Clinical Genetics 1976: 9: 593-602
Partial deletions and trisomies of chromosome 13; Mapping of bands associated with particular malformations B. NOEL,BERNADETTEQUACKAND MARIEODILE RE THO RE^ Centre Hospitalier, Chambbry and 1 Institut de Progenese, Paris, France New techniques of human karyotyping have allowed us to define accurately the banding pattern of six new cases with partial duplication or deficiency of chromosome 13. It now seems possible to draw a rough map of chromosome 13, correlating observed malformations and phenotypic features with specific chromosome regions. Partial monosomy shows clinical features which are the antithesis of the corresponding trisomic phenotype: (Lejeune 1966). Received 22 November, accepted f o r publication 22 December 1975
The trisomy 13 syndrome is characterized by a broad spectrum of congenital anomalies. Yunis & Hook (1966) reported two cases with a partial trisomy D1 syndrome, and tried to assign particular parts of the malformation syndrome to specific chromosome regions. We report six patients with duplications and deletions of parts of chromosome 13, and make a further attempt at karyotypephenotype correlations.
Material and Methods
Short-term lymphocyte cultures were harvested, and chromosome preparations were made by the standard techniques. Slides were studied after R-banding with Giemsa (Dutrillaux & Lejeune 1971), and with BuDW Acridine Orange (Dutrillaux et al. 1973).
Case Reports
A . Partial Trisomies Case l a , 73 539, a girl, now 6 years old, is not dysmorphic but is slightly mentally retarded (Fig. 1). The hands show clinodactyly and t” triradii; the dermatoglyphics of the parents are normal. Her karyotype shows 47 chromosomes, with an extra small marker chromosome. The mother was found to carry a reciprocal translocation between chromosomes 13 and 22 (Fig. 2). The karyotype of the child is interpreted as 47,XX, +der( 13), t(13; 22)(q12(2);pll)mat. She is therefore trisomic for the short arms and the juxtacentromeric part of the long arm of chromosome 13, as well as the short arm of No. 22 (Fig. 3). Case l b , 73 390, Six years later, the parents of Case l a (father 39 and mother 33) had a
594
NOEL, QUACK, AND RETHORE
Flg. 2. Partial karyotype of the mother showing reciprocal translocation between chromosomes 13 and 22.
Fig. 1. Case l a at age 3 yr 11 months.
male child, born prematurely after a normal pregnancy (Fig. 4). The child showed microcephaly with bossing of the forehead; trigonocephaly and an open anterior fontanelle; harelip with bilateral cleft palate; hypotelorism with antimongoloid slant of eyes and long incurved eyelashes; low-set malformed ears, and a short neck. There were no anomalies of the limbs, except narrow convex nails and bilateral simian creases. Axial triradii t” (Y)and bilateral ulnar loops in the hypothenar area were also observed.
There was dextrocardia with incomplete right bundle block, hypospadias and absence of the left ureter and kidney. 75 % HbF was found, and also increased polymorphonuclear neutrophil projections. The karyotype shows a missing 22 chromosome and an extra submetacentric marker, resulting in partial trisomy 13(q12(2)+ qter), with partial monosomy 22(pll +pter) (Fig. 5). Case Za, 68 273, a boy, was born to a mother who had previously had a stillbirth of 1500 g with hydrocephaly and polydactyly, and two spontaneous abortions. The father is 35 years old and the mother 33. The child is abnormally small, and microcephalic (Fig. 6). There is considerable psychomotor retardation and his cry is unusual; it sounds like a cat’s. The forehead is high and narrow; the hairline is low on neck and forehead; there
P A R T I A L D E L E T I O N S A N D T R I S O M I E S O F C H R O M O S O M E 13
595
Flg. 3. Karyotype of Case la. Flg. 4. Case l b at age 0 yr 1 month.
is synophris; the nose is short with widening of the alae nasi; there is heterochromia iridis (the interpupillary distance is 45 mm); and there is a discrete epicanthus. Micrognathia and a high-arched palate are present. The ears are malformed, the helix being fused with the initial part of the posterior root of the antihelix: there is no gutter to the helix. The right ear has a vertical ridge dividing the bowl of the conchus, and a preauricular fistula can be seen. The lobes are almost non-existent. The left ear is low set. Hexadactyly of the left hand and bilateral externally rotated legs with rocker-bottom heels are present. There is a hemangioma of the base of the neck. Psychomotor retardation is considerable, and there is generalized hypotonia. The EEG shows very slow activity for his age. The proximal palmar creases are distally placed.
