ones. TRISOMY
18
Trisomy 18 is a well-defined syndrome, and its clinical diagnosis requires the presence of all of its essential features. It has been recently reviewed by several authors. TM 30~
38
Weight at birth is usually small, tile average being 2,400 grams. Hydramnios has frequently been reported. The clinical picture is striking: the occiput is prominent with a narrow forehead; the ears are lowset and malformed; the nasal bridge is depressed and the nose itself is prominent. The receding small mandible as well as the small m o u t h give the face a miniature-like aspect. T h e sternum may be hypoplastic. Abnormalities of the lower girdle are almost constant: the pelvis is narrow and the hips are frequently dislocated. Anomalies of the perineat region are common, such as hypoplasia of the labia with hypertrophy of the clitoris and anal anomalies. T h e hands are remarkable. T h e fists are firmly clenched, and the index finger overlaps the third finger. Frequently the fifth finger overlaps the fourth. T h e feet are malformed and described as rockerbottom feet with the big toe pointing upward. Syndactyly of the second and third toes occurs frequently. These infants do not gain weight and are severely retarded. They usually die before the age Of 6 months, often in cardiac failure. Congenital heart disease, septal defect, or patent ductus is common. O n e child, however, with trisomy 18 is known to have lived
Chromosome 18: Topological approach
4 15
until the age of 10 years? 7 Less constant features include spina bifida, harelip with or without cleft palate, Meckel's diverticulum, renal anomalies, tracheoesophageal fistula, 26 phocomelia, 2s and arthrogryposis. 29 T h e dermal patterns in trisomy 18 are very characteristic and may be considered as a true dermatoglyphic syndrome. This was first demonstrated by Uchida, Patau, and Smith 3~ and later by Penrose. 4~ T h e fingers display an arch pattern. These are infrequent in normal people: 80 per cent have no arch and less than 2 per cent have 6 arches. U c h i d a pointed out that 17 of 1 8 trisomic patients had from 6 to 9 plain digital arches. A unilateral simian crease has often been found as well as has clinodactly of the fifth finger. T h e axial triradius is in the normal location. T h e frequency of trisomy 18 is difficult to evaluate. T h e only data available, Hecht and associates 2s and Heinrichs, Allen, and Nelson, 4~ give a rough estimate of one case per 600 to 800 live births. T h e syndrcme might thus occur as frequently as trisomy 21. As in trisomy 21, maternal age seems to be in the higher range when c c m p a r e d to the normal population. Lejeune 3s found the mean maternal age for 50 recorded cases to be 34.4 years. Although both maternal and paternal ages are above average, H e c h t and his group 2~ showed a significant relation to maternal rather thar~ to paternal age. An altered sex ratio has been pointed out by Ferguson-Smith42: in 31 cases there were 22 females and 9 males. Lejeune 3s noted the same excess of females; 40 females against 13 males (X2 = 13.5 for one degree of freed o m ) . Trisomic females do not live longer than trisomic males and the reasons for this alteration of the sex ratio are not clear. Lejeune 38 suggested a preferential intrauterine selection in favor of female fetuses, whereas Hecht and colleagues 2~ suggested an interaction between autosomal trisorny and sex determination. Chromosomal aberrations other than genuine trisomy 18 have been reported. T h e y involve complete or partial trisomy syndromes.
4 16
de Grouchy
T r a n s l o c a t i o n of chromosome 18 onto a No. 13-15 has been found. I n most instances2S, 4a-46 this translocation resulted in a new submediocentric chromosome, the 18 being translocated onto the short arms of one of the No. 13-15 chromosomes. I n one case 47 the fragment translocated onto the lower end of a No. 13-15 chromosome a n d gave rise to a long acrocentric one. I n this instance the a b n o r m a l chromosome h a d been inherited from the m o t h e r who was a 45 carrier of chromosome translocation. Translocation of a No. 18 onto another of the 17-18 chromosomes or a duplication of the long arms of the chromosome has been discovered in a child with typical features of the trisomy syndrome. 4s Translocation of an 18 onto a No. 4 chromosome was suggested in a female baby having a long No. 4-5 chromosome a n d exhibiting stigmas of the trisomy 18 syndrome2 9 T h e features reported were u n u s u a l : absence of the thumbs a n d absence of arches on the finger dermatoglyphic patterns. Extra chromosome 18 material has also been described in the form of supernumerary
Fig. IA. Photograph of the patient with "false" trisomy 18 syndrome showing the facies.
February 1965
chromosomes which are considered as deletions of No. 18. I n one case 5~ the clinical evidence is good a n d the deletion is small. I n a second case, 51 however, the extra chromosome is metacentric a n d the clinical evidence somewhat less impressive. F u r t h e r on we shall discuss a similar deletion of chromosome 18 in a disomic rather t h a n in a trisomic state. A complex aberration has been described by W a n g a n d co-authors 52 (case No. 1) in a male i n f a n t exhibiting signs of trisomy 18 syndrome. This was interpreted by the authors as a transtocation of a No. 18 fragment onto a No. 3 chromosome, with the formation of a ring chromosome by No. 3 a n d No. 18 chromosomes. These u n u s u a l types of aberrations of chromosome 18 point to the possibility of partial trisomy as originally suggested by Patau a n d colleagues. 5a U n f o r t u n a t e l y this
Fig. lB. The hands of the patient.
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Chromosome t8: Topological approach
possibility is not easily proved. If the patient has features of the trisomy syndrome, it is concluded that the extra chromosome material belongs to a No. 18. An unequivocal identification occurs only when, as in Brodie and Dallaire's case, 47 one of the parents is a carrier for the translocation. If the supernumerary chromosome fragment is considered to be from No. 18, the clinical information should be reported in considerable detail. This is necessary in order to develop eventually a chromosome map. Another variant of trisomy 18 has been discovered in normal trisomy 18 mosaicism. 2s' 5~ The clinical features were typical of the trisomy syndrome. Trisomy 18 has also been reported in association with another chromosomal aberration in the same patient: triplo X syndrome, 55 Klinefelter's syndrome XXY, 56 and trisomy 21. 57 These associations seem to be more frequent than expected. One explanation would be the presence of specific factors favoring nondisjunction, e.g., gene mutations. Also, as suggested by Lejeuene 58, 59 apparently "unharmful" chromosomal rearrangements such as balanced translocations could favor nondisjunction by an "inter-chromosomal reaction." We recently observed in an otherwise typical case of Turner's syndrome a translocation of a small fragment onto a 21-22. This translocation also present in the patient's mother as weI1 as in a healthy sister may have favored nondisjunction during maternal gametogenesis. With the improvement of cytologic techniques and the aid of electron microscopy, will it become possible to identify such minute chromosomal rearrangements? Their eugenic implications would then raise new problems. "FALSE"
TRISOMY
18 S Y N D R O M E
We recently suggested a diagnosis of trisomy 18 before studying the patient's chromosomes.* The child was a 5-month-old
":§ patient was under the care of Drs. J. Aubry and J. C. Dalloz. We thank them for allowing us to report this case.
4 17
Fig. 1C. Photograph of the patient with "false" trisomy 18 syndrome showing rockerbottom feet.
boy and the only child of healthy parents; father, aged 28; mother, aged 26. His birth weight was 3,000 grams and the pregnancy was uneventful. Clinical examination revealed a prominent occiput, a depressed nasal bridge, a small nose pointed upward, low-set ears, an arched palate, and a small receding mandible. The hands were characteristic of tris0my 18, the index finger overlapping the third one; bilateral club feet were present (Fig. 1). There was no congenital heart defect. The pelvis was of normal size. Fingerprints were difficult to examine; only two fingers had plain arches. Two peripheral blood samples and one aponeurosis biopsy were cultured. The chromosomal studies revealed a normal karyotype in all cells studied and no evidence of mosaicisrn or translocation.
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de Grouchy
T a b l e I. T h e different features of trisomy 18 with frequencies as c o m p u t e d by Lejeune. ss
External mal/ormations Ears: low set, malformed Microretrognathla Flexion of fingers (index over 3rd, 5th over 4th) Prominent oceiput Short sternum Dorsiflexion of big toe Narrow pelvis Hernia Equinovarus and/or rockerbottom feet Internal rnal[ormations Congenital heart defect Interventricular septal defect Patent ductus arteriosus Renal anomaly Meckel's diverticulum General anomalies Mental retardation Hypotrophya Hypertonicity
Frequeney
No. of cases analyzed
1.00 1.00
48 45
0.96 0.89 0.83 0.73 0.63 0.53
47 38 35 34 31 36
0.50
38
0.91
45
0.85 0.56 0.58 0:41
34 32 31 27
1.00 0.93 0.70
36 41 34
If one accepts that the p a t i e n t has n o r m a l chromosomes then it should be emphasized t h a t the pseudotrisomy 18 syndrome lacked two signs which seen essential: a high frequency of arches in the finger patterns a n d a n a r r o w pelvis. A n o t h e r patient, with n o r m a l chromosomes, was seen b y L a f o u r c a d e , Lejeune, a n d Berger. 6~ This infant also h a d most of the features of trisomy 18 syndrome except for the d e r m a t o g l y p h i c patterns, all fingers displaying whorls or loops. Recently M a r s h a l l a n d associates 61 reported u p o n a patient with a trisomy 13-15 syndrome a n d a n o r m a l karyotype. Again, the d e r m a t o g l y p h i c p a t t e r n was the only feature not compatible with the diagnosis. T h e i m p o r t a n c e of the dermatoglyphic patterns in trisomy 18, and possibly in trisomy 13-15, thus appears to be strongly emphasized. T h e etiology of pseudotrisomy 18 syndrome
Fig. 2. The patient with a deletion of the short arms of chromosome 18.
is unknown. T h e patient could be: (1) a person with undiagnosed mosaicism, (2) a carrier of a n o n d e t e c t a b l e translocation, (3) a carrier of a gene m u t a t i o n which mimics trisomy 18, (4) a victim of an embryopathy. U n f o r t u n a t e l y none of these hypotheses is supported by any evidence. Eventually further cases should bring new d a t a to shed light on this interesting problem. DELETION OF THE SHORT ARMS OF CHROMOSOME 18
This c h r o m o s o m a l a b e r r a t i o n was first observed in a 6-year-old boy exhibiting somatic malformations as well as m e n t a l r e t a r d a tion22, 63 T h e patient was born after an un= eventful pregnancy. His father a n d m o t h e r were 42 and 41 years of age, respectively, at the time of birth. O n e x a m i n a t i o n the child was n o r m a l in height and weight. His face was r o u n d and "expressionless, with hypertelorism, divergent squint, a n d epicanthic
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folds. His hands were coarse with high-set thumbs and clinodactyly of the fifth fingers. There was a bilateral syndactyly of the third and fourth toes. Somatic examination was otherwise normal. Mental retardation was obvious. Psychologic tests demonstrated a complete lack of verbal expression. His mental age corresponded to a 2 ~ - y e a r - o l d child (Fig. 2). Blood counts, electroencephalogram, x-rays of the skelton, and eye examination did not disclose abnormalities. Palm and fingerprints reveal the following: the fingers were short, both axial triradii were in the t' position, and the dermal patterns on the fingers were normal (Fig. 8). T h e karyotype analysis was performed from cultured peripheral blood leukocytes. 64
Fig. 3. Karyotype showing the deletion of the short arms of chromosome 18.
