Hum. Genet. 33, 213---222 (1976) © by Springer-Verlag 1976
Original Investigations A New Case of Trisomy for tile Distal Part of 13q Due to Maternal Translocation, t(9; 13)(p21 ;q21) M. J o t t e r a n d a n d E. J u i l l a r d Division de G6n6tique 16dicale, Centre Hospitalier Universitaire Vaudois, Lausanne (Suisse) Received April 26, 1976
Summary. The first child of a mother with a balanced translocation (9;13) revealed a trisomy for the distal third of 13q. Clinical signs were microcephaly, hemangiomata, tong incurred eyelashes, strabismus, enlarged bridge of the nose, abnormally long philtrum, higharched palate, low set ears, hexadactyly of the four extremities, umbilical and inguinal hernias, neonatal respiratory distress, psychomotor and growth retardation. The proband presented also male pseudohermaphroditism and trigonocephaly. This last trait is the object of a discussion in which cases of partial trisomy 13q cited in the literature are considered for study of the incidence of this dyscephaly in this particular syndrome. I~eeently it was possible to observe a new case of p a r t i a l t r i s o m y 13 affecting t h e d i s t a l t h i r d p o r t i o n of 13q. The p r e s e n t r e p o r t describes t h e p a t i e n t a n d his
Fig. 1. The proband's face Fig. 2. The proband's profile
214
lg. Jotterand and E. JuilIard
Fig. 3. The proband: external genital organs
f a m i l y as well as a r e l a t i v e l y c o m p l e t e c y t o g e n e t i c s t u d y of t h e a n o m a l y , its origin, a n d m o d e o f t r a n s m i s s i o n .
Case Report Family History. The pedigree (Fig. 4) shows a consanguinity between paternal and maternal families. The proband's mother (III-4) has a dizygotic twin sister (IIL5). In the same family there is a second set of dizygotic twins (III-7 and III-8). One twin of the latter set died at the age of 1 month of a cardiac malformation. At the proband's birth his father (III-3) and his mother (III-4) were 24 and 22 years old, respectively. Both are mentally and phenotypically normal. Three years later the mother had a miscarriage in the 14th week of pregnancy. At that time it was possible to do a karyotype of the miscarried embryo; the results will be commented on later. Several months later, at the end of 1974, the mother was pregnant again and an amnioeentesis was done on February 12, 1975. A phenotypically normal daughter (IV-5) was born on July 14, 1975. The karyotypes of the amniotic cells and of the daughter will also be presented later. No other particular signs are noted in the family history. Patient's History. On August 25, 1971, the propositus was born by cesarian section in the 37th week of gestation. The operation was required because of hypertension and albuminuria in the 36th week of pregnancy. At birth the child weighed 3130 g (50th--75th percentile), measured 48.5 em (50th~75th percentile), and the head circumference was 34 cm (75th percentile). One hour and 40 rain after birth, he was transferred from the Maternit6 to the Cliniquc Infantile because of a cyanotic and tachypneic state and multiple malformations. A symptomatic hypoglycemia appeared in the first hours of life and proved difficult to correct. The infant presented numerous particular clinical signs. The head showed the following: trigonoeephaly, hypotelorism, palpebr~l ptosis, long ineurved eyelashes, synophrys, enlarge-
A New Case of Trisomy for the Distal P a r t of 13q
215
I
I III
/3
IV
[] normal []
caryotype
not examined
(~ 4 6 j x x j t (13)9)(q21)p21) • •
461XYj der (9) t (13)9)(q 21~p2 I) mat spont, abort.
Fig. 4. Pedigree of proband's family m e n t of the bridge of the nose, long philtrum, maerostomia, high-arched palate, missing uvula, low set ears, and short neck. Cardiac auscultation revealed a mesoeardiae 3/6 systolic murmur. There was hexadactyly of the four extremities. The big toes were in dorsal flexion. A n umbilical hernia and two inguinal hernias were noted. The two small mobile masses (each with a diameter of nearly 1 era), felt in the inguinal folds, appeared to be testicles in retention. The external genital organs were ambiguous. The child h a d a clitoris in the f o r m of a penis with a false meatus at its extremity. The real urethral meatus was found at the base of the clitoris. The v u l v a had a normal aspect. The skin presented hemangiomata on the forehead, the occipital region, the back, and the thorax. A urograph revealed no urinary t r a c t anomalies. A radiologie examination of the urogenital region produced evidence of a well-developed vaginal cavity and bifid uterus. A n audiogram raised the question of diminished hearing capacity (Dr. de Reynier). The buecal smear was negative. The dermatoglyphie examinations showed bilaterally simian creases. A detailed analysis of the karyotype will be given later. Evolution o/the Case. A t the age of 4 months, the infant was rehospitalized to t r e a t his bilateral inguinal hernias. The operation revealed in the right inguinal canal one ovarianlike gonad, and a very short fallopian tube of normal configuration with normal vessels. I n the left inguinal canal there were two gonads. One gonad was large and testielelike b u t of fibrous consistency; the other was smaller, infarcted, and h a d in front of it a fallopian tube with normal vessels. A histologic examination of the gonads showed, on the right, immature testicular tissue. On the left, the larger gonad revealed only flbro-adipous tissue, without proof of being either a testicle or an ovary; the smaller consisted of immature testieular tissue with the presence of several Sertoli cells and the absence of Leydig cells. A t the age of 7 months, the child was rehospitalized to t r e a t his hexadactyly. At the same time a significant growth retardation was noted. The head circumference, which h a d been
216
M. Jotterand and E. Juillard
at the 75th percentile at birth was now at the 25th percentile. There was also severe psychomotor retardation. An EEG, recorded at this time, raised the question of epilepsy. At the age of 25 months, the infant was rehospitalized for bronchitis. At that time his stature was in the 10th--25th percentile, his weight in the 3rd percentile. At the age of 29 months the child was rehospitalized for the last time for bronchitis. His weight, stature, and head circumference were below the 3rd percentile. He was severely mentally retarded with a psychomotor development corresponding to that of an infant of 2 3 months. A generalized hypertonia and repeated seizures were noted. Some months later the child was placed in an institution for the severely retarded, where he died in August 1975 at the age of 35 months. No autopsy was done.