The mother carries a balanced translocation: 46,XX,t(5; 13)(pl3;q14(3)) The child is trisomic for 13q14(3)+qter, and monosomic for 5pl3+pter. Case 2b. A 5th pregnancy of the same parents ended in a stillbirth showing hydrocephaly, eye anomaly (neuroepithelial undifferentiated rosettes) and absent thumb. The karyotype (Fig. 7) showed this child to be trisomic for 5pl3+pter, and monosomic for 13q14(3)+qter. (13q14(1) and 14(2) are present.)
B . Deletions Case 3, 69446, a full-term male, birth weight 2700 g (Fig. 8). At 5 months, development appeared delayed, and the EEG showed
596
NOEL, QUACK, AND RETHORE
Fig. 5. Case l b . Chromosomes 13 and 22 with partial trisomy 13(q12+qter).
slow rhythms. At 2 years, his developmental age was between 2 and 4 months. He has microcephaly with flat skull; the forehead is vertical and prolonged by the bridge of his nose. The hair line is low. There is also hypotelorism, epicanthus and a mongoloid slant to the eyes. Bilateral colobomata of the iris involve the lens, but there are no pupillary or retinal lesions. The palate is wide and low arched. The neck is thick set and without skin folds. The ears are large and “cauliflower”-like. The conchus and the gutter of the helix are well defined. The lobule is large. The extremities are normal, apart from the absence of nail lunulae. The front of the thorax shows a well-developed sub-cutaneous blood vessel network. At the age of 3 the subject had his left leg amputated following an arterial embolus.
Fig. 6. Case 2a at age 2 yr 7 months,
On X-ray, he was found to have a dorsal scoliosis and retarded bone growth. On the left hand there is a simian crease, and there is a left triradius t’, but none on the right. The karyotype contains an unstable ring chromosome 13. This appears to cause variable distal deletions of chromosome 13 from q34 or q32+qter, and also a distal part of the short arms. Duplications of the ring, and its total loss from some cells, increase the complexity of the chromosomal mosaicism generated by this ring chromosome (Fig. 9). Case 4, 72 388, a full-term female, was adopted when she was 18 days old; her parents are unknown. At 18 months of age, severe anorexia and growth retardation were present (weight of 5 months, height
PARTIALDELETIONSANDTRISOMIESOFCHROMOSOME13
597
Flg. 7. Karyotype of the mother of cases 2a and b: 46,XX,t(5;13) (p13;q14).
Fig. 8. Case 3 at age 5 yr 3 months
of 11 months, and head circumference of 7 months). Generalized hypotonia was observed, together with strabismus and hyperexcitability. Her anxiously drawn face has a protruding nose and her large ears are well formed. There is no teeth anomaly. Facial asymmetry is marked; there is microphthalmia with aniscoria and nystagmus, but no retinoblastoma. No abnormalities were observed in the extremities or in visceral systems. (Figs. 10 and 11.) At 6 years, mental retardation was present. Verbal ability and spatial orientations were particularly disturbed. The IQ was 61 at 10 years. Her walk is stiff, with disturbed balance and disdiadokokinesis. At 15 years, the subject entered puberty which was proceeding normally. Marked scoliosis, with a large vertebral rotation and “hump back” were present, but otherwise there was good psychomotor development.
There was increased hemoglobin A 2 (1 1 %), but no minor thalassemic syndrome. Dermatoglyphics show an axial triradius t” and a decreased Cummings index on both sides. The karyotype is 46,XX,13q-. The deletion is apparently interstitial, involving the middle third of chromosome 13 between bands q21 and q31 (Fig. 12). The missing segments are 33q22, 21, (and part of q14?).