Chromosome 18: Topological approach
4 19
Analysis of 24 cells showed a consistent anomaly; one of the No. 17-18 chromosomes was replaced by an acrocentric whose length was equivalent to the long an-ns of the smallest of the three remaining No. 17-18 chromosomes. This anomaly was considered as a deletion of the short arms of a No. 18 (Fig.
3). A study of the patient's family revealed that one of his sisters has very similar features and is of low average intelligence. She has a normal karyotype as do both parents. T h e results of blood grouping were noncontributory. Neither the R h locus nor the Kidd locus are located on the deleted fragment since the propositus has both antigens E and e, as well as J K ~ and J K b.
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Fig. 4. A and B. Photographs of the patient with a partial deletion of the long arms of chromosome 18.
A second case of deletion of the short arms of a number 18 chromosome has been recorded by Buhler, Buhler, and Stalder ~5 in a child with an anomaly of thyroxine synthesis. Edwards 66 also observed two examples of the same deletion, one in a child, the other in an adult. Further details on these individuals are not known. PARTIAL DELETION LONG ARMS
OF THE
We have observed this chromosomal aberration in a girl at 1 year of age; she had severe growth and mental retardation as well as somatic m a l f o r m a t i o n s S T h e baby was born after 8 months of pregnancy. Both parents were healthy. T h e father was 40 and the mother 27 years of age. T h e patient has a normal sister, aged 2 ~ years. The patient's birth weight was 2,300 grams. At 1 year of age she measured 67 cm., i.e., 2 to 3 S.D.
below normal, and weighed 6,230 grams, 3 S.D. below normal; her head circumference was 41 cm., 1 S.D. below average for her height. A p a r t from this small degree of microcephaly she exhibited small ears, arched palate, broad chest with widely spaced and atrophied nipples, deep dimples at the back of her shoulders, and edema of the feet. Mental retardation was severe (Fig. 4, A, and B). Intravenous urography revealed "horseshoe" kidneys. T h e ophthalmologic examination revealed nystagmus and possible evidence of tapetoretinal degeneration. A repeat examination will be necessary to confirm this diagnosis. Although the baby did not seem to suffer from any degree of deafness, she was examined by an otologist (Pr. M. Ombredanne) for reasons to be discussed later. T h e pinnas were slightly smaller than average, the upper half being underdeveloped and the
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lower half n o r m a l ; the internal m e a t u s was slightly n a r r o w e d by hyperostosis of the posterior wall. I n the m i d d l e ear, both the tymp a n u m a n d the h a n d l e o f the malleus h a d a b n o r m a l fixations, which was considered to be suggestive of an atresia of the m i d d l e ear. A l t h o u g h some degree of deafness should be present, the young age of the b a b y p r e c l u d e d further examination. K a r y o t y p e analysis was p e r f o r m e d on three different cultures of p e r i p h e r a l blood leukocytes 68 a n d revealed the absence of one No. 17-18 chromosome a n d an extra chromosome resembling a No. 19-20 one (Fig. 5). T h e short arms of the extra chromosome were
Fig. 5. Karyotype showing the partial deletion of the long arms of chromosome 18.
Chromosome 18: Topological approach
42 1
similar in length to those of the r e m a i n i n g No. 17-18 ones. H e n c e this extra or a b n o r m a l chromosome was considered to have resulted from the deletion of half of the long arms of an 18 chromosome. This a n o m a l y was observed in all of the cells t h a t were analyzed (Fig. 5). P a l m a n d finger printing showed t h a t in b o t h hands a single p a l m a r crease was present. Axial triradii were in the n o r m a l t position. Fingerprints showed an a b n o r m a l n u m ber of whorls: 5 out of 10 fingers (Fig. 6). F a m i l y studies showed that the father, mother, and sister have n o r m a l karyotypes. Blood g r o u p i n g results show t h a t the M N
4 2 2 de Grouchy
February 1965
x \ It / g i / / w ~
\/>. t Fig. 6. Dermatoglyphic patterns of the hands in the case of a partial deletion of the long arms of chromosome 18.
and R h loci are not located on the deleted fragment. A similar karyotype has been observed by Lejeune 6~ in a patient still under clinical investigation. RING
CHROMOSOME
A ring chromosome for a No. 17-18 chromosome (most probably a No. 18) has been observed in 4 patients. T h e first patient, reported upon by W a n g and colleagues 52 (case No. 2) had severe mental retardation, I.Q. 53, as well as deafness due to an atresia of the middle ear, hypertelorism, bilateral epicanthic folds, and bilateral syndactyly of the second and third toes. T h e second patient studied by Genest, Leclerc, and Auger 7~ was a girl, aged, 3 years, who had hypertelorism, epieanthic folds, atresia of the middle ear, and club feet. Karyotype analysis revealed a probable translocation of a chromosome fragment onto a 13-15 as well as the: ring chromosome. T h e third patient, an infant, 1 year of age, described by Lucas and co-workers, 71 had a mosaic pattern with normal cells and cells with a ring chromosome. She had mild mental retardation, slight microcephaly, mild hypoplasia of the mandible, cleft palate, and congenital dislocation of the left hip.
Fig. 7. The patient with a ring chromosome No, 18.
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Chromosome 18: Topological approach
RIGHT
HAN~
423
(",,
deletion short arm
ring chr. LEFT HANDS
flog chr.
deletion short arm
Fig. 8. Comparison of the dermatoglyphic patterns in the patients with a deletion of the short arms and with a ring chromosome. A, Right hands. B, Left hands.
T h e fourth patient examined by my colleagues and myself ~2 is a Negro girl, 5 years of age, with mental retardation and somatic malformations. H e r father and mother are normal and were 37 and 27 years of age, respectively, at the time of her birth. She has two brothers, aged 8 and 3 years, and two sisters, aged 7 and 1 years. All are healthy. She was born prematurely at 8 months' gestation and weighed 2,300 grams. Her physical growth has been normal during
the first 2 years but her psychomotor development has been very retarded: she smiled at 8 months, sat up at 10, stood up at 14 months, and walked at 2.5 years of age. Her height was 100 cm.; her weight, 17.6 kilograms; and her cranial circumference, 51 cm. (average figures are: 106 cm. _+ 3.8; 17.1 Kg. __+ 1.9 and 50.3 cm. +_ 1.3 respectively). H e r face was somewhat peculiar due to a slight hypertelorism, slight bilateral epicanthic folds and low-set hair line. Ribs
424
de Grouchy
February 1965
Fig. 9. Different aspects of the ring chromosome,
are horizontal and nipples are set far apart and there was a bilateral pterygium colli more pronounced on the left than on the right side (Fig. 7). She has marked generalized hypotonia. O t h e r clinical and laboratory tests are within normal limits. Dermatoglyphie patterns displayed that the fingers were short and the fifth finger was slightly curved. Axial triradii were in position t p and there was a bilateral radial loop which was very striking. Fingerprints showed whorls on all fingers except on the thumbs which had an ulnar loop (Fig. 8). This pattern is quite rare especially in females. Cytogenetic studies were performed from two cultures of peripheral blood leukocytes .5 and revealed that one of the No. 17-18 ehro-
mosomes was replaced by an abnormal chromosome. This chromosome had various forms in different cells, e.g., ring, disk, or figure eight (Figs. 9 - - 1 1 ) . This structure is considered to be a ring chromosome as described previously in man, in drosophilia 73 and in maize. TM T h e different appearances of the abnormal structure were due to the different angles from which it was seen (Fig. 10). Pairing of the remaining chromosomes showed that the abnormal ring chromosome was most likely a No. 18 (Fig. 11). Family studies revealed that both parents and all siblings have normal karyotypes. Results of blood grouping studies were noncontributory: neither the MNSs locus nor the Kidd locus were located on the missing fragments.
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DISCUSSION Partial deletions are frequently a consequence of chromosomal r e a r r a n g e m e n t s such as translocations or ring chromosomes. I t is likely t h a t syndromes resulting from measurable deletions will eventually contribute to the construction of the h u m a n chromosome map. T h e first observation of a true deletion was by Jacobs a n d co-workers 7~ in the X chromosome a n d has been confirmed by others. 7~ T h e Ph 1 chromosome first observed by Nowell and H u n g e r f o r d 77 is the first instance of an autosomal deletion. However, this a b e r r a t i o n is in a somatic chromosome a n d occurs d u r i n g life. This is also true for other deletions observed in leukemia. 7s Possibly the first "congenital" deletion of an autosome to be r e p o r t e d is the deletion of the short arms of No. 18 discussed in this paper22 T r u e deletions have also been found for other chromosomes. L e j e u n e a n d associates79, so B55k, Atkins, and Santesson, sl a n d G r o u c h y a n d co-workers, s2 have described a new syndrome consisting of severe m e n t a l retardation, hypertelorism, dermatoglyphic anomalies, a very peculiar cry similar to t h a t of a cat, a n d a deletion of half of the short arms of a No. 5 chromosome. Deletions which seem reproducible a n d well defined m a y be the consequence of breakages at "weak" points on the chromosome arms. I t is also possible that m a n y deletions occur d u r i n g gametogenesis a n d that only a few of t h e m are compatible with life. T h e most favored time of occurrence for deletions seems to be d u r i n g gametogenesis. E x c e p t for a deleted X no instance of deletion of an autosome in the mosaic state is known. 76 R i n g chromosomes were first studied by M o r g a n ra a n d later by Schultz a n d Catcheside sa in the closed-X chromosomes of Drosophila melanogaster. M c C l i n t o c U 4 studied ring autosomes in maize. I n general such chromosomes do not a p p e a r stable in these organisms. R i n g chromosomes result from the breaking of the two ends of a n o r m a l chromosome
Chromosome 18: Topological approach
425
followed by fusion of both broken surfaces in such a m a n n e r as to p r o d u c e a closed ring (Fig. 12). I n general, ring chromosomes in these e x p e r i m e n t a l species are unstable. I n maize they m a y give rise, by a m e c h a n i s m not well understood, to double-sized ring chromosomes with two centromeres. W h e n such a ring is stretched on the spindle at anaphase, one c e n t r o m e r e at each pole, it m a y break a t any two points at r a n d o m , a n d lead to two new ring chromosomes of different sizes in each d a u g h t e r cell. This cycle of breakage-fusion-bridge eventually produces considerable mosaicism in the tissue in which it occurs. 84 Population studies on ring chromosomes in e x p e r i m e n t a l organisms reveal t h a t they are rapidly eliminated. Ring chromosomes have been observed in h u m a n cells in the following instances: (1) I n two m a l i g n a n t tumors studied by L e v a n 85 a n d in leukocytes f r o m a leukemic patientSO; (2) in cells i r r a d i a t e d either in vivo or in vitro ( T o u g h a n d his group 87 observed ring chromosomes in patients who h a d received
r
Fig. 10. Drawings showing the different aspects of a ring chromosome according to the degree of contraction and the angle at which it is seen.