Method and Material The cytogenetic examinations were done using lymphoeytes cultivated according to a modification of Moorhead's method (1960). One part of the metaphases obtained were colored with oreein and the other part were treated first with trypsin and then colored with a Giems~solution (Seabright, 1971) to obtain G bands. A chromosome analysis (Fig. 4) was done of the proband (IV-3), his father (III-3), mother (III-4), the twin sister (III-5), and the parents of the mother (II-4 and II-5). Analys~s were also performed on the miscarried embryo IV-4 and on the child IV-5.
Cytogenetie Findings The p r o b a n d (IV-3) presents a m o d a l n u m b e r of 2 N = 46 (Fig. 5). N o r m a l X a n d Y chromosomes confer to t h e i n f a n t a genetically well-defined sex, whereas t h e e x t e r n a l genital organs are m o r e female t h a n male. A l t h o u g h groups A, B, D, E, F, a n d G p r e s e n t no p a r t i c u l a r i t y , group C is r e m a r k a b l e in t h a t pair 9 reveals two different chromosomes. One (placed on t h e left in t h e k a r y o t y p e ) conforms to t h e n o r m a l (Paris Conference, 1971), t h e other, with a long a r m c o m p l e t e l y homologous to its p a r t n e r ' s , presents an a b n o r m a l l y d e v e l o p e d short a r m w i t h s u p p l e m e n t a r y m a t e r i a l a t its distal e x t r e m i t y . I t was possible to i d e n t i f y t h e n a t u r e of t h e s u p e r n u m e r a r y f r a g m e n t b y a s t u d y of t h e m a t e r n a l k a r y o t y p e . I n t h e m o t h e r (Fig. 6), in a d d i t i o n to t h e a s y m m e t r i c a l n i n t h p a i r identified in IV-3, t h e r e is a p a i r of h e t e r o m o r p h i e chromosomes consisting of elements of t h e 13th pair, one of which is n o r m a l a n d t h e o t h e r a m p u t a t e d a t t h e distal end of its long a r m (Fig. 7B). A reciprocal t r a n s l o c a t i o n has t a k e n place affecting t h e s h o r t a r m of one chromosome 9 a n d t h e long a r m of one chromosome 13 (Fig. 7A). W i t h a careful analysis of t h e G b a n d s it is possible to surmise t h a t t h e r u p t u r e zone (R) for chromosome 9 is l o c a t e d between b a n d s 9p13 a n d 9p22; for chromosome 13 this zone e x t e n d s from 13q14 to 13@2. The p r o b a n d ' s f a t h e r presents a n o r m a l k a r y o t y p e as well as t h e t w i n sister of I I I - 4 a n d t h e p a r e n t s of I I I - 4 . T h e fibroblasts coming from t h e culture of e m b r y o n i c f r a g m e n t s of IV-4 r e v e a l a female chromosome f o r m u l a in all w a y s identical to t h a t of t h e mother, 4 6 , X X , t (9 ; 13) (p21 ; q21). The i n t e r p r e t a t i o n of this result should be a p p r o a c h e d c a u t i o u s l y because it is impossible to exclude c o m p l e t e l y a c o n t a m i n a t i o n of t h e fetal cells b y elements of m a t e r n a l origin. Concerning IV-5, an amnioeentesis m a d e it possible to i d e n t i f y a fetus of t h e female sex possessing t h e b a l a n c e d m a t e r n a l transloeation, 4 6 , X X , t ( 9 ; 1 3 ) ( p 2 I ;
A New Case of Trisomy for the Distal Part of 13q
217
Fig. 5. Giemsx-banded karyotype of propositus, presenting a 9p + chromosome : 46,XY,der(9), t(9; 13) (p21 ;q21) mat
Fig. 6. Giemsa-banded karyotype of proband's mother: 46,XX,t(9; 13) (p21 ; q21)
218
M. Jotterand and E. Juillard
®
i31
I
2 3
9
13
F~
9
9 p+
13 q-
13
Fig. 7A and B. Schematic representation of realization of the (9;13) reciprocal translocation. (A) Chromosome pairs 9 and 13 and presumed breaking points (R) implied by translocation. (B) Chromosomes pairs 9 and 13 after translocation has taken place q21). This chromosome formula was confirmed b y a karyologic examination of the newborn's lymphocytes. Discussion The case of partiM trisomy 13 studied here can be added to one p a r t of Schinzel's table (1974), where this author compares the most recent clinical data concerning the total trisomy 13 and the partial trisomy 13 for the distal long arm (Table 1).
A New Case of Trisomy for the Distal Part of 13q
219
Table 1. Some of the main clinical features of: (A) total trisomy 13 (Taylor, 1968), (B) partial trisomy for the distal 1/3--2/3 of 13q (10 eases reported by Sehinzel, 1974), (C) partial trisomy for the distal 2/3 of 13q (1 case in Sehinzel, 1974), (D) partial trisomy for the distal 1/3 of 13q (original ease studied here)
Microeephaly Hemangiomes Long ineurved eyelashes Mierophtalmia Colobomata Low set and/or malformed ears Cleft lip/palate I-Iexadactyly Congenital heart defect Inguinal and/or umbilical hernia Respiratory distress p. partum Nuclear projections of neutrophils
Full trisomy 13 A
Partial trisomy of 13q
1/3--2/3 dist. 2/3 dist.