+
Discussion
Partiul Trisomies (Cases l a , I b and 2a) The clinical picture of complete trisomy 13 is well known (Patau and al. 1960, Taylor 1968, Berger 1971, Hamerton 1971, Berger et al. 1972, Giroud and al. 1974). Cases of partial trisomy 13, identified by chromosome banding, have been published by Wil-
598
NOEL, QUACK, A N D RETHORE
Flg. 9. Small and large 13 rings of Case 3. Flg. 10. Case 4: side view at age 14 yr 6 months.
son et al. (1973), Taysi et al. (1973), Escobar et al. (1974), Escobar & Yunis (1974) and Fryns et al. (1975). A consideration of these cases, and of our own observations (Cases l a , l b and 2a) enables us to make some tentative generalizations about the clinical picture determined by trisomy of specific regions of chromosome 13 (Fig. 13). Trisoiny of short arm and band q l l : The malformation syndrome is not severe, although microcephaly, strabismus and abnormal dermatoglyphics are observed. Trisomy of the long arm: 1. Bands q12, 413, q14 appear to provoke a certain degree of cerebral holosphere, and a midline splitting of facial structure, with harelip and cleft palate. Eye anomalies, cardiac, renal and genital malformations are observed.
2. Bands q21, q22 are associated with an unusual facies with bossing of the forehead, narrow temples, and a wide, short nasal pyramid. Ear malformations, hyper- or hypotonia, and elevated fetal hemoglobin are present. 3 . Bands q31-q32 are associated with malformations of the extremities - polydactyly and club feet. 4. Band q33 is associated with inguinal or umbilical hernia. Deletions (Cases 2 b and 4 ) Deletion of bands q14-21. A deletion or rearrangement of this region may be associated with retinoblastoma (Ikeuchi et al. 1974, Orye et al. 1974), although Howard et al. (1974) conclude that retinoblastoma cannot be related to the loss of a specific region of chromosome 13.
PARTIAL DELETIONSANDTRISOMIES OF CHROMOSOME 13
599
Fig. 12. Case 4: chromosome 13 deletion.
Flg. 11. Case 4.
Bands q2I and q22. Their deficiency is related to an unusual facies with protruding nose and forehead, which has the opposite appearance to the trisomic for the same chromatid segment. There are also various skeletal anomalies: scoliosis, malformed pelvis, extra vertebrae and coxa valga. Bands q3I-34. These appear to play a role in malformations of the extremities (thumb aplasia, syndactyly). Ring 13 Chromosome (Case 3) The mitotic instability of ring chromosomes produces complex duplication/deficiency mosaics (Hoo and al. 1974). It would be very interesting if the “Greek profile” of the ring 13 chromosome carrier were due to the conjunction of a protruding nose and a
forehead with narrow temples, resulting from a duplication deficiency of q21-22. In conclusion, our observations permit us to draw a tentative correlation between particular malformations and specific chromosome bands (Fig. 14). Lewandowski & Yunis (1975) have now produced a phenotypic map of chromosome 13 which corroborates our main findings. Acknowledgments
These observations were carried out in Departments of Pediatrics and Pedopsychiatry: Case l a and b - Drs Thomb, Bovier Lapierre and Chabert (ChambCry); Case 2 Prof. Lafourcade (Pitie SalpCtriGre); Case 3 - Dr Versmke (Thorens); and Case 4
-
NOEL, QUACK, A N D RETHORE
600
I
.*'
I
I
1
case 1 a
>
I
nuclear projections
1
I
case 9: _ . ~ _
sloping of forehead cerebral holosphere 3
cardiac, r e n a l , g e n i t a l malf.
case 2 b 4
2
cleft lip and palate microphthalmia colobom
3
dystonia bossing of forehead, narrow temples
dystonia strabimnua
pH
i-.
3
c..e
4
P
2
3
hbF hypertelorimn short nose h y p o t e l o r i m , epicanthus' ear m l f . no gutter, preauric fistule case 2a
-rfl 1
club f e e t po1YQCtYlY
Ca 7M
I
3
3
3 Or
I
un 3
I I
case 3
1
hernia
7
Flg. 13. Schematic drawing of chromosome 13, according to partial trisomies or deletions.
Prof. Jeune, Drs Laurent, Kohler and Marcou (Lyon, Annecy). Their contributions are gratefully acknowledged, as is the help of Dr Martin Bobrow, who corrected the manuscript.
References
Berger, R. (1971). Trisomie 13. Presse mkd. 44, 1969-1972* Berger, R., G . Percheron & R. Escourolle (1972). Monosomies D Dartielles. Nouv. presse mCd. 16, 1089-1090.