426
de Grouch.y
February 1965
Fig. 11. Karyotype obtained from the patient
with a ring chromosome.
x-ray t h e r a p y ; Bender and Gooch ss a n d G r o u c h y a n d colleagues s9 demonstrated ring chromosomes in experimentaliy i r r a d i a t e d cells) ; (3) in a 42-week-old fetus with severe m a l f o r m a t i o n s a n d a ring chromosome instead of one 13-15 chromosomeg~ (4) in patients with congenital malformations compatible with life (two cases are r e p o r t e d of g o n a d a l dysgenesis in females, in each of w h o m one X chromosome was a ring chromosome) .91, 9~ A ring chromosome has also been observed in the No. 6-12 group in a boy with mental retardation, 9"a a n d a ring chromosome was described in the No. 13-15 group in a boy with m a l f o r m a t i o n s c o m p a r a ble to those seen in trisomy 17-18. 52 I r r a d i a tion h a d been p e r f o r m e d on the m o t h e r of
the latter child before conception. O t h e r aberrations, including a possible 17-18 translocation were seen. F o u r instances of 17-18 ring chromosomes are now known, including those in the p a t i e n t described here22, t0, ~1 F r o m a clinical standpoint, the several No. 18 deletion syndromes reviewed here have m a n y symptoms in common. M e n t a l r e t a r d a tion has been observed in one case of deletion of the short arms, in two cases of a ring chromosome, TM ~ a n d in the one case of partial deletion of the long arms discussed here. I t was not m e n t i o n e d in Genest's p a tient with a ring chromosome. '~ Hypertelorism a n d epicanthic folds have been described in one case of deletion of the short arms as well as in three cases of ring
Volume 66 Number 2
chromosome (Wang, ~z Genest, TM and ours72). These symptoms were not seen in association with deletion of the long arms. Atresia of the middle ear has been found in two cases of ring chromosomes ( W a n g 52 and Genest 7~ ; it was not present in our case of deletion of the short arms. Hence we speculated that this anomaly was attributable to the loss of a segment located near the lower end of the chromosome# 2 This ear defect was then looked for and eventually discovered in our patient with a deletion of a long arm, thus supporting our hypothesis. Dermatoglyphic patterns also pose interesting questions. First, the hands of the child with the deletion of the short arms were similar to those of the child with a ring chromosome: fingers were short, the fifth was slightly bent, and, in each instance, the axial triradii were in position t'. However, the high frequency of whorls was present only in the second one. W e had thus related this high frequency to the loss of the lower extremity of the chromosome. This idea was supporte d when the child with a partial deletion of the long arms also displayed a high number of whorls. A bilateral simian crease was observed only in the case of partial deletion of the long arms. This sign is also part of the clinical pictures of trisomy 21 and of the "Cri du Chat" (cat's cry) syndrome5 T M Hence it may be tt-~e consequence of loss or excess of genetic material. Furthermore, syndactyly of the second and third toes observed in the patients with deletion of the short arms of the chromosome and in one patient with a ring chromosome may be related to the loss of a segment of the short arm. I n Fig. 13 we have, in a very tentative fashion, summarized these ohservations and tried to relate the clinical anomalies to the loss of different segments of the chromosome. Ring chromosomes are a consequence of breakage of the two ends of the chromosomes. I n different individuals breakage m a y have occurred at different levels. Thus, if syndactyly of the toes is present only in Wang's case 52 and not in the patient de-
Chromosome 18: Topological approach
42 7
scribed here, this may m e a n that the breakage level was closer to the centromere in the first case than in the second one and that the region in the c h r o m o s o m e - - w h i c h when deleted is responsible for syndactyly--is located between these two levels. Conversely, hypertelorism and epicanthic folds, present in all cases, may be related to the loss of the tip of the chromosome. As mental deficiency is present in both deletion of the short arms and partial deletion of the long arms, two regions have been indicated on the map, one on each arm. Tapetoretinal abiotrophy, present only in partial deletion of the long arms, has also been placed on this arm. We emphasize that this m a p is entirely speculative and that it is not a "genic" map, rather it is merely an attempt to locate regions which when deleted may be responsible for certain phenotypic signs. With the reservation that the chromosome 18 we have discussed is the same as that responsible for the trisomy 17-18 syndrome, it also becomes tempting to match the features of deletion syndromes with features of trisomic syndromes; for instance, hypertelorism" and broad facies versus narrow forehead, excess of whorls versus excess of arch-finger patterns, or elevated axial triradius versus a normal position. These speculations provide leads for future research. Before mapping a chromosome in the true genetic sense, the main problem wilt be to know the exact relation between the loss (or
i
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B
i m
B c
D
D
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H
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jJ Fig. 12. Drawing showing how a ring chromosome is produced.
428
de Grouchy
February 1965
excess) of a given region and a given symptom. Hypertelorism, for instance, is present in the patient with deletion of the short arms of a chromosome 18, as in the "Cri du Chat" syndrome in which there is partial deletion of the short arms of No. 5 chromosome. Thus the question may be asked: Is the normal distance between both eyes under the control of many loci located on different chromosomes, with the loss of any one being responsible for hypertelorism? Similar questions may be raised in respect to the dermatoglyphic patterns: Why, for instance, is the axial triradius in an abnormal location in, among others, trisomy 21, Turner's syndrome, or the Cri du Chat syndrome ? How can the simian crease be a consequence of an excess as wetI as a loss of genetic material?
These speculations of chromosomal aberrations are but a few of the aspects of the problems which will evolve from the study of the development of living beings. The continued identification and study of individuais with chromosome aberrations, and particuIarly those with structuraI abnormalities may give additional information toward the construction of a chromosome map. Such studies may be concerned with identification of specific loci, e.g., genes determining the blood groups. They may also be concerned with genes at multiple loci which specify a congenital malformation. This latter approach emphasizes the need for careful examination and documentation of clinicaI findings. It is one of the approaches to the study of developmental anomalies.
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]Fig. 13. A tentative map of segments from chromosome 18 which when deleted are responsible for the different clinical features mentioned along the chromosome.
Volume 66 Number 2
T h e author acknowledges the invaluable help of Dr. Stanley W. Wright in preparing the manuscript.
Chromosome 18: Topological approach
18.
REFERENCES 1. Lejeune, J., Gautier, M., and Turpin, R.: Les chromosomes humains en culture de tissus, Compt. rend. Acad. so. 248: 602, 1959. 2. Jerome, H., Lejeune, J., and Turpin, R.: l~tude de l'excr~tion urinaire de certains m~tabolites due tryptophane chez les enfants mongoliens, Compt. rend. Acad. sc. 251: 474, 1960. 3. Jerome, H.: Anomalies due m6tabolisme du tryptophane dans la maladie mongolienne, Bull. et mfm. Soc. m6d. hop., Paris, 113: 168, 1962. 4. O'Brien, D., and Groshek, A.: The abnormality of tryptophane metabolism in children with mongolism, Arch. Dis. Childhood 37: 17, 1962. 5. Nowell, P. C., and Hungerford, D. A.: A minute chromosome in human chronic granulocytic leukaemla, Science 132: 1497, 1960. 6. Turpin, R., and Bernyer, G.: De l'influence de l'h6rddit6 sur la formule d'Arneth (cas particulier du mongolisme), Rev. Hemat. 2: 189, 1947. 7. Alter, A. A., Lee, S. L., Pourfar, M., and Dobkin, G.: Studies of leukocyte alkaline phosphatase in mongolism: a possible chromosome marker, Blood 22: 165, 1963. 8. Trubowitz, S., Kirman, D., and Masek, B.: The leucocyte alkaline phosphatase in mongolism, Lancet 2: 486, 1962. 9. King, M. J., Gillis, E. M., and Baikie, A. G.: The polymorph alkaline phosphatase in mongolism, Lancet 2: 661, 1962. I0. Brandt, N. J., Froland, A., Mikkelsen, M., Nielsen, A., and Tolstrup, N.: Galactosaemia locus and the Down's syndrome chromosome, Lancet 2: 700, 1963. 11. Edwards, J. H.~ Harnden, D. G., Cameron, A. H., Crosse, V. M. and Wolff, O. H.: A new trisomic syndrome, Lancet 1: 787, 1960. I2. Patau~ K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P.: Multiple congenital anomaly caused by an extra autosome, Lancet 1: 790. 13. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: A new autosomal trisomy syndrome. Multiple congenital anomalies caused by an extra chromosome, J. P•DIAT. 57: 338. 14. Smith, D. W., Patau, K., and Therman, E.: AutosomaI trisomy syndromes, Lancet 2:211, 1961. 15. German, J. L., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., and Bearn, A. G.: Autosomal trisomy of a group 16-18 chromosome, J. PEmAT. 60: 503, 1962. 16. Gottlieb, M. P., Hirschhorn, K., Cooper, H. L., Lusskin, N., Moloshok, R. E., and Hodes, H. L.: Trisomy-17 syndrome, J. Dis. Child. 105: 213, 1962. 17. Koenig, E. U., Lubs, H. A., and Brandt,
19. 20.
21. 22. 23.
24. 25. 26.
27. 28.
29.
30. 31.
32. 33. 34. 35.
429
L. K.: The relationship between congenital anomalies and autosomal chromosomal abnormalities, Yale J. Biol. Med. 35: 189, 1962. Rosenfield, R. L., Breibart, S., Isaacs, H., Klevit, H. D., and Mellman, W. J.: Trisomy of chromosomes 13-15 and 17-18; its association with infantile arteriosclerosis, Am. J. M. Sc. 244: 763, 1962. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: The No. 18 trisomy syndrome, J. PEDIAT. 60: 513, 1962. Townes, P. L., Manning, J. A., and Dehart, G. K.: Trisomy 18 (16-18) associated with congenital and optic atrophy, J. PEDIAT. 61: 755, 1962. Uchida, I., Bowman, J. M., and Wang, H. C.: The 18-trlsomy syndrome, New Engtand J. Med. 266: 1198, 1962. Voorhess, M. L., Vaharu, T., and Gardner, L. I.: Trisomy 16-18 syndrome, Lancet 2: 992, 1962. Weiss, L., DiGeorge, A. M., and Baird, H. W.: Four infants with the trisomy 18 syndrome and one with trisomy 18 mosaicism, J. Dis. Child. 10~: 533, 1962. Finley, W. H., Finley, S. C., and Carte, E. T.: 17-18 trisomy syndrome, J. Dis. Child. 106: 591, 1963. I-Iecht, F., Bryant, J. S., Motulsky, A. G., and Giblett, E. R.: The No. 17-18 (E) trisomy syndrome, J. PEDIAT. 63: 605, 1963. Holman, G. H., Erkman, B., Zacharias, D. L., and Koch, H. F.: The trisomy 18 syndrome. Two new clinical variants--one associated with tracheo-esophageal fistula and the other with probable familial occurrence, New England J. Med. 268: 982, 1963. Lejeune, J., Delthil, P., and Berger, R.: Sur un cas de trisomie 17, Arch. fran~, p6diat. 20: 737, 1963. Oikawa, K., Kochen, J. A., Schorr, J. B., and Hirschhorn, K.: Trisomy 17 syndrome with phocomelia due to complete and partial chromosomal trisomy, J. PEDIAT. 63: 715, 1963. Pfeiffer, R. A., and Huther, W.: Trisomie des Chromosomes. Nr 18 unter dem Bild einer Arthrogryposis multiplex congenita, Med. clln. 58: 1110, 1963. Steinberg, J. B., and Jackson, J. F.: The 16-18 trisomy syndrome, J. Dis. Child. 105: 213, 1963. Townes, P. L., Kreutner, K. A., Kreutner, A., and Manning, J.: Observations on the pathology of the trisomy 17-18 syndrome, J. PEDIAT. 62: 703, 1963. Trowell, H. R., and Hilton, H. B.: A case of trisomy 18 syndrome, Human Chr. Newsletter, 10: 15, 1963. Nakagome, Y., Komiya, K., and Arina, M.: A case of trisomy 18 syndrome, Paediat. Univ. Tokyo 8: 48, 1963. Brown, C. D., Patterson, P., and Van Mierrop, L. H. S.: The 18 trisomy syndrome, Human Chrom. Newsletter 8: 10, 1963. Hansen, H. G., Tolksdorf, M., Zinat-Bakhsh, H., Lehmann, W., Nitsch, K., and Wiede-
4 30
36. 37, 38. 39. 40. 41. 42. 43.