1/3 dist.
B
C
D
16/25 15/21
5/10 6/10 3/10 3/10 2/10 9/10 1/10 8/10 3/10 4/10 4/10 1/10
-+ + ----~-@ ---
,-]@ @ ? -,~-~? -+
19/25 6/18 23/25 18/26 19/25 19/26 10/25 25/27
A study of this table shows t h a t the partial trisomies for the distal 2/3 and for the distal 1/3 of 13q present common phenotypieal characteristics, the same as those which are the most frequent in total trisomy 13. As most of the eases described up to now, our patient presents microcephaly, hemangiomata on the forehead, occipital region, back and thorax, long ineurved eyelashes, strabismus, enlarged bridge of the nose, abnormally long philtrum, high-arched palate, low set ears, hexadactyly of the four extremities, umbilical and inguinal hernias, neonatal respiratory distress, and psychomotor retardation. In addition he presents a severe growth retardation, concerning which it would be interesting to consider Sehinzel's paper (1974), where he joins other writers in saying: "other features typical for full trisomy 13, such severe growth retardation, arhineneephaly, microphtMmia, colobomata, cleft lip and/or palate and hyperconvex fingernails are rarely found in cases of partial trisomy 13q." Although in cases 1 and 3 studied b y Schinzel, the first died too young (at 3 months) for an eventual growth retardation to be verified and the third presented a relatively normal growth, ease 2 nevertheless resembles our patient. His weight and height values, inferior to the third percentile, attest to a certain statural retardation. Finally the proband presents two particular signs, a male pseudohermaphroditism and a trigonoeephaly. As the ambiguity and the malformations of the external genital organs are associated with m a n y different chromosome mutations, it is impossible to consider these traits as a criterion for the definition of partial trisomy 13. Concerning trigonocephaly, it would be of interest to review literature about partial trisomy for the distal long arm of chromosome 13. In 1964, Stalder described a ease of translocation implicating one chromosome of group D. This patient presented a mierocephaly and a particular wide anterior fontanelle but no trigonocephaly or anomaly of the frontal region. Yunis et al.
220
M. Jotterand and E. Juillard
(1966) reported the case of 2 patients carrying a supplementary chromosome. Because of the clinical signs of the patients--according to Yunis affected with a [orme ]ruste of trisomy D 1 s y n d r o m e - - and the results of autoradiography, the supplementary elements were tentatively identified as part of group D. Case B of Yunis is not of interest here because it deals with trisomy D for the proximal part of the long arm. However, case A, trisomic for the distal 4/5 of 13q presented a brachycephalic skull. I n addition a patient with partial trisomy D of proximal type (first described by Macintyre, 1964) was compared to patients A and B. Bloom and Gerald (1968) in their study of the localization of genes on chromosome 13, related 2 new cases. Patient 1 was trisomic for proximal part of 13q, whereas Patient 2 had a particular chromosome formula revealing an association of a translocation (2 ; 13) and an unequal crossing-over which resulted in a partial trisomy of the distal end of 13q. These findings were further supported by the extremely low rate of fetal hemoglobin and absence of nuclear projection of neutrophils. Hereupon ¥unis et al. in the paper discussed above tentatively localized on D 1 the loci responsible for the determination of two characteristics typical of trisomy D, the elevated level of fetal hemoglobin, and the increased neutrophil nuclear projections (Huehns et al., 1963, 1964; Hecht et al., 1964). Concerning the skull, Patient 2 of Bloom and Gerald presented a microcephaly without other malformations. I n 1968, Broholm published a complex case of chromosome aberration of group D in a young girl. The proband presented clinical signs suggesting Cornelia de Lange syndrome. No trigonoeephaly was noted. Rosenkranz et al. (1972) wrote about an infant with unbalanced D/E translocation. There was no cephalic particularity other than a head circumference of 33 cm at birth and an anterior fontanelle wider than normal. I n 1972 as well, Surana et al. on the one hand, and Hauksdottir et al. on the other hand, described two types of partial trisomies deriving from pericentric inversions of chromosome 13. Surana's patient had no frontal bossing. Hauksdottir examined a large family of which two members carried a chromosome anomaly consisting of an inversion associated with a duplication deficiency. Neither of these two children possessed a prominent forehead. Taysi (1973) described a third case of pericentrie inversion of chromosome 13 with duplication deficiency resulting in a 1/2 distal trisomy 13. For the first time in the study of partial trisomy 13, a trigonocephaly with bilaterally depressed temporal regions was found. A partial trisomy for the distal 1/3 of 13q translocated on chromosome 21 was the object of study for Talvik et al. (1974), who described the proband as microcephalic and trigonocephalie. Schinzel (1974) related 2 cases, one of which was trisomic for the distal 2/3 of 13q. This subject presented no dyscephaly. Escobar (1974) observed characteristic signs of trisomy 13 plus a trigonocephaly in a child with a trisomy for the distal 1/3 of 13% Also in 1974, Stoll et al. conducted a study which concerned a trisomy for the distal 2/3 of 13q due to translocation (3;13), the carrier of which had a mierocephaly with a [font ]uyant. Recently, the same author (Stoll et al., 1976) had the occasion to observe an unusual partial trisomy 13 due to the presence of an abnormal 13p + chromosome. The short arms of this abnormal element contained the q2 and q3 bands of the
A New Case of Trisomy for the Distal Part of 13q
221
long arm of another chromosome 13. The patient was a black male with a small and narrow forehead. There was no further description concerning the presence of an eventual trigonocephaly. Finally Majewski (pers. comm.) observed a case of partial trisomy 13, 46,XX, t (9 ; 13) (p22 ; q14) very similar to the original ease studied here. Majewski's patient presented a pronounced trigonocephaly. To conclude, out of 16 subjects with 13q distal trisomy reported here, 5 shouted evidence of trigonocephaly. The question is raised as to whether the presence of this particular trait constitutes a criterion for distinguishing total trisomy 13 from partial trisomy 13. To this end, the s t u d y of the importance of the trisomic segment length in the 5 eases cited above would be of interest. 1. 2. 3. 4. 5.