PARTIALDELETIONSANDTRISOMIESOFCHROMOSOME13
601
13 RING I'i~llTIirL TRISOXY
12
'
'
congenital heart disease a h renal tract, anal imperf hypospadias arhinencephalia
case 3
microphthalmia, colobome
hyper-hypotonia m a l l pelvis capillary hemangioma
21
I
SCOliOSiS
I
Greek p r o f i l e
abnorml feet polydactyly aim. thumbs
3)
1 II
hyperconvex nails flexion of fingers
I
34
FIg. 14. Schematic drawing of chromosome 13: clinical correlations with ring 13 cases.
Dutrillaux, B. & J. Lejeune (1971). Sur une nouvelle technique d'analyse du caryotype humain. C. R. Acad. Sci. (Paris) 272, 26382640. Dutrillaux, B., C. Laurent, J. Couturier L J. Lejeune (1973). Coloration par l'Acridine Orange de chromosomes prkalablement trai-
t6s par le 5 bromodkoxyuridine. C. R. Acad. Sci. (Paris) 276, 3179.
Escobar, J. I., 0. Sanchez & I. J. Yunis (1974). Trisomy for the distal segment of chromosome 13. Amer. J . Dis. Child 128, 217-220. Escobar, J. I. t J. J. Yunis (1974). Trisomy for the proximal segment of the long arm of
602
NOEL, QUACK, AND RETHORE
chromosome 13. Amer. J . Dis. Child. 128, 221-222. Fryns, J . P., E. Eggermont, H. Verresen 8r H. Van den Berghe (1975). Partial trisomy 13, karyotype 46,XY,6 t (13 q - 6q). Hum. Genet. 21, 41-54. Giroud, A., Ch. Deluchat & J. Boue (1974). Aberrations chromosomiques et rnalformations spicialement prosenciphaliques. C . R. SOC. Biol. (Paris) 168, 203-210. Hamerton, J. L. (1971). Human Cytogenetics. New York, London, Academic Press, pp. 295-536. Hoo, J. J., U. Obermann t H. Cramer (1974). The behavior of ring chromosome 13. Hum. Genet. 24, 161-171. Howard, R. O., W. R. Breg, D. M. Albert t R. L. Lesser (1974). Retinoblastoma and chromosome abnormality. Arch. Ophthal. 92, 490-494. lkeuchi, T., S. Sonta & M. Sasaki (1974). Hyjita and Kikako Isunenatsu 46, XY, del 13 (q 22). Hum. Genet. 21, 309-314. Lejeune, J. (1966). Types et contretypes. JournPes Parisiennes de Pkdiarrie, ed. medicale, Flarnmarion, Paris, pp. 75-83. Lejeune, J. (1967). Modkle thkorique de la ripartition des duplications et des dkficiences dans les chromosomes en anneaux. C . R. Acad. Sci. (Paris) 264, 2588. Lejeune, J . (1968). Duplications des structures circulaires. Ann. Gknit. 11, 71-79. Lewandowski, R. C. & J. J . Yunis (1975). New
+
chromosomal syndromes, Amer. J. Dis. Child. 129, 515-529. Orye, E., M. J. Delbeke & B. Vandenabeele (1974). Retinoblastoma and long arm deletion of chromosome 13. Attempts to define the deleted segment. Clin. Genet. 5 , 457-464. Patau, K., D. W. Smith, E. Therman, S. C. Inhan & H. P. Wagner (1960). Multiple congenital anomaly caused by an extra autosome. Lancet i, 790-793. Taylor, A. (1968). Autosomal trisomy syndrome a detailed study of 27 cases of Edwards syndrome and 27 cases of Patau's syndromes. J. med. Genet. 5, 227-252. Taysi, K., M. Bobrow, S. Balci, K. Madan, M. Atasu t B. Say (1973). Duplicationldeficiency product of a pericentric inversion in man: a cause of D1 trisomy syndrome. J . Pediat. 82, 263-268. Wilson, M. G., J. Towner & A. Fujimoto (1973). Retinoblastoma and D chromosome deletion. Arner. J . hum. Genet. 25, 57-61. Yunis, J. J. & E. B. Hook (1966). Deoxyribonucleic acid replication and mapping of the D1 chromosome. Amer. J. Dis. Child. 111, 83-89. Address: B. Noel, M.D. Centre Hospitalier 73011 Chamber?, France
Partial deletions and trisomies of chromosome 13; Mapping of bands associated with particular malformations B. NOEL,BERNADETTEQUACKAND MARIEODILE RE THO RE^ Centre Hospitalier, Chambbry and 1 Institut de Progenese, Paris, France New techniques of human karyotyping have allowed us to define accurately the banding pattern of six new cases with partial duplication or deficiency of chromosome 13. It now seems possible to draw a rough map of chromosome 13, correlating observed malformations and phenotypic features with specific chromosome regions. Partial monosomy shows clinical features which are the antithesis of the corresponding trisomic phenotype: (Lejeune 1966). Received 22 November, accepted f o r publication 22 December 1975
The trisomy 13 syndrome is characterized by a broad spectrum of congenital anomalies. Yunis & Hook (1966) reported two cases with a partial trisomy D1 syndrome, and tried to assign particular parts of the malformation syndrome to specific chromosome regions. We report six patients with duplications and deletions of parts of chromosome 13, and make a further attempt at karyotypephenotype correlations.