44. 45. 46. 47.
48. 49.
50. 51. 52.
53.
54. 55.
de Grouchy
mann, H. R.: Malformation syndrome with trisomy amongst the chromosomes of the group 16-18, Human Chrom. Newsletter 9: 12, 1963. German, J.: Personal communication, 1964. Ozonoff, M. B., Steinbach, H. L., and Mamunes, P.: The trisomy 18 syndrome, Am. J. Roentgenol. 91: 618, 1964. Lejeune, J.: Les Chromosomes humains, Vol. 1, Paris, 1964, Gauthier~Villars, Ed. Uchida, I. A., Patau, K., and Smith, D. W.: Dermal patterns of 18 and D1 trisomics, Am. J. Human Genet. 14: 345, 1962. Penrose, L. S.: Finger prints, palms and chromosomes, Nature 197" 933, 1963. Heinrichs, E. I-I., Allen, S. W., and Nelson, P. S.: Simultaneous 18 trisomy and 21 trisomy cluster, Lancet 2" 468, 1963. Ferguson-Smith, M. A.: Abnormal sex ratio in the autosomal trisomy syndromes, Lancet 2: 357, 1962. Vislie, H., Wehn, M., Brogger, A., and Mohr, J.: Chromosome abnormalities in a mother and two mentally retarded children, Lancet 2: 76, 1962. Breibart, S., Mellman, W., and Eberlein, W. R.: A 13-15/18 chromosome translocation, J. PEDIAT. 63: 714, 1963. Hecht, F., Bryant, J., Arakaki, D., Kaplan, E., and Gentile, G.: Trisomy 18 syndrome due to de novo translocation, Lancet 1:114, 1963. Lejeune, J., and Berger, R.: Trisomie partielle par translocation 17~ (13-15) probable, Arch. fran~, p6diat. (In press, 1964..) Brodie, H. R., and Dallaire, L.: The E syndrome (trisomy 17-18) resulting from a maternal chromosomal translocation, Canad. M. A. J. 87: 559, 1962. Rohde, R. A., Lee, A., and Sapin, S.: A new trisomy translocation chromosome (long arm E / E ) , Lancet 2: 1309, 1963. Gagnon, J., Archambault, L., Laberge, E., and Katyk-Longtin, N.: Trisomie partielle 18 par insertion ou translocation 4/18, Union m6d. Canada 92: 311, 1963. Crawford, M. D. A.: Multiple congenital anomaly associated with an extra chromosome, Lancet 2: 22, 1961. Froland, A., Hoist, G., and Tersleu, E.: Multiple anomalies associated with an extra small autosome, Cytogenetics 2: 99, 1963. Wang, H. C., Melnyck, J., McDonald, L. T., Uchida, I. A., Cart, D. H., and Goldberg, B.: Ring chromosomes in human beings, Nature 195" 733, 1962. Patau, K., Therman, E., Smith, D. W., Inhorn, S. L., and Picken, B. F.: Partial trisomy syndromes. I. Sturge-Webers disease, Am. J. Human Genet. 13: 287, 1961. Koulischer, L., Pelt, S., and Perier, O.: A case of trisomy-18 mosaicism, Lancet 2: 945, 1963. Uehida, I. A., Lewis, A. J., Bowman, J. M., and Wang, H. C.: A case of double trisomy: trisomy No. 18 and triplo X, J. PEDIAT. 60: 499, 1962.
February 1965
56. Haylock, J., Fitzgerald, M., Danks, D., and Dennet, X.: Two cases of the 18-trisomy syndrome, one in combination with the XXY karyotype, Human Chrom. Newsletter 9: 15, 1963. 57, Gagnon, J., Katyk-Longtin, N., de Groot, J. A., and Barbeau, A.: Double trisomie autosomique ~ 48 chromosomes (21 + 18), Union m~d. Canada 90" 1220, 1961. 58. Lejeune, J.: Autosnmal disorders, Pediatrics 32" 326, 1963. 59. Lejeune, J., Lafourcade, J., Sahnon, C., and Turpin, R.: Translocation familiale 2,--~22. Association ~ un syndrome de Turner haplo X, Am. J. Human Genet. 6: 3, 1963. 60. Lafourcade, J., Lejeune, J., and Berger, R.: Personal communication, 1964. 61. Marshall, R., Newnham, R. E., Rawstron, J. R., Ellis, J. R., and Stevens, L. J.: Features of 13-15 trisomy syndrome with normM karyntype, Lancet 1: 556, 1964. 62. Grouchy, J. de, Lamy M., Thieffry, S., Arthuis, M., and Salmon, C.: Dysmorphie complexe avec oligophrfinie: dfilfition des bras courts d'un chromosome 17-18, Compt. rend. Acad. sc. 256: 1028, 1963. 63. Thieffry, S., Arthuis, M., Grouchy, J. de, Lamy, M., and Salmon, C.: D~lfition des bras courts d'un chromosome 17-18: dysmorphies complexes avec oligophrgnie, Arch. franw pfidiat. 20: 740, 1963. 64. Grouchy, J. de, Lamy, M., and Roubin, M.: I~tude du caryotype ~ partir d'une culture de leucocytes, Ann. Pediat. 39: 188, 1963. 65. Buhler, E. M., Buhler, U. K., and Stalder, G. R.: Partial monosomy 18 and anomaly of thyroxine synthesis, Lancet 1: 170, 1964. 66. Edwards, J. H.: Personal communication, 1964. 67. Grouchy, J. de, Roger, P., Salmon, C., and Lamy, M.: D~l~tion partielle des bras longs du chromosome 18, Path. Biol. 12: 579, 1964. 68. Grouchy, J. de, Roubin, M., and Passage, E.: Microtechnique pour 1' Etude des chromosomes humains ~ partir d'une culture de leucocytes sanguins, Ann. G~n~t. 7: 45, 1964. 69. Lejeune, J.: Personal communication, 1964. 70. Genest, P., Leclerc, R., and Auger, C.: Ring chromosome and partial translocation in the same cell, Lancet 1: 1426, 1963. 71. Lucas, M., Kemp, N. H., Ellis, J. R., and Marshall, R.: A small autosomal ring chromosome in a female infant with congenital malformations, Am. Human Genet. 27: 189, 1963. 72. Grouchy, J. de, Lfiv~que, B., Debauchez, C., Lamy, M., and Marie, J.: Chromosome 17-18 en anneau et malformations cong~nitales chez une fille, Ann. G~nfit. 7" 17, 1964. 73. Morgan, L. V.: A closed X chromosome in Drosophila melanogaster, Genetics 23" 315, 1933. 74. McClintock, B.: A correlation of ring shaped chromosomes with variegation in Zea mays, Proc. National Acad. So. 18: 677, 1932. 75. Jacobs, P. A., Harnden, D. G., Court-Brown,
Volume 66
76.
77.
78.
79.
80.
8I. 82.
83.
Number 2
W. M., Goldstein, J., Close, H. G., Macgregor, T. N., Maclean, N., and Strong, J. A.: Abnormalities involving the X chromosome in women, Lancet 1: 1213, 1960. Grouchy, J. de, Lamy, M., Yaneva, H., Salomon, S., and Netter, A.: Further abnormalities of the X chromosome in primary amenorrhoea or in severe olygomenorrhoea, Lancet 2: 777, 1961. Nowell, P. C., and Hungerford, D. A.: Chromosome studies on normal and leukemic human leukocytes, J. National Cancer Inst. 25: 85, 1960. Grouchy, J. de, and Lamy, M.: D616tion partielle d'un chromosome moyen dans une leuc6mie aigu~ lymphoblastique, Rev. fran~. et Clin. Biol. 7: 639, 1962. Lejeune, J., Lafourcade, J., Berger, R., Vialatte, J., Boeswillwald, M., Seringe, P., and Turpin, R.: Trois case de ddl&ion partielle du bras court d'un chromosome 5, Compt. rend. Acad. sc. 257: 3098, 1963. Lejeune, J., Lafourcade, J., Grouchy, J. de, Berger, R., Gautier, M., and Turpin, R.: Dfl6tion partielle du bras court du chromosome 5. Individualisation d'un nouvel &at morbide, Semaine h6p. 40: 1169, 1964. B65k, J. A., Atkins, L., and Santesson, B.: Some new data on autosomal aberrations in man, Path. Biol. 11: 1159, 1963. Grouchy, J. de, Arthuis, M., Salmon, C., Lamy, M., and Thieffry, S.: Le syndrome du cri du chat. Une nouvelle observation, Ann. Gdn&. 7: 13, 1964. Schultz, J., and Catcheside, D. G.: The nature
Chromosome t8: Topological approach
43I
of closed X chromosomes in Drosophila melanogaster, J. Genet. 35: 315, 1937. 84. White, M. J. D.: Animal cytology and evolution, Cambridge, 1954, University Press, pp. 454, 1954. 85. Levan, A.: Self perpetuating ring chromosomes in two human tumours, Hereditas 42: 366, 1956. 86. Baikie, A. G., Court-Brown, W. M., Jacobs, P. A., and Milne, J. S.: Chromosome studies in human leukaemia, Lancet 2: 425, 1959. 87. Tough, I., Buckton, K., Baikie, A. G., and Court-Brown, W. 1VL: X-ray induced chrc~mosome damage in man, Lancet 2: 849, 1960. 88. Bender, M. A., and Gooch, P. C.: Types and rates of X-ray induced chromosome aberrations in human blood irradiated in vitro, Proc. National Acad. So. 48: 522, 1962. 89. Grouchy, J. de.: Cytogenetic studies in irradiated medullar and blood cells, Proc. 9th Congress European Society of Haematology, 1963. 90. Bain, A. D., and Gauld, I. K.: Multiple congenital abnormalities associated with ring chromosome, Lancet 2: 304, 1963. 91. Lindsten, J., and Tillinger, K. G.: Self-perpetuating ring chromosome in a patient with gonadM dysgenesis, Lancet 1: 593, t962. 92. Luers, T., Struck, E., and Nevinny-Stickel, J.: Self-perpetuating ring chromosome in gonadal dysgenesis, Lancet 2: 887, 1963. 93. Smith-White, S., Peacock, W. J., Turner, B., and den Dulk, G. M.: A ring chromosome in man, Nature 197: 102, 1963.