Taysi Escobar Talvik Majewski original case
partial partial partial partial partial
trisomy trisomy trisomy trisomy trisomy
for for for for for
the the the the the
distal distal distal distal distal
1/2 of 1/3 1/3 1/3 1/3
of of of of
13q, 13% 13q, 13q, 13%
Although examination of these results suggests the existence of a relationship between the presence of trigonocephaly and trisomy for the distal 1/3 or the distal 1/2 of 13q, it is not possible to conclude t h a t the frontal bossing constitutes a characteristic sign of partial trisomy 13. Furthermore Stalder, Broholm, and I~osenkranz, a m o n g others, observed several eases of partial trisomy 13 in which the subjects did not present this cephalic malformation. References
Bloom, G. E., Gerald, P. S. : Localization of genes on chromosome 13: analysis of two kindreds. Amer. J. hum. Genet. 20, 495--511 (1968) Broholm, K.-A., Eeg-Olofson, 0., Hall, B. : An inherited chromosome aberration in a girl with signs of de Lange syndrome. Acta paediat, scand. 57, 547--552 (1968) Escobar, J. I., Sanchez, 0., Yunis, J. J. : Trisomy for the distal segment of chromosome 13. Amer. J. Dis. Child. 128, 217--220 (1974) Hauksdottir, H., tIalldorsson, S., Jensson, 0., Mikkelsen, M., McDermott, A. : Pericentric inversion of chromosome No. 13 in a large family leading to duplication deficiency causing congenital malformations in three individuals. J. reed. Genet. 9, 413--421 (1972) Hecht, F., Huehns, E. P~., Lutzner, M. : Nuclear abnormalities of neutrophils in the D 1 trisomy syndrome, abstracted. J. Pedlar. 65, 1089 (1964) Huehns, E. R., Hecht, F., Keil, J. V., Motulsky, A. G. : Developmental hemoglobin anomalies in a chromosomal triplication: ])1 trisomy syndrome. Proc. nat. Acad. Sci (Wash.) 51, 89 (1963) Huehns, E. R., Lutzner, M., Hecht, F. : Nuclear abnormalities of the neutrophils in ])1 (13--15)trisomy syndrome. Lancet 1964 I, 589 Macintyre, M. N., Staples, W. I., LaPolla, J. J.- Partial D 1 trisomy in a child whose mother and maternal grandmother demonstrate a D/F tr~nslocation, abstracted. Amer. Soc. hum. Genet 21 (1964) Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. : Chromosome preparations of leukocytes cultured from peripheral blood. Exp. Cell Res. 20, 613 (1960) l~osenkranz, W., Kaloud, H.: Nicht balanzierte D/E-Translokation. Pi~diat. u. Pi~dol. 7, 377--379 (1972) Schinzel, A., Schmid, W., Mfirset, G. : Different forms of incomplete trisomy 13. Mosaicism and partial trisomy for the proximal and distal long arm. tIumangenetik 22, 287--298 (1974)
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Seabright, M. : Rapid banding technique for human chromosomes. Lancet 1971 lI, 971 Stalder, G. R., Biihler, E. ~ . , Gadola, G., Widmer, 1~., Freuler, F. : A family with balanced D1--C s translocation carriers and unbalanced offspring. Humangenetik 1, 197--200 (1964) Stoll, C., Halb, A. : Trisomie 13 partielle par translocation 46, XX, t (3 ; 13) (p 26; q 21) materhelle. Pediatrie XXIX, 725--729 (1974) Stoll, C., Messer, J., Weitzenblum, S., Warter, S. : An unusual partial trisomy 13. Clin. Genet. 9, 1--5 (1976) Surana, 1~. B., Conen, P. E. : Inherited pericentric inversion of a group D (13--15) chromosome. J. med. Genet. 9, 105--110 (1972) Talvik, T., Mikelsaar, A.-V., Mikelsaar, R., K~osaar, M., Tfiiir, S.: Inherited translocations in two families (t(14q-[- ;10q-) and t(13q-;21q+). Humangenetik 19, 215--226 (1973) Taylor, A. I. : Autosomal trisomy syndromes : a detailed study of 27 cases of Edward's and 27 cases of Patau's syndrome. J. reed. Genet. 5, 227--252 (1968) Taysi, K., Bobrow, M., Balci, S., Madan, K., Atasu, M., Say, B. : Duplication/deficiency product of a pericentric inversion in man: a cause of D 1 trisomy syndrome. J. Pediat. 82, 263--268 (1973) Yunis, J. J., Hook, E. B. : Desoxyribonucleic acid replication and mapping of the D 1 chromosome. Amer. J. Dis. Child. 3, 83--89 (1966) Dr. M. Jotterand-Bellomo H6pital Cantonal Universitaire Div. autonome de g@n~tique m~dicale Ctt-1011 Lausanne, Suisse
Original Investigations A New Case of Trisomy for tile Distal Part of 13q Due to Maternal Translocation, t(9; 13)(p21 ;q21) M. J o t t e r a n d a n d E. J u i l l a r d Division de G6n6tique 16dicale, Centre Hospitalier Universitaire Vaudois, Lausanne (Suisse) Received April 26, 1976
Summary. The first child of a mother with a balanced translocation (9;13) revealed a trisomy for the distal third of 13q. Clinical signs were microcephaly, hemangiomata, tong incurred eyelashes, strabismus, enlarged bridge of the nose, abnormally long philtrum, higharched palate, low set ears, hexadactyly of the four extremities, umbilical and inguinal hernias, neonatal respiratory distress, psychomotor and growth retardation. The proband presented also male pseudohermaphroditism and trigonocephaly. This last trait is the object of a discussion in which cases of partial trisomy 13q cited in the literature are considered for study of the incidence of this dyscephaly in this particular syndrome. I~eeently it was possible to observe a new case of p a r t i a l t r i s o m y 13 affecting t h e d i s t a l t h i r d p o r t i o n of 13q. The p r e s e n t r e p o r t describes t h e p a t i e n t a n d his
Fig. 1. The proband's face Fig. 2. The proband's profile
214
lg. Jotterand and E. JuilIard
Fig. 3. The proband: external genital organs
f a m i l y as well as a r e l a t i v e l y c o m p l e t e c y t o g e n e t i c s t u d y of t h e a n o m a l y , its origin, a n d m o d e o f t r a n s m i s s i o n .