Material and Methods
Short-term lymphocyte cultures were harvested, and chromosome preparations were made by the standard techniques. Slides were studied after R-banding with Giemsa (Dutrillaux & Lejeune 1971), and with BuDW Acridine Orange (Dutrillaux et al. 1973).
Case Reports
A . Partial Trisomies Case l a , 73 539, a girl, now 6 years old, is not dysmorphic but is slightly mentally retarded (Fig. 1). The hands show clinodactyly and t” triradii; the dermatoglyphics of the parents are normal. Her karyotype shows 47 chromosomes, with an extra small marker chromosome. The mother was found to carry a reciprocal translocation between chromosomes 13 and 22 (Fig. 2). The karyotype of the child is interpreted as 47,XX, +der( 13), t(13; 22)(q12(2);pll)mat. She is therefore trisomic for the short arms and the juxtacentromeric part of the long arm of chromosome 13, as well as the short arm of No. 22 (Fig. 3). Case l b , 73 390, Six years later, the parents of Case l a (father 39 and mother 33) had a
594
NOEL, QUACK, AND RETHORE
Flg. 2. Partial karyotype of the mother showing reciprocal translocation between chromosomes 13 and 22.
Fig. 1. Case l a at age 3 yr 11 months.
male child, born prematurely after a normal pregnancy (Fig. 4). The child showed microcephaly with bossing of the forehead; trigonocephaly and an open anterior fontanelle; harelip with bilateral cleft palate; hypotelorism with antimongoloid slant of eyes and long incurved eyelashes; low-set malformed ears, and a short neck. There were no anomalies of the limbs, except narrow convex nails and bilateral simian creases. Axial triradii t” (Y)and bilateral ulnar loops in the hypothenar area were also observed.
There was dextrocardia with incomplete right bundle block, hypospadias and absence of the left ureter and kidney. 75 % HbF was found, and also increased polymorphonuclear neutrophil projections. The karyotype shows a missing 22 chromosome and an extra submetacentric marker, resulting in partial trisomy 13(q12(2)+ qter), with partial monosomy 22(pll +pter) (Fig. 5). Case Za, 68 273, a boy, was born to a mother who had previously had a stillbirth of 1500 g with hydrocephaly and polydactyly, and two spontaneous abortions. The father is 35 years old and the mother 33. The child is abnormally small, and microcephalic (Fig. 6). There is considerable psychomotor retardation and his cry is unusual; it sounds like a cat’s. The forehead is high and narrow; the hairline is low on neck and forehead; there
P A R T I A L D E L E T I O N S A N D T R I S O M I E S O F C H R O M O S O M E 13
595
Flg. 3. Karyotype of Case la. Flg. 4. Case l b at age 0 yr 1 month.
is synophris; the nose is short with widening of the alae nasi; there is heterochromia iridis (the interpupillary distance is 45 mm); and there is a discrete epicanthus. Micrognathia and a high-arched palate are present. The ears are malformed, the helix being fused with the initial part of the posterior root of the antihelix: there is no gutter to the helix. The right ear has a vertical ridge dividing the bowl of the conchus, and a preauricular fistula can be seen. The lobes are almost non-existent. The left ear is low set. Hexadactyly of the left hand and bilateral externally rotated legs with rocker-bottom heels are present. There is a hemangioma of the base of the neck. Psychomotor retardation is considerable, and there is generalized hypotonia. The EEG shows very slow activity for his age. The proximal palmar creases are distally placed.