Chromosome l& A topologic approach Jean de Grouchy PARIS~
FRANCE
loci) controlling leukogenesis is located on the lower half of chromcsome 21. More recently it has been suggested that loci controlling the synthesis of the enzymes, alkaline phosphatase, and galactose-one-phosphate-uridyl transferase might be located on chromosome 21. An excessive activity of these enzymes has indeed been reported in trisomy 21. 7-1~ Although not offering quite as exciting opportunities for study as chromosome 21, various abnormalities of chromosome t8 have been observed which are associated with particular clinical syndromes, Their study offers an opportunity for a tentative discussion of certain loci located on chromosome 18. The trisomic condition for No. 18 first documented by Edwards and associates 11 and then by Patau and co-workers 12 and Smith and his group 13 is now known to be the cause of a well-defined syndrome. :t4.a5 The true identity of the chromosome responsible for this trisomy is still a matter of discussion, however. According to the Denver classification, it was first considered as a No. 1711 and later as a No. 18.12, la, 21, a2-a4 Recent studies with autoradiographic labeling of the chromosomes now suggest that the chromosome involved in the trisomy 17-18 syndrome is indeed chromosome 1876 With this restric-
S I s c e the discovery by Lejeune, Gautier, and Turpin 1 that the trisomic condition for chromosome 21 is the cause of mongolism, this particular chromosome has attracted considerable attention. Some of the loci responsible for m3ngolian features, when in a trisomic state, are now under direct assault by geneticists. This is indeed the case of the locus or loci governing one of the tryptophan metabolism pathways. As first suggested by Jerome and colleagues, 2,a and later by O'Brien and Groshek 4 trisomy for these loci may result in excessive enzyme production and deviation of tryptophan metabolism. The discovery of the relation of partial deletion of chromosome 21 to the Philadelphia chromosome in chronic myeloid leukemia s and the finding by Turpin and Bernyer 6 that there are fewer lobulations of the polymorphonuclear cells in mongolism have led to the hypothesis that a particular locus (or
From the Clinique de Gdndtique M~dicle, Hapital de En[ants Malades, 149, rue de S~vres, Paris X V ~ France. This work was supported by a grant of the United States Public Health Service No. HD 0032004. A lecture sponsored by the Foreign Lectureship Program of the JOCRNALOF PEDIATRICS Educational Foundation.
414
Volume 66 Number 2
tion on the true identity of the chromosome, we shall first discuss trisomy 18. In the second part of this paper we shall discuss partial deletions of chromosome 13. These have been observed as true deletions or as ring chromosomes. It is possible that we see aberrations of chromosome 18 more frequently than of other chromosomes solely because it is not essential that all segments are rigorously disomic. Hence, chromosome mapping, if possible, may concern "unimportant" chromosomes before "important" ones. TRISOMY
18
Trisomy 18 is a well-defined syndrome, and its clinical diagnosis requires the presence of all of its essential features. It has been recently reviewed by several authors. TM 30~
38
Weight at birth is usually small, tile average being 2,400 grams. Hydramnios has frequently been reported. The clinical picture is striking: the occiput is prominent with a narrow forehead; the ears are lowset and malformed; the nasal bridge is depressed and the nose itself is prominent. The receding small mandible as well as the small m o u t h give the face a miniature-like aspect. T h e sternum may be hypoplastic. Abnormalities of the lower girdle are almost constant: the pelvis is narrow and the hips are frequently dislocated. Anomalies of the perineat region are common, such as hypoplasia of the labia with hypertrophy of the clitoris and anal anomalies. T h e hands are remarkable. T h e fists are firmly clenched, and the index finger overlaps the third finger. Frequently the fifth finger overlaps the fourth. T h e feet are malformed and described as rockerbottom feet with the big toe pointing upward. Syndactyly of the second and third toes occurs frequently. These infants do not gain weight and are severely retarded. They usually die before the age Of 6 months, often in cardiac failure. Congenital heart disease, septal defect, or patent ductus is common. O n e child, however, with trisomy 18 is known to have lived
Chromosome 18: Topological approach
4 15
until the age of 10 years? 7 Less constant features include spina bifida, harelip with or without cleft palate, Meckel's diverticulum, renal anomalies, tracheoesophageal fistula, 26 phocomelia, 2s and arthrogryposis. 29 T h e dermal patterns in trisomy 18 are very characteristic and may be considered as a true dermatoglyphic syndrome. This was first demonstrated by Uchida, Patau, and Smith 3~ and later by Penrose. 4~ T h e fingers display an arch pattern. These are infrequent in normal people: 80 per cent have no arch and less than 2 per cent have 6 arches. U c h i d a pointed out that 17 of 1 8 trisomic patients had from 6 to 9 plain digital arches. A unilateral simian crease has often been found as well as has clinodactly of the fifth finger. T h e axial triradius is in the normal location. T h e frequency of trisomy 18 is difficult to evaluate. T h e only data available, Hecht and associates 2s and Heinrichs, Allen, and Nelson, 4~ give a rough estimate of one case per 600 to 800 live births. T h e syndrcme might thus occur as frequently as trisomy 21. As in trisomy 21, maternal age seems to be in the higher range when c c m p a r e d to the normal population. Lejeune 3s found the mean maternal age for 50 recorded cases to be 34.4 years. Although both maternal and paternal ages are above average, H e c h t and his group 2~ showed a significant relation to maternal rather thar~ to paternal age. An altered sex ratio has been pointed out by Ferguson-Smith42: in 31 cases there were 22 females and 9 males. Lejeune 3s noted the same excess of females; 40 females against 13 males (X2 = 13.5 for one degree of freed o m ) . Trisomic females do not live longer than trisomic males and the reasons for this alteration of the sex ratio are not clear. Lejeune 38 suggested a preferential intrauterine selection in favor of female fetuses, whereas Hecht and colleagues 2~ suggested an interaction between autosomal trisorny and sex determination. Chromosomal aberrations other than genuine trisomy 18 have been reported. T h e y involve complete or partial trisomy syndromes.
4 16
de Grouchy
T r a n s l o c a t i o n of chromosome 18 onto a No. 13-15 has been found. I n most instances2S, 4a-46 this translocation resulted in a new submediocentric chromosome, the 18 being translocated onto the short arms of one of the No. 13-15 chromosomes. I n one case 47 the fragment translocated onto the lower end of a No. 13-15 chromosome a n d gave rise to a long acrocentric one. I n this instance the a b n o r m a l chromosome h a d been inherited from the m o t h e r who was a 45 carrier of chromosome translocation. Translocation of a No. 18 onto another of the 17-18 chromosomes or a duplication of the long arms of the chromosome has been discovered in a child with typical features of the trisomy syndrome. 4s Translocation of an 18 onto a No. 4 chromosome was suggested in a female baby having a long No. 4-5 chromosome a n d exhibiting stigmas of the trisomy 18 syndrome2 9 T h e features reported were u n u s u a l : absence of the thumbs a n d absence of arches on the finger dermatoglyphic patterns. Extra chromosome 18 material has also been described in the form of supernumerary
Fig. IA. Photograph of the patient with "false" trisomy 18 syndrome showing the facies.
February 1965
chromosomes which are considered as deletions of No. 18. I n one case 5~ the clinical evidence is good a n d the deletion is small. I n a second case, 51 however, the extra chromosome is metacentric a n d the clinical evidence somewhat less impressive. F u r t h e r on we shall discuss a similar deletion of chromosome 18 in a disomic rather t h a n in a trisomic state. A complex aberration has been described by W a n g a n d co-authors 52 (case No. 1) in a male i n f a n t exhibiting signs of trisomy 18 syndrome. This was interpreted by the authors as a transtocation of a No. 18 fragment onto a No. 3 chromosome, with the formation of a ring chromosome by No. 3 a n d No. 18 chromosomes. These u n u s u a l types of aberrations of chromosome 18 point to the possibility of partial trisomy as originally suggested by Patau a n d colleagues. 5a U n f o r t u n a t e l y this
Fig. lB. The hands of the patient.
Volume 66 Number 2
Chromosome t8: Topological approach
possibility is not easily proved. If the patient has features of the trisomy syndrome, it is concluded that the extra chromosome material belongs to a No. 18. An unequivocal identification occurs only when, as in Brodie and Dallaire's case, 47 one of the parents is a carrier for the translocation. If the supernumerary chromosome fragment is considered to be from No. 18, the clinical information should be reported in considerable detail. This is necessary in order to develop eventually a chromosome map. Another variant of trisomy 18 has been discovered in normal trisomy 18 mosaicism. 2s' 5~ The clinical features were typical of the trisomy syndrome. Trisomy 18 has also been reported in association with another chromosomal aberration in the same patient: triplo X syndrome, 55 Klinefelter's syndrome XXY, 56 and trisomy 21. 57 These associations seem to be more frequent than expected. One explanation would be the presence of specific factors favoring nondisjunction, e.g., gene mutations. Also, as suggested by Lejeuene 58, 59 apparently "unharmful" chromosomal rearrangements such as balanced translocations could favor nondisjunction by an "inter-chromosomal reaction." We recently observed in an otherwise typical case of Turner's syndrome a translocation of a small fragment onto a 21-22. This translocation also present in the patient's mother as weI1 as in a healthy sister may have favored nondisjunction during maternal gametogenesis. With the improvement of cytologic techniques and the aid of electron microscopy, will it become possible to identify such minute chromosomal rearrangements? Their eugenic implications would then raise new problems. "FALSE"
TRISOMY
18 S Y N D R O M E
We recently suggested a diagnosis of trisomy 18 before studying the patient's chromosomes.* The child was a 5-month-old
":§ patient was under the care of Drs. J. Aubry and J. C. Dalloz. We thank them for allowing us to report this case.
4 17
Fig. 1C. Photograph of the patient with "false" trisomy 18 syndrome showing rockerbottom feet.
boy and the only child of healthy parents; father, aged 28; mother, aged 26. His birth weight was 3,000 grams and the pregnancy was uneventful. Clinical examination revealed a prominent occiput, a depressed nasal bridge, a small nose pointed upward, low-set ears, an arched palate, and a small receding mandible. The hands were characteristic of tris0my 18, the index finger overlapping the third one; bilateral club feet were present (Fig. 1). There was no congenital heart defect. The pelvis was of normal size. Fingerprints were difficult to examine; only two fingers had plain arches. Two peripheral blood samples and one aponeurosis biopsy were cultured. The chromosomal studies revealed a normal karyotype in all cells studied and no evidence of mosaicisrn or translocation.