Case Report Family History. The pedigree (Fig. 4) shows a consanguinity between paternal and maternal families. The proband's mother (III-4) has a dizygotic twin sister (IIL5). In the same family there is a second set of dizygotic twins (III-7 and III-8). One twin of the latter set died at the age of 1 month of a cardiac malformation. At the proband's birth his father (III-3) and his mother (III-4) were 24 and 22 years old, respectively. Both are mentally and phenotypically normal. Three years later the mother had a miscarriage in the 14th week of pregnancy. At that time it was possible to do a karyotype of the miscarried embryo; the results will be commented on later. Several months later, at the end of 1974, the mother was pregnant again and an amnioeentesis was done on February 12, 1975. A phenotypically normal daughter (IV-5) was born on July 14, 1975. The karyotypes of the amniotic cells and of the daughter will also be presented later. No other particular signs are noted in the family history. Patient's History. On August 25, 1971, the propositus was born by cesarian section in the 37th week of gestation. The operation was required because of hypertension and albuminuria in the 36th week of pregnancy. At birth the child weighed 3130 g (50th--75th percentile), measured 48.5 em (50th~75th percentile), and the head circumference was 34 cm (75th percentile). One hour and 40 rain after birth, he was transferred from the Maternit6 to the Cliniquc Infantile because of a cyanotic and tachypneic state and multiple malformations. A symptomatic hypoglycemia appeared in the first hours of life and proved difficult to correct. The infant presented numerous particular clinical signs. The head showed the following: trigonoeephaly, hypotelorism, palpebr~l ptosis, long ineurved eyelashes, synophrys, enlarge-
A New Case of Trisomy for the Distal P a r t of 13q
215
I
I III
/3
IV
[] normal []
caryotype
not examined
(~ 4 6 j x x j t (13)9)(q21)p21) • •
461XYj der (9) t (13)9)(q 21~p2 I) mat spont, abort.
Fig. 4. Pedigree of proband's family m e n t of the bridge of the nose, long philtrum, maerostomia, high-arched palate, missing uvula, low set ears, and short neck. Cardiac auscultation revealed a mesoeardiae 3/6 systolic murmur. There was hexadactyly of the four extremities. The big toes were in dorsal flexion. A n umbilical hernia and two inguinal hernias were noted. The two small mobile masses (each with a diameter of nearly 1 era), felt in the inguinal folds, appeared to be testicles in retention. The external genital organs were ambiguous. The child h a d a clitoris in the f o r m of a penis with a false meatus at its extremity. The real urethral meatus was found at the base of the clitoris. The v u l v a had a normal aspect. The skin presented hemangiomata on the forehead, the occipital region, the back, and the thorax. A urograph revealed no urinary t r a c t anomalies. A radiologie examination of the urogenital region produced evidence of a well-developed vaginal cavity and bifid uterus. A n audiogram raised the question of diminished hearing capacity (Dr. de Reynier). The buecal smear was negative. The dermatoglyphie examinations showed bilaterally simian creases. A detailed analysis of the karyotype will be given later. Evolution o/the Case. A t the age of 4 months, the infant was rehospitalized to t r e a t his bilateral inguinal hernias. The operation revealed in the right inguinal canal one ovarianlike gonad, and a very short fallopian tube of normal configuration with normal vessels. I n the left inguinal canal there were two gonads. One gonad was large and testielelike b u t of fibrous consistency; the other was smaller, infarcted, and h a d in front of it a fallopian tube with normal vessels. A histologic examination of the gonads showed, on the right, immature testicular tissue. On the left, the larger gonad revealed only flbro-adipous tissue, without proof of being either a testicle or an ovary; the smaller consisted of immature testieular tissue with the presence of several Sertoli cells and the absence of Leydig cells. A t the age of 7 months, the child was rehospitalized to t r e a t his hexadactyly. At the same time a significant growth retardation was noted. The head circumference, which h a d been
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M. Jotterand and E. Juillard
at the 75th percentile at birth was now at the 25th percentile. There was also severe psychomotor retardation. An EEG, recorded at this time, raised the question of epilepsy. At the age of 25 months, the infant was rehospitalized for bronchitis. At that time his stature was in the 10th--25th percentile, his weight in the 3rd percentile. At the age of 29 months the child was rehospitalized for the last time for bronchitis. His weight, stature, and head circumference were below the 3rd percentile. He was severely mentally retarded with a psychomotor development corresponding to that of an infant of 2 3 months. A generalized hypertonia and repeated seizures were noted. Some months later the child was placed in an institution for the severely retarded, where he died in August 1975 at the age of 35 months. No autopsy was done.