The mother carries a balanced translocation: 46,XX,t(5; 13)(pl3;q14(3)) The child is trisomic for 13q14(3)+qter, and monosomic for 5pl3+pter. Case 2b. A 5th pregnancy of the same parents ended in a stillbirth showing hydrocephaly, eye anomaly (neuroepithelial undifferentiated rosettes) and absent thumb. The karyotype (Fig. 7) showed this child to be trisomic for 5pl3+pter, and monosomic for 13q14(3)+qter. (13q14(1) and 14(2) are present.)
B . Deletions Case 3, 69446, a full-term male, birth weight 2700 g (Fig. 8). At 5 months, development appeared delayed, and the EEG showed
596
NOEL, QUACK, AND RETHORE
Fig. 5. Case l b . Chromosomes 13 and 22 with partial trisomy 13(q12+qter).
slow rhythms. At 2 years, his developmental age was between 2 and 4 months. He has microcephaly with flat skull; the forehead is vertical and prolonged by the bridge of his nose. The hair line is low. There is also hypotelorism, epicanthus and a mongoloid slant to the eyes. Bilateral colobomata of the iris involve the lens, but there are no pupillary or retinal lesions. The palate is wide and low arched. The neck is thick set and without skin folds. The ears are large and “cauliflower”-like. The conchus and the gutter of the helix are well defined. The lobule is large. The extremities are normal, apart from the absence of nail lunulae. The front of the thorax shows a well-developed sub-cutaneous blood vessel network. At the age of 3 the subject had his left leg amputated following an arterial embolus.
Fig. 6. Case 2a at age 2 yr 7 months,
On X-ray, he was found to have a dorsal scoliosis and retarded bone growth. On the left hand there is a simian crease, and there is a left triradius t’, but none on the right. The karyotype contains an unstable ring chromosome 13. This appears to cause variable distal deletions of chromosome 13 from q34 or q32+qter, and also a distal part of the short arms. Duplications of the ring, and its total loss from some cells, increase the complexity of the chromosomal mosaicism generated by this ring chromosome (Fig. 9). Case 4, 72 388, a full-term female, was adopted when she was 18 days old; her parents are unknown. At 18 months of age, severe anorexia and growth retardation were present (weight of 5 months, height
PARTIALDELETIONSANDTRISOMIESOFCHROMOSOME13
597
Flg. 7. Karyotype of the mother of cases 2a and b: 46,XX,t(5;13) (p13;q14).
Fig. 8. Case 3 at age 5 yr 3 months
of 11 months, and head circumference of 7 months). Generalized hypotonia was observed, together with strabismus and hyperexcitability. Her anxiously drawn face has a protruding nose and her large ears are well formed. There is no teeth anomaly. Facial asymmetry is marked; there is microphthalmia with aniscoria and nystagmus, but no retinoblastoma. No abnormalities were observed in the extremities or in visceral systems. (Figs. 10 and 11.) At 6 years, mental retardation was present. Verbal ability and spatial orientations were particularly disturbed. The IQ was 61 at 10 years. Her walk is stiff, with disturbed balance and disdiadokokinesis. At 15 years, the subject entered puberty which was proceeding normally. Marked scoliosis, with a large vertebral rotation and “hump back” were present, but otherwise there was good psychomotor development.
There was increased hemoglobin A 2 (1 1 %), but no minor thalassemic syndrome. Dermatoglyphics show an axial triradius t” and a decreased Cummings index on both sides. The karyotype is 46,XX,13q-. The deletion is apparently interstitial, involving the middle third of chromosome 13 between bands q21 and q31 (Fig. 12). The missing segments are 33q22, 21, (and part of q14?).