4 18
February 1965
de Grouchy
T a b l e I. T h e different features of trisomy 18 with frequencies as c o m p u t e d by Lejeune. ss
External mal/ormations Ears: low set, malformed Microretrognathla Flexion of fingers (index over 3rd, 5th over 4th) Prominent oceiput Short sternum Dorsiflexion of big toe Narrow pelvis Hernia Equinovarus and/or rockerbottom feet Internal rnal[ormations Congenital heart defect Interventricular septal defect Patent ductus arteriosus Renal anomaly Meckel's diverticulum General anomalies Mental retardation Hypotrophya Hypertonicity
Frequeney
No. of cases analyzed
1.00 1.00
48 45
0.96 0.89 0.83 0.73 0.63 0.53
47 38 35 34 31 36
0.50
38
0.91
45
0.85 0.56 0.58 0:41
34 32 31 27
1.00 0.93 0.70
36 41 34
If one accepts that the p a t i e n t has n o r m a l chromosomes then it should be emphasized t h a t the pseudotrisomy 18 syndrome lacked two signs which seen essential: a high frequency of arches in the finger patterns a n d a n a r r o w pelvis. A n o t h e r patient, with n o r m a l chromosomes, was seen b y L a f o u r c a d e , Lejeune, a n d Berger. 6~ This infant also h a d most of the features of trisomy 18 syndrome except for the d e r m a t o g l y p h i c patterns, all fingers displaying whorls or loops. Recently M a r s h a l l a n d associates 61 reported u p o n a patient with a trisomy 13-15 syndrome a n d a n o r m a l karyotype. Again, the d e r m a t o g l y p h i c p a t t e r n was the only feature not compatible with the diagnosis. T h e i m p o r t a n c e of the dermatoglyphic patterns in trisomy 18, and possibly in trisomy 13-15, thus appears to be strongly emphasized. T h e etiology of pseudotrisomy 18 syndrome
Fig. 2. The patient with a deletion of the short arms of chromosome 18.
is unknown. T h e patient could be: (1) a person with undiagnosed mosaicism, (2) a carrier of a n o n d e t e c t a b l e translocation, (3) a carrier of a gene m u t a t i o n which mimics trisomy 18, (4) a victim of an embryopathy. U n f o r t u n a t e l y none of these hypotheses is supported by any evidence. Eventually further cases should bring new d a t a to shed light on this interesting problem. DELETION OF THE SHORT ARMS OF CHROMOSOME 18
This c h r o m o s o m a l a b e r r a t i o n was first observed in a 6-year-old boy exhibiting somatic malformations as well as m e n t a l r e t a r d a tion22, 63 T h e patient was born after an un= eventful pregnancy. His father a n d m o t h e r were 42 and 41 years of age, respectively, at the time of birth. O n e x a m i n a t i o n the child was n o r m a l in height and weight. His face was r o u n d and "expressionless, with hypertelorism, divergent squint, a n d epicanthic
Volume 66 Number 2
folds. His hands were coarse with high-set thumbs and clinodactyly of the fifth fingers. There was a bilateral syndactyly of the third and fourth toes. Somatic examination was otherwise normal. Mental retardation was obvious. Psychologic tests demonstrated a complete lack of verbal expression. His mental age corresponded to a 2 ~ - y e a r - o l d child (Fig. 2). Blood counts, electroencephalogram, x-rays of the skelton, and eye examination did not disclose abnormalities. Palm and fingerprints reveal the following: the fingers were short, both axial triradii were in the t' position, and the dermal patterns on the fingers were normal (Fig. 8). T h e karyotype analysis was performed from cultured peripheral blood leukocytes. 64
Fig. 3. Karyotype showing the deletion of the short arms of chromosome 18.
Chromosome 18: Topological approach
4 19
Analysis of 24 cells showed a consistent anomaly; one of the No. 17-18 chromosomes was replaced by an acrocentric whose length was equivalent to the long an-ns of the smallest of the three remaining No. 17-18 chromosomes. This anomaly was considered as a deletion of the short arms of a No. 18 (Fig.
3). A study of the patient's family revealed that one of his sisters has very similar features and is of low average intelligence. She has a normal karyotype as do both parents. T h e results of blood grouping were noncontributory. Neither the R h locus nor the Kidd locus are located on the deleted fragment since the propositus has both antigens E and e, as well as J K ~ and J K b.
420
de Grouchy
February 1965
Fig. 4. A and B. Photographs of the patient with a partial deletion of the long arms of chromosome 18.
A second case of deletion of the short arms of a number 18 chromosome has been recorded by Buhler, Buhler, and Stalder ~5 in a child with an anomaly of thyroxine synthesis. Edwards 66 also observed two examples of the same deletion, one in a child, the other in an adult. Further details on these individuals are not known. PARTIAL DELETION LONG ARMS
OF THE
We have observed this chromosomal aberration in a girl at 1 year of age; she had severe growth and mental retardation as well as somatic m a l f o r m a t i o n s S T h e baby was born after 8 months of pregnancy. Both parents were healthy. T h e father was 40 and the mother 27 years of age. T h e patient has a normal sister, aged 2 ~ years. The patient's birth weight was 2,300 grams. At 1 year of age she measured 67 cm., i.e., 2 to 3 S.D.
below normal, and weighed 6,230 grams, 3 S.D. below normal; her head circumference was 41 cm., 1 S.D. below average for her height. A p a r t from this small degree of microcephaly she exhibited small ears, arched palate, broad chest with widely spaced and atrophied nipples, deep dimples at the back of her shoulders, and edema of the feet. Mental retardation was severe (Fig. 4, A, and B). Intravenous urography revealed "horseshoe" kidneys. T h e ophthalmologic examination revealed nystagmus and possible evidence of tapetoretinal degeneration. A repeat examination will be necessary to confirm this diagnosis. Although the baby did not seem to suffer from any degree of deafness, she was examined by an otologist (Pr. M. Ombredanne) for reasons to be discussed later. T h e pinnas were slightly smaller than average, the upper half being underdeveloped and the
Volume 66 Number 2
lower half n o r m a l ; the internal m e a t u s was slightly n a r r o w e d by hyperostosis of the posterior wall. I n the m i d d l e ear, both the tymp a n u m a n d the h a n d l e o f the malleus h a d a b n o r m a l fixations, which was considered to be suggestive of an atresia of the m i d d l e ear. A l t h o u g h some degree of deafness should be present, the young age of the b a b y p r e c l u d e d further examination. K a r y o t y p e analysis was p e r f o r m e d on three different cultures of p e r i p h e r a l blood leukocytes 68 a n d revealed the absence of one No. 17-18 chromosome a n d an extra chromosome resembling a No. 19-20 one (Fig. 5). T h e short arms of the extra chromosome were
Fig. 5. Karyotype showing the partial deletion of the long arms of chromosome 18.
Chromosome 18: Topological approach
42 1
similar in length to those of the r e m a i n i n g No. 17-18 ones. H e n c e this extra or a b n o r m a l chromosome was considered to have resulted from the deletion of half of the long arms of an 18 chromosome. This a n o m a l y was observed in all of the cells t h a t were analyzed (Fig. 5). P a l m a n d finger printing showed t h a t in b o t h hands a single p a l m a r crease was present. Axial triradii were in the n o r m a l t position. Fingerprints showed an a b n o r m a l n u m ber of whorls: 5 out of 10 fingers (Fig. 6). F a m i l y studies showed that the father, mother, and sister have n o r m a l karyotypes. Blood g r o u p i n g results show t h a t the M N
4 2 2 de Grouchy
February 1965
x \ It / g i / / w ~
\/>. t Fig. 6. Dermatoglyphic patterns of the hands in the case of a partial deletion of the long arms of chromosome 18.
and R h loci are not located on the deleted fragment. A similar karyotype has been observed by Lejeune 6~ in a patient still under clinical investigation. RING
CHROMOSOME
A ring chromosome for a No. 17-18 chromosome (most probably a No. 18) has been observed in 4 patients. T h e first patient, reported upon by W a n g and colleagues 52 (case No. 2) had severe mental retardation, I.Q. 53, as well as deafness due to an atresia of the middle ear, hypertelorism, bilateral epicanthic folds, and bilateral syndactyly of the second and third toes. T h e second patient studied by Genest, Leclerc, and Auger 7~ was a girl, aged, 3 years, who had hypertelorism, epieanthic folds, atresia of the middle ear, and club feet. Karyotype analysis revealed a probable translocation of a chromosome fragment onto a 13-15 as well as the: ring chromosome. T h e third patient, an infant, 1 year of age, described by Lucas and co-workers, 71 had a mosaic pattern with normal cells and cells with a ring chromosome. She had mild mental retardation, slight microcephaly, mild hypoplasia of the mandible, cleft palate, and congenital dislocation of the left hip.
Fig. 7. The patient with a ring chromosome No, 18.
Volume 66 Number 2
Chromosome 18: Topological approach
RIGHT
HAN~
423
(",,
deletion short arm
ring chr. LEFT HANDS
flog chr.
deletion short arm
Fig. 8. Comparison of the dermatoglyphic patterns in the patients with a deletion of the short arms and with a ring chromosome. A, Right hands. B, Left hands.
T h e fourth patient examined by my colleagues and myself ~2 is a Negro girl, 5 years of age, with mental retardation and somatic malformations. H e r father and mother are normal and were 37 and 27 years of age, respectively, at the time of her birth. She has two brothers, aged 8 and 3 years, and two sisters, aged 7 and 1 years. All are healthy. She was born prematurely at 8 months' gestation and weighed 2,300 grams. Her physical growth has been normal during
the first 2 years but her psychomotor development has been very retarded: she smiled at 8 months, sat up at 10, stood up at 14 months, and walked at 2.5 years of age. Her height was 100 cm.; her weight, 17.6 kilograms; and her cranial circumference, 51 cm. (average figures are: 106 cm. _+ 3.8; 17.1 Kg. __+ 1.9 and 50.3 cm. +_ 1.3 respectively). H e r face was somewhat peculiar due to a slight hypertelorism, slight bilateral epicanthic folds and low-set hair line. Ribs
424
de Grouchy
February 1965
Fig. 9. Different aspects of the ring chromosome,
are horizontal and nipples are set far apart and there was a bilateral pterygium colli more pronounced on the left than on the right side (Fig. 7). She has marked generalized hypotonia. O t h e r clinical and laboratory tests are within normal limits. Dermatoglyphie patterns displayed that the fingers were short and the fifth finger was slightly curved. Axial triradii were in position t p and there was a bilateral radial loop which was very striking. Fingerprints showed whorls on all fingers except on the thumbs which had an ulnar loop (Fig. 8). This pattern is quite rare especially in females. Cytogenetic studies were performed from two cultures of peripheral blood leukocytes .5 and revealed that one of the No. 17-18 ehro-
mosomes was replaced by an abnormal chromosome. This chromosome had various forms in different cells, e.g., ring, disk, or figure eight (Figs. 9 - - 1 1 ) . This structure is considered to be a ring chromosome as described previously in man, in drosophilia 73 and in maize. TM T h e different appearances of the abnormal structure were due to the different angles from which it was seen (Fig. 10). Pairing of the remaining chromosomes showed that the abnormal ring chromosome was most likely a No. 18 (Fig. 11). Family studies revealed that both parents and all siblings have normal karyotypes. Results of blood grouping studies were noncontributory: neither the MNSs locus nor the Kidd locus were located on the missing fragments.