Method and Material The cytogenetic examinations were done using lymphoeytes cultivated according to a modification of Moorhead's method (1960). One part of the metaphases obtained were colored with oreein and the other part were treated first with trypsin and then colored with a Giems~solution (Seabright, 1971) to obtain G bands. A chromosome analysis (Fig. 4) was done of the proband (IV-3), his father (III-3), mother (III-4), the twin sister (III-5), and the parents of the mother (II-4 and II-5). Analys~s were also performed on the miscarried embryo IV-4 and on the child IV-5.
Cytogenetie Findings The p r o b a n d (IV-3) presents a m o d a l n u m b e r of 2 N = 46 (Fig. 5). N o r m a l X a n d Y chromosomes confer to t h e i n f a n t a genetically well-defined sex, whereas t h e e x t e r n a l genital organs are m o r e female t h a n male. A l t h o u g h groups A, B, D, E, F, a n d G p r e s e n t no p a r t i c u l a r i t y , group C is r e m a r k a b l e in t h a t pair 9 reveals two different chromosomes. One (placed on t h e left in t h e k a r y o t y p e ) conforms to t h e n o r m a l (Paris Conference, 1971), t h e other, with a long a r m c o m p l e t e l y homologous to its p a r t n e r ' s , presents an a b n o r m a l l y d e v e l o p e d short a r m w i t h s u p p l e m e n t a r y m a t e r i a l a t its distal e x t r e m i t y . I t was possible to i d e n t i f y t h e n a t u r e of t h e s u p e r n u m e r a r y f r a g m e n t b y a s t u d y of t h e m a t e r n a l k a r y o t y p e . I n t h e m o t h e r (Fig. 6), in a d d i t i o n to t h e a s y m m e t r i c a l n i n t h p a i r identified in IV-3, t h e r e is a p a i r of h e t e r o m o r p h i e chromosomes consisting of elements of t h e 13th pair, one of which is n o r m a l a n d t h e o t h e r a m p u t a t e d a t t h e distal end of its long a r m (Fig. 7B). A reciprocal t r a n s l o c a t i o n has t a k e n place affecting t h e s h o r t a r m of one chromosome 9 a n d t h e long a r m of one chromosome 13 (Fig. 7A). W i t h a careful analysis of t h e G b a n d s it is possible to surmise t h a t t h e r u p t u r e zone (R) for chromosome 9 is l o c a t e d between b a n d s 9p13 a n d 9p22; for chromosome 13 this zone e x t e n d s from 13q14 to 13@2. The p r o b a n d ' s f a t h e r presents a n o r m a l k a r y o t y p e as well as t h e t w i n sister of I I I - 4 a n d t h e p a r e n t s of I I I - 4 . T h e fibroblasts coming from t h e culture of e m b r y o n i c f r a g m e n t s of IV-4 r e v e a l a female chromosome f o r m u l a in all w a y s identical to t h a t of t h e mother, 4 6 , X X , t (9 ; 13) (p21 ; q21). The i n t e r p r e t a t i o n of this result should be a p p r o a c h e d c a u t i o u s l y because it is impossible to exclude c o m p l e t e l y a c o n t a m i n a t i o n of t h e fetal cells b y elements of m a t e r n a l origin. Concerning IV-5, an amnioeentesis m a d e it possible to i d e n t i f y a fetus of t h e female sex possessing t h e b a l a n c e d m a t e r n a l transloeation, 4 6 , X X , t ( 9 ; 1 3 ) ( p 2 I ;
A New Case of Trisomy for the Distal Part of 13q
217
Fig. 5. Giemsx-banded karyotype of propositus, presenting a 9p + chromosome : 46,XY,der(9), t(9; 13) (p21 ;q21) mat
Fig. 6. Giemsa-banded karyotype of proband's mother: 46,XX,t(9; 13) (p21 ; q21)
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M. Jotterand and E. Juillard
®
i31
I
2 3
9
13
F~
9
9 p+
13 q-
13
Fig. 7A and B. Schematic representation of realization of the (9;13) reciprocal translocation. (A) Chromosome pairs 9 and 13 and presumed breaking points (R) implied by translocation. (B) Chromosomes pairs 9 and 13 after translocation has taken place q21). This chromosome formula was confirmed b y a karyologic examination of the newborn's lymphocytes. Discussion The case of partiM trisomy 13 studied here can be added to one p a r t of Schinzel's table (1974), where this author compares the most recent clinical data concerning the total trisomy 13 and the partial trisomy 13 for the distal long arm (Table 1).
A New Case of Trisomy for the Distal Part of 13q
219
Table 1. Some of the main clinical features of: (A) total trisomy 13 (Taylor, 1968), (B) partial trisomy for the distal 1/3--2/3 of 13q (10 eases reported by Sehinzel, 1974), (C) partial trisomy for the distal 2/3 of 13q (1 case in Sehinzel, 1974), (D) partial trisomy for the distal 1/3 of 13q (original ease studied here)
Microeephaly Hemangiomes Long ineurved eyelashes Mierophtalmia Colobomata Low set and/or malformed ears Cleft lip/palate I-Iexadactyly Congenital heart defect Inguinal and/or umbilical hernia Respiratory distress p. partum Nuclear projections of neutrophils
Full trisomy 13 A
Partial trisomy of 13q
1/3--2/3 dist. 2/3 dist.