+
Discussion
Partiul Trisomies (Cases l a , I b and 2a) The clinical picture of complete trisomy 13 is well known (Patau and al. 1960, Taylor 1968, Berger 1971, Hamerton 1971, Berger et al. 1972, Giroud and al. 1974). Cases of partial trisomy 13, identified by chromosome banding, have been published by Wil-
598
NOEL, QUACK, A N D RETHORE
Flg. 9. Small and large 13 rings of Case 3. Flg. 10. Case 4: side view at age 14 yr 6 months.
son et al. (1973), Taysi et al. (1973), Escobar et al. (1974), Escobar & Yunis (1974) and Fryns et al. (1975). A consideration of these cases, and of our own observations (Cases l a , l b and 2a) enables us to make some tentative generalizations about the clinical picture determined by trisomy of specific regions of chromosome 13 (Fig. 13). Trisoiny of short arm and band q l l : The malformation syndrome is not severe, although microcephaly, strabismus and abnormal dermatoglyphics are observed. Trisomy of the long arm: 1. Bands q12, 413, q14 appear to provoke a certain degree of cerebral holosphere, and a midline splitting of facial structure, with harelip and cleft palate. Eye anomalies, cardiac, renal and genital malformations are observed.
2. Bands q21, q22 are associated with an unusual facies with bossing of the forehead, narrow temples, and a wide, short nasal pyramid. Ear malformations, hyper- or hypotonia, and elevated fetal hemoglobin are present. 3 . Bands q31-q32 are associated with malformations of the extremities - polydactyly and club feet. 4. Band q33 is associated with inguinal or umbilical hernia. Deletions (Cases 2 b and 4 ) Deletion of bands q14-21. A deletion or rearrangement of this region may be associated with retinoblastoma (Ikeuchi et al. 1974, Orye et al. 1974), although Howard et al. (1974) conclude that retinoblastoma cannot be related to the loss of a specific region of chromosome 13.
PARTIAL DELETIONSANDTRISOMIES OF CHROMOSOME 13
599
Fig. 12. Case 4: chromosome 13 deletion.
Flg. 11. Case 4.
Bands q2I and q22. Their deficiency is related to an unusual facies with protruding nose and forehead, which has the opposite appearance to the trisomic for the same chromatid segment. There are also various skeletal anomalies: scoliosis, malformed pelvis, extra vertebrae and coxa valga. Bands q3I-34. These appear to play a role in malformations of the extremities (thumb aplasia, syndactyly). Ring 13 Chromosome (Case 3) The mitotic instability of ring chromosomes produces complex duplication/deficiency mosaics (Hoo and al. 1974). It would be very interesting if the “Greek profile” of the ring 13 chromosome carrier were due to the conjunction of a protruding nose and a
forehead with narrow temples, resulting from a duplication deficiency of q21-22. In conclusion, our observations permit us to draw a tentative correlation between particular malformations and specific chromosome bands (Fig. 14). Lewandowski & Yunis (1975) have now produced a phenotypic map of chromosome 13 which corroborates our main findings. Acknowledgments
These observations were carried out in Departments of Pediatrics and Pedopsychiatry: Case l a and b - Drs Thomb, Bovier Lapierre and Chabert (ChambCry); Case 2 Prof. Lafourcade (Pitie SalpCtriGre); Case 3 - Dr Versmke (Thorens); and Case 4
-
NOEL, QUACK, A N D RETHORE
600
I
.*'
I
I
1
case 1 a
>
I
nuclear projections
1
I
case 9: _ . ~ _
sloping of forehead cerebral holosphere 3
cardiac, r e n a l , g e n i t a l malf.
case 2 b 4
2
cleft lip and palate microphthalmia colobom
3
dystonia bossing of forehead, narrow temples
dystonia strabimnua
pH
i-.
3
c..e
4
P
2
3
hbF hypertelorimn short nose h y p o t e l o r i m , epicanthus' ear m l f . no gutter, preauric fistule case 2a
-rfl 1
club f e e t po1YQCtYlY
Ca 7M
I
3
3
3 Or
I
un 3
I I
case 3
1
hernia
7
Flg. 13. Schematic drawing of chromosome 13, according to partial trisomies or deletions.
Prof. Jeune, Drs Laurent, Kohler and Marcou (Lyon, Annecy). Their contributions are gratefully acknowledged, as is the help of Dr Martin Bobrow, who corrected the manuscript.
References
Berger, R. (1971). Trisomie 13. Presse mkd. 44, 1969-1972* Berger, R., G . Percheron & R. Escourolle (1972). Monosomies D Dartielles. Nouv. presse mCd. 16, 1089-1090.