Volume 66 Number 2
DISCUSSION Partial deletions are frequently a consequence of chromosomal r e a r r a n g e m e n t s such as translocations or ring chromosomes. I t is likely t h a t syndromes resulting from measurable deletions will eventually contribute to the construction of the h u m a n chromosome map. T h e first observation of a true deletion was by Jacobs a n d co-workers 7~ in the X chromosome a n d has been confirmed by others. 7~ T h e Ph 1 chromosome first observed by Nowell and H u n g e r f o r d 77 is the first instance of an autosomal deletion. However, this a b e r r a t i o n is in a somatic chromosome a n d occurs d u r i n g life. This is also true for other deletions observed in leukemia. 7s Possibly the first "congenital" deletion of an autosome to be r e p o r t e d is the deletion of the short arms of No. 18 discussed in this paper22 T r u e deletions have also been found for other chromosomes. L e j e u n e a n d associates79, so B55k, Atkins, and Santesson, sl a n d G r o u c h y a n d co-workers, s2 have described a new syndrome consisting of severe m e n t a l retardation, hypertelorism, dermatoglyphic anomalies, a very peculiar cry similar to t h a t of a cat, a n d a deletion of half of the short arms of a No. 5 chromosome. Deletions which seem reproducible a n d well defined m a y be the consequence of breakages at "weak" points on the chromosome arms. I t is also possible that m a n y deletions occur d u r i n g gametogenesis a n d that only a few of t h e m are compatible with life. T h e most favored time of occurrence for deletions seems to be d u r i n g gametogenesis. E x c e p t for a deleted X no instance of deletion of an autosome in the mosaic state is known. 76 R i n g chromosomes were first studied by M o r g a n ra a n d later by Schultz a n d Catcheside sa in the closed-X chromosomes of Drosophila melanogaster. M c C l i n t o c U 4 studied ring autosomes in maize. I n general such chromosomes do not a p p e a r stable in these organisms. R i n g chromosomes result from the breaking of the two ends of a n o r m a l chromosome
Chromosome 18: Topological approach
425
followed by fusion of both broken surfaces in such a m a n n e r as to p r o d u c e a closed ring (Fig. 12). I n general, ring chromosomes in these e x p e r i m e n t a l species are unstable. I n maize they m a y give rise, by a m e c h a n i s m not well understood, to double-sized ring chromosomes with two centromeres. W h e n such a ring is stretched on the spindle at anaphase, one c e n t r o m e r e at each pole, it m a y break a t any two points at r a n d o m , a n d lead to two new ring chromosomes of different sizes in each d a u g h t e r cell. This cycle of breakage-fusion-bridge eventually produces considerable mosaicism in the tissue in which it occurs. 84 Population studies on ring chromosomes in e x p e r i m e n t a l organisms reveal t h a t they are rapidly eliminated. Ring chromosomes have been observed in h u m a n cells in the following instances: (1) I n two m a l i g n a n t tumors studied by L e v a n 85 a n d in leukocytes f r o m a leukemic patientSO; (2) in cells i r r a d i a t e d either in vivo or in vitro ( T o u g h a n d his group 87 observed ring chromosomes in patients who h a d received
r
Fig. 10. Drawings showing the different aspects of a ring chromosome according to the degree of contraction and the angle at which it is seen.
426
de Grouch.y
February 1965
Fig. 11. Karyotype obtained from the patient
with a ring chromosome.
x-ray t h e r a p y ; Bender and Gooch ss a n d G r o u c h y a n d colleagues s9 demonstrated ring chromosomes in experimentaliy i r r a d i a t e d cells) ; (3) in a 42-week-old fetus with severe m a l f o r m a t i o n s a n d a ring chromosome instead of one 13-15 chromosomeg~ (4) in patients with congenital malformations compatible with life (two cases are r e p o r t e d of g o n a d a l dysgenesis in females, in each of w h o m one X chromosome was a ring chromosome) .91, 9~ A ring chromosome has also been observed in the No. 6-12 group in a boy with mental retardation, 9"a a n d a ring chromosome was described in the No. 13-15 group in a boy with m a l f o r m a t i o n s c o m p a r a ble to those seen in trisomy 17-18. 52 I r r a d i a tion h a d been p e r f o r m e d on the m o t h e r of
the latter child before conception. O t h e r aberrations, including a possible 17-18 translocation were seen. F o u r instances of 17-18 ring chromosomes are now known, including those in the p a t i e n t described here22, t0, ~1 F r o m a clinical standpoint, the several No. 18 deletion syndromes reviewed here have m a n y symptoms in common. M e n t a l r e t a r d a tion has been observed in one case of deletion of the short arms, in two cases of a ring chromosome, TM ~ a n d in the one case of partial deletion of the long arms discussed here. I t was not m e n t i o n e d in Genest's p a tient with a ring chromosome. '~ Hypertelorism a n d epicanthic folds have been described in one case of deletion of the short arms as well as in three cases of ring
Volume 66 Number 2
chromosome (Wang, ~z Genest, TM and ours72). These symptoms were not seen in association with deletion of the long arms. Atresia of the middle ear has been found in two cases of ring chromosomes ( W a n g 52 and Genest 7~ ; it was not present in our case of deletion of the short arms. Hence we speculated that this anomaly was attributable to the loss of a segment located near the lower end of the chromosome# 2 This ear defect was then looked for and eventually discovered in our patient with a deletion of a long arm, thus supporting our hypothesis. Dermatoglyphic patterns also pose interesting questions. First, the hands of the child with the deletion of the short arms were similar to those of the child with a ring chromosome: fingers were short, the fifth was slightly bent, and, in each instance, the axial triradii were in position t'. However, the high frequency of whorls was present only in the second one. W e had thus related this high frequency to the loss of the lower extremity of the chromosome. This idea was supporte d when the child with a partial deletion of the long arms also displayed a high number of whorls. A bilateral simian crease was observed only in the case of partial deletion of the long arms. This sign is also part of the clinical pictures of trisomy 21 and of the "Cri du Chat" (cat's cry) syndrome5 T M Hence it may be tt-~e consequence of loss or excess of genetic material. Furthermore, syndactyly of the second and third toes observed in the patients with deletion of the short arms of the chromosome and in one patient with a ring chromosome may be related to the loss of a segment of the short arm. I n Fig. 13 we have, in a very tentative fashion, summarized these ohservations and tried to relate the clinical anomalies to the loss of different segments of the chromosome. Ring chromosomes are a consequence of breakage of the two ends of the chromosomes. I n different individuals breakage m a y have occurred at different levels. Thus, if syndactyly of the toes is present only in Wang's case 52 and not in the patient de-
Chromosome 18: Topological approach
42 7
scribed here, this may m e a n that the breakage level was closer to the centromere in the first case than in the second one and that the region in the c h r o m o s o m e - - w h i c h when deleted is responsible for syndactyly--is located between these two levels. Conversely, hypertelorism and epicanthic folds, present in all cases, may be related to the loss of the tip of the chromosome. As mental deficiency is present in both deletion of the short arms and partial deletion of the long arms, two regions have been indicated on the map, one on each arm. Tapetoretinal abiotrophy, present only in partial deletion of the long arms, has also been placed on this arm. We emphasize that this m a p is entirely speculative and that it is not a "genic" map, rather it is merely an attempt to locate regions which when deleted may be responsible for certain phenotypic signs. With the reservation that the chromosome 18 we have discussed is the same as that responsible for the trisomy 17-18 syndrome, it also becomes tempting to match the features of deletion syndromes with features of trisomic syndromes; for instance, hypertelorism" and broad facies versus narrow forehead, excess of whorls versus excess of arch-finger patterns, or elevated axial triradius versus a normal position. These speculations provide leads for future research. Before mapping a chromosome in the true genetic sense, the main problem wilt be to know the exact relation between the loss (or
i
A
~QA
B
i m
B c
D
D
E
E
F
F
I G
G
c~
CAO
H
i
I
I
jJ Fig. 12. Drawing showing how a ring chromosome is produced.
428
de Grouchy
February 1965
excess) of a given region and a given symptom. Hypertelorism, for instance, is present in the patient with deletion of the short arms of a chromosome 18, as in the "Cri du Chat" syndrome in which there is partial deletion of the short arms of No. 5 chromosome. Thus the question may be asked: Is the normal distance between both eyes under the control of many loci located on different chromosomes, with the loss of any one being responsible for hypertelorism? Similar questions may be raised in respect to the dermatoglyphic patterns: Why, for instance, is the axial triradius in an abnormal location in, among others, trisomy 21, Turner's syndrome, or the Cri du Chat syndrome ? How can the simian crease be a consequence of an excess as wetI as a loss of genetic material?
These speculations of chromosomal aberrations are but a few of the aspects of the problems which will evolve from the study of the development of living beings. The continued identification and study of individuais with chromosome aberrations, and particuIarly those with structuraI abnormalities may give additional information toward the construction of a chromosome map. Such studies may be concerned with identification of specific loci, e.g., genes determining the blood groups. They may also be concerned with genes at multiple loci which specify a congenital malformation. This latter approach emphasizes the need for careful examination and documentation of clinicaI findings. It is one of the approaches to the study of developmental anomalies.
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]Fig. 13. A tentative map of segments from chromosome 18 which when deleted are responsible for the different clinical features mentioned along the chromosome.
Volume 66 Number 2
T h e author acknowledges the invaluable help of Dr. Stanley W. Wright in preparing the manuscript.
Chromosome 18: Topological approach
18.
REFERENCES 1. Lejeune, J., Gautier, M., and Turpin, R.: Les chromosomes humains en culture de tissus, Compt. rend. Acad. so. 248: 602, 1959. 2. Jerome, H., Lejeune, J., and Turpin, R.: l~tude de l'excr~tion urinaire de certains m~tabolites due tryptophane chez les enfants mongoliens, Compt. rend. Acad. sc. 251: 474, 1960. 3. Jerome, H.: Anomalies due m6tabolisme du tryptophane dans la maladie mongolienne, Bull. et mfm. Soc. m6d. hop., Paris, 113: 168, 1962. 4. O'Brien, D., and Groshek, A.: The abnormality of tryptophane metabolism in children with mongolism, Arch. Dis. Childhood 37: 17, 1962. 5. Nowell, P. C., and Hungerford, D. A.: A minute chromosome in human chronic granulocytic leukaemla, Science 132: 1497, 1960. 6. Turpin, R., and Bernyer, G.: De l'influence de l'h6rddit6 sur la formule d'Arneth (cas particulier du mongolisme), Rev. Hemat. 2: 189, 1947. 7. Alter, A. A., Lee, S. L., Pourfar, M., and Dobkin, G.: Studies of leukocyte alkaline phosphatase in mongolism: a possible chromosome marker, Blood 22: 165, 1963. 8. Trubowitz, S., Kirman, D., and Masek, B.: The leucocyte alkaline phosphatase in mongolism, Lancet 2: 486, 1962. 9. King, M. J., Gillis, E. M., and Baikie, A. G.: The polymorph alkaline phosphatase in mongolism, Lancet 2: 661, 1962. I0. Brandt, N. J., Froland, A., Mikkelsen, M., Nielsen, A., and Tolstrup, N.: Galactosaemia locus and the Down's syndrome chromosome, Lancet 2: 700, 1963. 11. Edwards, J. H.~ Harnden, D. G., Cameron, A. H., Crosse, V. M. and Wolff, O. H.: A new trisomic syndrome, Lancet 1: 787, 1960. I2. Patau~ K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P.: Multiple congenital anomaly caused by an extra autosome, Lancet 1: 790. 13. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: A new autosomal trisomy syndrome. Multiple congenital anomalies caused by an extra chromosome, J. P•DIAT. 57: 338. 14. Smith, D. W., Patau, K., and Therman, E.: AutosomaI trisomy syndromes, Lancet 2:211, 1961. 15. German, J. L., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., and Bearn, A. G.: Autosomal trisomy of a group 16-18 chromosome, J. PEmAT. 60: 503, 1962. 16. Gottlieb, M. P., Hirschhorn, K., Cooper, H. L., Lusskin, N., Moloshok, R. E., and Hodes, H. L.: Trisomy-17 syndrome, J. Dis. Child. 105: 213, 1962. 17. Koenig, E. U., Lubs, H. A., and Brandt,
19. 20.