1/3 dist.
B
C
D
16/25 15/21
5/10 6/10 3/10 3/10 2/10 9/10 1/10 8/10 3/10 4/10 4/10 1/10
-+ + ----~-@ ---
,-]@ @ ? -,~-~? -+
19/25 6/18 23/25 18/26 19/25 19/26 10/25 25/27
A study of this table shows t h a t the partial trisomies for the distal 2/3 and for the distal 1/3 of 13q present common phenotypieal characteristics, the same as those which are the most frequent in total trisomy 13. As most of the eases described up to now, our patient presents microcephaly, hemangiomata on the forehead, occipital region, back and thorax, long ineurved eyelashes, strabismus, enlarged bridge of the nose, abnormally long philtrum, high-arched palate, low set ears, hexadactyly of the four extremities, umbilical and inguinal hernias, neonatal respiratory distress, and psychomotor retardation. In addition he presents a severe growth retardation, concerning which it would be interesting to consider Sehinzel's paper (1974), where he joins other writers in saying: "other features typical for full trisomy 13, such severe growth retardation, arhineneephaly, microphtMmia, colobomata, cleft lip and/or palate and hyperconvex fingernails are rarely found in cases of partial trisomy 13q." Although in cases 1 and 3 studied b y Schinzel, the first died too young (at 3 months) for an eventual growth retardation to be verified and the third presented a relatively normal growth, ease 2 nevertheless resembles our patient. His weight and height values, inferior to the third percentile, attest to a certain statural retardation. Finally the proband presents two particular signs, a male pseudohermaphroditism and a trigonoeephaly. As the ambiguity and the malformations of the external genital organs are associated with m a n y different chromosome mutations, it is impossible to consider these traits as a criterion for the definition of partial trisomy 13. Concerning trigonocephaly, it would be of interest to review literature about partial trisomy for the distal long arm of chromosome 13. In 1964, Stalder described a ease of translocation implicating one chromosome of group D. This patient presented a mierocephaly and a particular wide anterior fontanelle but no trigonocephaly or anomaly of the frontal region. Yunis et al.
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M. Jotterand and E. Juillard
(1966) reported the case of 2 patients carrying a supplementary chromosome. Because of the clinical signs of the patients--according to Yunis affected with a [orme ]ruste of trisomy D 1 s y n d r o m e - - and the results of autoradiography, the supplementary elements were tentatively identified as part of group D. Case B of Yunis is not of interest here because it deals with trisomy D for the proximal part of the long arm. However, case A, trisomic for the distal 4/5 of 13q presented a brachycephalic skull. I n addition a patient with partial trisomy D of proximal type (first described by Macintyre, 1964) was compared to patients A and B. Bloom and Gerald (1968) in their study of the localization of genes on chromosome 13, related 2 new cases. Patient 1 was trisomic for proximal part of 13q, whereas Patient 2 had a particular chromosome formula revealing an association of a translocation (2 ; 13) and an unequal crossing-over which resulted in a partial trisomy of the distal end of 13q. These findings were further supported by the extremely low rate of fetal hemoglobin and absence of nuclear projection of neutrophils. Hereupon ¥unis et al. in the paper discussed above tentatively localized on D 1 the loci responsible for the determination of two characteristics typical of trisomy D, the elevated level of fetal hemoglobin, and the increased neutrophil nuclear projections (Huehns et al., 1963, 1964; Hecht et al., 1964). Concerning the skull, Patient 2 of Bloom and Gerald presented a microcephaly without other malformations. I n 1968, Broholm published a complex case of chromosome aberration of group D in a young girl. The proband presented clinical signs suggesting Cornelia de Lange syndrome. No trigonoeephaly was noted. Rosenkranz et al. (1972) wrote about an infant with unbalanced D/E translocation. There was no cephalic particularity other than a head circumference of 33 cm at birth and an anterior fontanelle wider than normal. I n 1972 as well, Surana et al. on the one hand, and Hauksdottir et al. on the other hand, described two types of partial trisomies deriving from pericentric inversions of chromosome 13. Surana's patient had no frontal bossing. Hauksdottir examined a large family of which two members carried a chromosome anomaly consisting of an inversion associated with a duplication deficiency. Neither of these two children possessed a prominent forehead. Taysi (1973) described a third case of pericentrie inversion of chromosome 13 with duplication deficiency resulting in a 1/2 distal trisomy 13. For the first time in the study of partial trisomy 13, a trigonocephaly with bilaterally depressed temporal regions was found. A partial trisomy for the distal 1/3 of 13q translocated on chromosome 21 was the object of study for Talvik et al. (1974), who described the proband as microcephalic and trigonocephalie. Schinzel (1974) related 2 cases, one of which was trisomic for the distal 2/3 of 13q. This subject presented no dyscephaly. Escobar (1974) observed characteristic signs of trisomy 13 plus a trigonocephaly in a child with a trisomy for the distal 1/3 of 13% Also in 1974, Stoll et al. conducted a study which concerned a trisomy for the distal 2/3 of 13q due to translocation (3;13), the carrier of which had a mierocephaly with a [font ]uyant. Recently, the same author (Stoll et al., 1976) had the occasion to observe an unusual partial trisomy 13 due to the presence of an abnormal 13p + chromosome. The short arms of this abnormal element contained the q2 and q3 bands of the
A New Case of Trisomy for the Distal Part of 13q
221
long arm of another chromosome 13. The patient was a black male with a small and narrow forehead. There was no further description concerning the presence of an eventual trigonocephaly. Finally Majewski (pers. comm.) observed a case of partial trisomy 13, 46,XX, t (9 ; 13) (p22 ; q14) very similar to the original ease studied here. Majewski's patient presented a pronounced trigonocephaly. To conclude, out of 16 subjects with 13q distal trisomy reported here, 5 shouted evidence of trigonocephaly. The question is raised as to whether the presence of this particular trait constitutes a criterion for distinguishing total trisomy 13 from partial trisomy 13. To this end, the s t u d y of the importance of the trisomic segment length in the 5 eases cited above would be of interest. 1. 2. 3. 4. 5.
