Humangenetik 29, 233--241 (1975) © by Springer-Verlag 1975

Partial Trisomy 9q: A New Syndrome C a t h e r i n e T u r l e a u ~, J . de G r o u c h y 1, F r a n ~ o i s e C h a v i n - C o l i n ~, Miehelle l%oubin ~, P. E . B r i s s a u d 2, G. l~epess62, A n n e S a f a r a, a n d P. B o r n i c h e s 1HSpital des Enfants Malades, Paris, France, ~H6pital Trousseau, Paris, France, aHSpital Saint-Vincent-de-Paul, Paris, France Received May 9, 1975

Summa'ry. Two unrelated patients with a strikingly similar phenotype (low birth weight and poor thriving; mental retardation; dolichocephaly; beaked nose; deeply set eyes; prominent maxilla and receding small chin; long fingers with a peculiar clench) were partially trisomie for two different segments of 9q. The segment found to be trisomic in both patients is small and corresponds to the q31 q32 region. This new syndrome is compared to observations of trisomy 9 reported in the literature.

Introduction T w o u n r e l a t e d p a t i e n t s w i t h a s t r i k i n g l y s i m i l a r clinical p i c t u r e , allow t h e d e l i n e a t i o n of a n e w s y n d r o m e d u e t o t r i s o m y of a v e r y s h o r t s e g m e n t of 9q, t h e q 3 1 q 3 2 region. Case R e p o r t s

Case 1. The patient (obs. No. 5031), a male, was born on April 22, 1970, after a normal 40-week pregnancy. I-Iis mother, a physiotherapist, was 28 years old. She took oral contraceptives from July 1967 to the end of 1969. The baby was conceived 6 months later. The father, a geophysicist, was 29 years old. A normal brother was born on February 25, 1963. There was no miscarriage. The child's weight at birth was 2300 g, his length 50 cm, his head circumference 32.5 cm, and his chest perimeter 29 cm. Apgar was 10 at 1 rain. Cyanosis was noted at 6 days and congenital heart disease was diagnosed (I.V. septal defect). At 6 weeks he underwent surgery for a pyloric stenosis. Psychomotor development was slow: the child smiled at 2 months, and recognized his mother at 5 months. A test performed at 12 months was hampered by important motor disorders, poor vision (myopia and strabismus), and atrophy of the palate and uvula. I-Iis I.Q. was estimated at 55--60. ~Then last seen, at 4 10/12 years, the patient had deteriotated considerably. He was agitated (although he never had convulsions), with stereotyped movements of the hands. He did not walk nor speak. He was aggressive and tyrannical He measured 99 cm and weighed 15 kg. Craniofacial dysmorphia included microcephaly (head circumference : 42 cm at 13 months and 47 cm at 4 10/12 years) and dolichocephaly; hypotelorism (20/70 ram), bilateral epicanthaI folds, convergent strabismus, beaked nose with a well indicated nasofrontal angle, a small and well designed mouth with a short upper lip, a small and triangular chin and well formed and normally set ears. The fingers were long with a very peculiar position; they were clutched over the thumb and the index overlaped the other fingers. Toes were long with an abnormal implantation. The external genitalia were normal (Fig. 1). The child suffered from continuous diarrhea and vomiting.

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Fig, 1 a and b. The patients phenotypes. (a) First patient. (b) Second patient

Partial Trisomy 9q: A New Syndrome

235

X-rays of the skeleton, gazeous encephalography, and chromatography of urinary aminoacids were normal. The I.V. defect healed spontaneously. Blood grouping of the patient and his parents showed no abnormal transmission (Table 1). Blood dotting factors were within normal values. Case 2. The patient (obs. No. 6885) was born on August 21, 1974, after a 41-week pregnancy (last menses on October 31, 1973). The mother was 22 years old. She took oral contraceptives for 1 year from July 1972 until July 1973. She had an induced abortion in 1970. The father, a police officer, was 31 years old. The child's weight at birth was 2760 g, his length 48 em, his head circumference 36 era, and chest circumference 35 era. Apgar was 7 at 1 and 10 at 5 rain. The baby was brought to hospital at 2 months of age because of slow thriving (3060 g at 3 weeks) and infection. At 5 months she weighed 4700 g, measured 64 era, and her head circumference was 42 era. She was hypotonie. She held her head up and smiled. The main features included dolichoeephMy and protruding forehead (but no microcephaly), narrow horizontal palpebral fissures with deeply set eye sockets, very slight hypotelorism (25/77), absence of epieanthal folds, a beaked nose and a well indicated nasofrontal angle, a sm~I1 but well designed mouth, a long upper lip with prominent pillars of the philtrum, a small pointed chin with retrognathia and large, round, and low set ears. The fingers were long and clenched over the thumb, the index overlapping the other fingers and the nails were triangular with a narrow base. The toes were long and abnormally implanted. The external genitalia were normal (Fig. 1). X-rays of the skeleton revealed 13 dorsal vertebrae and 13 ribs on the left. E,C.G. and I.V.U. were normal. Blood grouping showed no abnormal transmission of blood factors (Table 1).

eytogenetie Studies Chromosome studies were done from leucocyte cultures. The following b a n d i n g techniques were applied: g b a n d s (Dutrillaux a n d Lejeune, 1971), G b a n d s (Finaz a n d Grouchy, 1972), C b a n d s (Yunis et al., 1971), T b a n d s (Dutrillaux, 1973), Q b a n d s (Caspersson et al., 1970), ehromatid identification (Latt, 1974; D u t r i l l a u x , 1975).