PARTIALDELETIONSANDTRISOMIESOFCHROMOSOME13
601
13 RING I'i~llTIirL TRISOXY
12
'
'
congenital heart disease a h renal tract, anal imperf hypospadias arhinencephalia
case 3
microphthalmia, colobome
hyper-hypotonia m a l l pelvis capillary hemangioma
21
I
SCOliOSiS
I
Greek p r o f i l e
abnorml feet polydactyly aim. thumbs
3)
1 II
hyperconvex nails flexion of fingers
I
34
FIg. 14. Schematic drawing of chromosome 13: clinical correlations with ring 13 cases.
Dutrillaux, B. & J. Lejeune (1971). Sur une nouvelle technique d'analyse du caryotype humain. C. R. Acad. Sci. (Paris) 272, 26382640. Dutrillaux, B., C. Laurent, J. Couturier L J. Lejeune (1973). Coloration par l'Acridine Orange de chromosomes prkalablement trai-
t6s par le 5 bromodkoxyuridine. C. R. Acad. Sci. (Paris) 276, 3179.
Escobar, J. I., 0. Sanchez & I. J. Yunis (1974). Trisomy for the distal segment of chromosome 13. Amer. J . Dis. Child 128, 217-220. Escobar, J. I. t J. J. Yunis (1974). Trisomy for the proximal segment of the long arm of
602
NOEL, QUACK, AND RETHORE
chromosome 13. Amer. J . Dis. Child. 128, 221-222. Fryns, J . P., E. Eggermont, H. Verresen 8r H. Van den Berghe (1975). Partial trisomy 13, karyotype 46,XY,6 t (13 q - 6q). Hum. Genet. 21, 41-54. Giroud, A., Ch. Deluchat & J. Boue (1974). Aberrations chromosomiques et rnalformations spicialement prosenciphaliques. C . R. SOC. Biol. (Paris) 168, 203-210. Hamerton, J. L. (1971). Human Cytogenetics. New York, London, Academic Press, pp. 295-536. Hoo, J. J., U. Obermann t H. Cramer (1974). The behavior of ring chromosome 13. Hum. Genet. 24, 161-171. Howard, R. O., W. R. Breg, D. M. Albert t R. L. Lesser (1974). Retinoblastoma and chromosome abnormality. Arch. Ophthal. 92, 490-494. lkeuchi, T., S. Sonta & M. Sasaki (1974). Hyjita and Kikako Isunenatsu 46, XY, del 13 (q 22). Hum. Genet. 21, 309-314. Lejeune, J. (1966). Types et contretypes. JournPes Parisiennes de Pkdiarrie, ed. medicale, Flarnmarion, Paris, pp. 75-83. Lejeune, J. (1967). Modkle thkorique de la ripartition des duplications et des dkficiences dans les chromosomes en anneaux. C . R. Acad. Sci. (Paris) 264, 2588. Lejeune, J . (1968). Duplications des structures circulaires. Ann. Gknit. 11, 71-79. Lewandowski, R. C. & J. J . Yunis (1975). New
+
chromosomal syndromes, Amer. J. Dis. Child. 129, 515-529. Orye, E., M. J. Delbeke & B. Vandenabeele (1974). Retinoblastoma and long arm deletion of chromosome 13. Attempts to define the deleted segment. Clin. Genet. 5 , 457-464. Patau, K., D. W. Smith, E. Therman, S. C. Inhan & H. P. Wagner (1960). Multiple congenital anomaly caused by an extra autosome. Lancet i, 790-793. Taylor, A. (1968). Autosomal trisomy syndrome a detailed study of 27 cases of Edwards syndrome and 27 cases of Patau's syndromes. J. med. Genet. 5, 227-252. Taysi, K., M. Bobrow, S. Balci, K. Madan, M. Atasu t B. Say (1973). Duplicationldeficiency product of a pericentric inversion in man: a cause of D1 trisomy syndrome. J . Pediat. 82, 263-268. Wilson, M. G., J. Towner & A. Fujimoto (1973). Retinoblastoma and D chromosome deletion. Arner. J . hum. Genet. 25, 57-61. Yunis, J. J. & E. B. Hook (1966). Deoxyribonucleic acid replication and mapping of the D1 chromosome. Amer. J. Dis. Child. 111, 83-89. Address: B. Noel, M.D. Centre Hospitalier 73011 Chamber?, France