Taysi Escobar Talvik Majewski original case
partial partial partial partial partial
trisomy trisomy trisomy trisomy trisomy
for for for for for
the the the the the
distal distal distal distal distal
1/2 of 1/3 1/3 1/3 1/3
of of of of
13q, 13% 13q, 13q, 13%
Although examination of these results suggests the existence of a relationship between the presence of trigonocephaly and trisomy for the distal 1/3 or the distal 1/2 of 13q, it is not possible to conclude t h a t the frontal bossing constitutes a characteristic sign of partial trisomy 13. Furthermore Stalder, Broholm, and I~osenkranz, a m o n g others, observed several eases of partial trisomy 13 in which the subjects did not present this cephalic malformation. References
Bloom, G. E., Gerald, P. S. : Localization of genes on chromosome 13: analysis of two kindreds. Amer. J. hum. Genet. 20, 495--511 (1968) Broholm, K.-A., Eeg-Olofson, 0., Hall, B. : An inherited chromosome aberration in a girl with signs of de Lange syndrome. Acta paediat, scand. 57, 547--552 (1968) Escobar, J. I., Sanchez, 0., Yunis, J. J. : Trisomy for the distal segment of chromosome 13. Amer. J. Dis. Child. 128, 217--220 (1974) Hauksdottir, H., tIalldorsson, S., Jensson, 0., Mikkelsen, M., McDermott, A. : Pericentric inversion of chromosome No. 13 in a large family leading to duplication deficiency causing congenital malformations in three individuals. J. reed. Genet. 9, 413--421 (1972) Hecht, F., Huehns, E. P~., Lutzner, M. : Nuclear abnormalities of neutrophils in the D 1 trisomy syndrome, abstracted. J. Pedlar. 65, 1089 (1964) Huehns, E. R., Hecht, F., Keil, J. V., Motulsky, A. G. : Developmental hemoglobin anomalies in a chromosomal triplication: ])1 trisomy syndrome. Proc. nat. Acad. Sci (Wash.) 51, 89 (1963) Huehns, E. R., Lutzner, M., Hecht, F. : Nuclear abnormalities of the neutrophils in ])1 (13--15)trisomy syndrome. Lancet 1964 I, 589 Macintyre, M. N., Staples, W. I., LaPolla, J. J.- Partial D 1 trisomy in a child whose mother and maternal grandmother demonstrate a D/F tr~nslocation, abstracted. Amer. Soc. hum. Genet 21 (1964) Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. : Chromosome preparations of leukocytes cultured from peripheral blood. Exp. Cell Res. 20, 613 (1960) l~osenkranz, W., Kaloud, H.: Nicht balanzierte D/E-Translokation. Pi~diat. u. Pi~dol. 7, 377--379 (1972) Schinzel, A., Schmid, W., Mfirset, G. : Different forms of incomplete trisomy 13. Mosaicism and partial trisomy for the proximal and distal long arm. tIumangenetik 22, 287--298 (1974)
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Seabright, M. : Rapid banding technique for human chromosomes. Lancet 1971 lI, 971 Stalder, G. R., Biihler, E. ~ . , Gadola, G., Widmer, 1~., Freuler, F. : A family with balanced D1--C s translocation carriers and unbalanced offspring. Humangenetik 1, 197--200 (1964) Stoll, C., Halb, A. : Trisomie 13 partielle par translocation 46, XX, t (3 ; 13) (p 26; q 21) materhelle. Pediatrie XXIX, 725--729 (1974) Stoll, C., Messer, J., Weitzenblum, S., Warter, S. : An unusual partial trisomy 13. Clin. Genet. 9, 1--5 (1976) Surana, 1~. B., Conen, P. E. : Inherited pericentric inversion of a group D (13--15) chromosome. J. med. Genet. 9, 105--110 (1972) Talvik, T., Mikelsaar, A.-V., Mikelsaar, R., K~osaar, M., Tfiiir, S.: Inherited translocations in two families (t(14q-[- ;10q-) and t(13q-;21q+). Humangenetik 19, 215--226 (1973) Taylor, A. I. : Autosomal trisomy syndromes : a detailed study of 27 cases of Edward's and 27 cases of Patau's syndrome. J. reed. Genet. 5, 227--252 (1968) Taysi, K., Bobrow, M., Balci, S., Madan, K., Atasu, M., Say, B. : Duplication/deficiency product of a pericentric inversion in man: a cause of D 1 trisomy syndrome. J. Pediat. 82, 263--268 (1973) Yunis, J. J., Hook, E. B. : Desoxyribonucleic acid replication and mapping of the D 1 chromosome. Amer. J. Dis. Child. 3, 83--89 (1966) Dr. M. Jotterand-Bellomo H6pital Cantonal Universitaire Div. autonome de g@n~tique m~dicale Ctt-1011 Lausanne, Suisse