21. 22. 23.
24. 25. 26.
27. 28.
29.
30. 31.
32. 33. 34. 35.
429
L. K.: The relationship between congenital anomalies and autosomal chromosomal abnormalities, Yale J. Biol. Med. 35: 189, 1962. Rosenfield, R. L., Breibart, S., Isaacs, H., Klevit, H. D., and Mellman, W. J.: Trisomy of chromosomes 13-15 and 17-18; its association with infantile arteriosclerosis, Am. J. M. Sc. 244: 763, 1962. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: The No. 18 trisomy syndrome, J. PEDIAT. 60: 513, 1962. Townes, P. L., Manning, J. A., and Dehart, G. K.: Trisomy 18 (16-18) associated with congenital and optic atrophy, J. PEDIAT. 61: 755, 1962. Uchida, I., Bowman, J. M., and Wang, H. C.: The 18-trlsomy syndrome, New Engtand J. Med. 266: 1198, 1962. Voorhess, M. L., Vaharu, T., and Gardner, L. I.: Trisomy 16-18 syndrome, Lancet 2: 992, 1962. Weiss, L., DiGeorge, A. M., and Baird, H. W.: Four infants with the trisomy 18 syndrome and one with trisomy 18 mosaicism, J. Dis. Child. 10~: 533, 1962. Finley, W. H., Finley, S. C., and Carte, E. T.: 17-18 trisomy syndrome, J. Dis. Child. 106: 591, 1963. I-Iecht, F., Bryant, J. S., Motulsky, A. G., and Giblett, E. R.: The No. 17-18 (E) trisomy syndrome, J. PEDIAT. 63: 605, 1963. Holman, G. H., Erkman, B., Zacharias, D. L., and Koch, H. F.: The trisomy 18 syndrome. Two new clinical variants--one associated with tracheo-esophageal fistula and the other with probable familial occurrence, New England J. Med. 268: 982, 1963. Lejeune, J., Delthil, P., and Berger, R.: Sur un cas de trisomie 17, Arch. fran~, p6diat. 20: 737, 1963. Oikawa, K., Kochen, J. A., Schorr, J. B., and Hirschhorn, K.: Trisomy 17 syndrome with phocomelia due to complete and partial chromosomal trisomy, J. PEDIAT. 63: 715, 1963. Pfeiffer, R. A., and Huther, W.: Trisomie des Chromosomes. Nr 18 unter dem Bild einer Arthrogryposis multiplex congenita, Med. clln. 58: 1110, 1963. Steinberg, J. B., and Jackson, J. F.: The 16-18 trisomy syndrome, J. Dis. Child. 105: 213, 1963. Townes, P. L., Kreutner, K. A., Kreutner, A., and Manning, J.: Observations on the pathology of the trisomy 17-18 syndrome, J. PEDIAT. 62: 703, 1963. Trowell, H. R., and Hilton, H. B.: A case of trisomy 18 syndrome, Human Chr. Newsletter, 10: 15, 1963. Nakagome, Y., Komiya, K., and Arina, M.: A case of trisomy 18 syndrome, Paediat. Univ. Tokyo 8: 48, 1963. Brown, C. D., Patterson, P., and Van Mierrop, L. H. S.: The 18 trisomy syndrome, Human Chrom. Newsletter 8: 10, 1963. Hansen, H. G., Tolksdorf, M., Zinat-Bakhsh, H., Lehmann, W., Nitsch, K., and Wiede-
4 30
36. 37, 38. 39. 40. 41. 42. 43.
44. 45. 46. 47.
48. 49.
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February 1965
56. Haylock, J., Fitzgerald, M., Danks, D., and Dennet, X.: Two cases of the 18-trisomy syndrome, one in combination with the XXY karyotype, Human Chrom. Newsletter 9: 15, 1963. 57, Gagnon, J., Katyk-Longtin, N., de Groot, J. A., and Barbeau, A.: Double trisomie autosomique ~ 48 chromosomes (21 + 18), Union m~d. Canada 90" 1220, 1961. 58. Lejeune, J.: Autosnmal disorders, Pediatrics 32" 326, 1963. 59. Lejeune, J., Lafourcade, J., Sahnon, C., and Turpin, R.: Translocation familiale 2,--~22. Association ~ un syndrome de Turner haplo X, Am. J. Human Genet. 6: 3, 1963. 60. Lafourcade, J., Lejeune, J., and Berger, R.: Personal communication, 1964. 61. Marshall, R., Newnham, R. E., Rawstron, J. R., Ellis, J. R., and Stevens, L. J.: Features of 13-15 trisomy syndrome with normM karyntype, Lancet 1: 556, 1964. 62. Grouchy, J. de, Lamy M., Thieffry, S., Arthuis, M., and Salmon, C.: Dysmorphie complexe avec oligophrfinie: dfilfition des bras courts d'un chromosome 17-18, Compt. rend. Acad. sc. 256: 1028, 1963. 63. Thieffry, S., Arthuis, M., Grouchy, J. de, Lamy, M., and Salmon, C.: D~lfition des bras courts d'un chromosome 17-18: dysmorphies complexes avec oligophrgnie, Arch. franw pfidiat. 20: 740, 1963. 64. Grouchy, J. de, Lamy, M., and Roubin, M.: I~tude du caryotype ~ partir d'une culture de leucocytes, Ann. Pediat. 39: 188, 1963. 65. Buhler, E. M., Buhler, U. K., and Stalder, G. R.: Partial monosomy 18 and anomaly of thyroxine synthesis, Lancet 1: 170, 1964. 66. Edwards, J. H.: Personal communication, 1964. 67. Grouchy, J. de, Roger, P., Salmon, C., and Lamy, M.: D~l~tion partielle des bras longs du chromosome 18, Path. Biol. 12: 579, 1964. 68. Grouchy, J. de, Roubin, M., and Passage, E.: Microtechnique pour 1' Etude des chromosomes humains ~ partir d'une culture de leucocytes sanguins, Ann. G~n~t. 7: 45, 1964. 69. Lejeune, J.: Personal communication, 1964. 70. Genest, P., Leclerc, R., and Auger, C.: Ring chromosome and partial translocation in the same cell, Lancet 1: 1426, 1963. 71. Lucas, M., Kemp, N. H., Ellis, J. R., and Marshall, R.: A small autosomal ring chromosome in a female infant with congenital malformations, Am. Human Genet. 27: 189, 1963. 72. Grouchy, J. de, Lfiv~que, B., Debauchez, C., Lamy, M., and Marie, J.: Chromosome 17-18 en anneau et malformations cong~nitales chez une fille, Ann. G~nfit. 7" 17, 1964. 73. Morgan, L. V.: A closed X chromosome in Drosophila melanogaster, Genetics 23" 315, 1933. 74. McClintock, B.: A correlation of ring shaped chromosomes with variegation in Zea mays, Proc. National Acad. So. 18: 677, 1932. 75. Jacobs, P. A., Harnden, D. G., Court-Brown,
Volume 66
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Number 2
W. M., Goldstein, J., Close, H. G., Macgregor, T. N., Maclean, N., and Strong, J. A.: Abnormalities involving the X chromosome in women, Lancet 1: 1213, 1960. Grouchy, J. de, Lamy, M., Yaneva, H., Salomon, S., and Netter, A.: Further abnormalities of the X chromosome in primary amenorrhoea or in severe olygomenorrhoea, Lancet 2: 777, 1961. Nowell, P. C., and Hungerford, D. A.: Chromosome studies on normal and leukemic human leukocytes, J. National Cancer Inst. 25: 85, 1960. Grouchy, J. de, and Lamy, M.: D616tion partielle d'un chromosome moyen dans une leuc6mie aigu~ lymphoblastique, Rev. fran~. et Clin. Biol. 7: 639, 1962. Lejeune, J., Lafourcade, J., Berger, R., Vialatte, J., Boeswillwald, M., Seringe, P., and Turpin, R.: Trois case de ddl&ion partielle du bras court d'un chromosome 5, Compt. rend. Acad. sc. 257: 3098, 1963. Lejeune, J., Lafourcade, J., Grouchy, J. de, Berger, R., Gautier, M., and Turpin, R.: Dfl6tion partielle du bras court du chromosome 5. Individualisation d'un nouvel &at morbide, Semaine h6p. 40: 1169, 1964. B65k, J. A., Atkins, L., and Santesson, B.: Some new data on autosomal aberrations in man, Path. Biol. 11: 1159, 1963. Grouchy, J. de, Arthuis, M., Salmon, C., Lamy, M., and Thieffry, S.: Le syndrome du cri du chat. Une nouvelle observation, Ann. Gdn&. 7: 13, 1964. Schultz, J., and Catcheside, D. G.: The nature
Chromosome t8: Topological approach
43I
of closed X chromosomes in Drosophila melanogaster, J. Genet. 35: 315, 1937. 84. White, M. J. D.: Animal cytology and evolution, Cambridge, 1954, University Press, pp. 454, 1954. 85. Levan, A.: Self perpetuating ring chromosomes in two human tumours, Hereditas 42: 366, 1956. 86. Baikie, A. G., Court-Brown, W. M., Jacobs, P. A., and Milne, J. S.: Chromosome studies in human leukaemia, Lancet 2: 425, 1959. 87. Tough, I., Buckton, K., Baikie, A. G., and Court-Brown, W. 1VL: X-ray induced chrc~mosome damage in man, Lancet 2: 849, 1960. 88. Bender, M. A., and Gooch, P. C.: Types and rates of X-ray induced chromosome aberrations in human blood irradiated in vitro, Proc. National Acad. So. 48: 522, 1962. 89. Grouchy, J. de.: Cytogenetic studies in irradiated medullar and blood cells, Proc. 9th Congress European Society of Haematology, 1963. 90. Bain, A. D., and Gauld, I. K.: Multiple congenital abnormalities associated with ring chromosome, Lancet 2: 304, 1963. 91. Lindsten, J., and Tillinger, K. G.: Self-perpetuating ring chromosome in a patient with gonadM dysgenesis, Lancet 1: 593, t962. 92. Luers, T., Struck, E., and Nevinny-Stickel, J.: Self-perpetuating ring chromosome in gonadal dysgenesis, Lancet 2: 887, 1963. 93. Smith-White, S., Peacock, W. J., Turner, B., and den Dulk, G. M.: A ring chromosome in man, Nature 197: 102, 1963.