Case 1. C o n v e n t i o n a l s t a i n i n g first showed, in 1971, t h a t the propositus had 46 chromosomes, with only one n o r m a l 9 recognizable b y its secondary constriction. The second 9 was replaced b y a large chromosome a p p r o x i m a t e l y the size of a B, with two secondary constrictions, one j u x t a e e n t r o m e r i e , the other a p p a r e n t l y larger a n d located in the middle of the long arm (Fig. 2). I t was t h e n concluded t h a t this chromosome resulted from a " t a n d e m " duplication of 9q. This hypothesis was confirmed b y Q b a n d i n g a n d later b y R, G, C, a n d T b a n d i n g techniques which further d e m o n s t r a t e d t h a t the resulting t r i s o m y 9q is in fact incomplete. The distal p a r t of the chromosome corresponds to a n entire 9q. The proximal p a r t corresponds to 9q with a t e r m i n a l deletion as from q33. The p a t i e n t is therefore trisomie for the q l l q 3 3 segment: 46,XY,dup(9) ( q l l q 3 3 ) d i r . C b a n d i n g showed a n u n u s u a l aspect of the distal secondary constriction which is longer t h a n the proximal one a n d has a n a r r o w i n g in its middle (a constriction of the constriction), the entire chromosome t h u s appearing to be dicentrie. The ehromatid identification m e t h o d showed t h a t the existence of the extra secondary constriction in the middle of the long arm does n o t induce chromatid exchange at t h a t level. The k a r y o t y p e s of b o t h p a r e n t s a n d of the p a t i e n t ' s b r o t h e r were normal.

C. Turleau et al.

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Table 1. Erythroeytic blood groups and serum factors of both patients and their relatives Erythrocytie blood groups Case 1 Patient Brother Mother Father

Tri 9q Normal Normal Normal

Case 2 Patient Tri 9q Mother Transl. Father Normal Mat Gr Mother Normal Mat Gr Father Transl.

0 A1 0 A1

CeDEe CeDEe CCDee CeDEe

K~k+ K--k~K~k~K--k~-

Kp Kp Kp Kp

(a--b+) (a b + ) (a--b+) a--b+)

MSs MSs MNss MSs

P1 P1 L e ( a - - b + ) P1 Le ( a - - b + ) P1 Le ( a + b - - )

A A1 A~ A1B A~B

ccDEe ceddee eeDEe CcDee CeDee

kk kk kk kk kk

Kp Kp Kp Kp Kp

(a--) (a--) (a~-b~-) (a--) (a--)

MNSs MSS NSs NSs MSs

P1 P1 P1 P1 P1

Le Le Le Le Le

(a~-) (a--) (a--) (a--) (a--)

Case 2. W i t h c o n v e n t i o n a l staining t h e p a t i e n t h a d an a p p a r e n t l y n o r m a l k a r y o t y p e . B a n d i n g techniques showed t h e presence of an e x t r a s h o r t f r a g m e n t t r a n s l o c a t e d onto t h e d i s t a l end of t h e long a r m of a 4 : 4 6 , X X , 4 q ~ - (Fig. 3). A f a m i l y s t u d y showed t h a t t h e m o t h e r is t h e carrier of a t r a n s l o c a t i o n 4 6 , X X , t ( 4 ; 9)(q33 ; q31). I t is n o t e w o r t h y t h a t t h e a b n o r m a l 9 h a d lost its s e c o n d a r y constriction. The p a t i e n t is therefore trisomie for t h e q31qter s e g m e n t : 46,XX,der(4)t(4 ;9) ( q 3 3 ; q 3 1 ) m a t (Fig. 3).

Fig. 2. Chromosomes No. 9 from the first patient after staining by different techniques

Partial Trisomy 9q: A New Syndrome

Erythrocytic blood groups

Serum factors tip

Fy ( a + b + ) Jk ( a + b + ) F y ( a + b + ) Jk ( a + b + ) F y ( a + b + ) Jk ( a + b - - ) Fy(a+b+) Jk(a+b+)

Lu ( a - - b + ) Lu ( a - - b + ) Lu ( a - - b + ) Lu(a--b@)

1.1 2.1 1.i 2.1

Fy Fy Fy Fy Fy

Lu Lu Lu Lu Lu

2.2 2.2 2.2 2.2 2.2

(a--) (a+) (a--) (a@) (a+)

Jk Jk Jk Jk Jk

(a--) (a@) (a--) (a+) (a+)

237

(a--) (a@b--) (a--) (a--) (a+b+)

Tf Ge

Gm

PhA AK PGM1 PGM~

1.1 a - - b @ x - - AB 2.1 1.1 1.1 a - - b + x - B 1.1 2.1 1.1 a - - b + x - - AB 1.1 2.1 1.1 a + b + x + B 2.I 1.1 C 2.1 a--b-I-x-B 1.1 C 2.1 a - - b + x - B 1.1 C 2.1 a--b-~-x-- AB 1.1 C 2.1 a ~ + x - B 1.1 C 2.1 a + b + x - - AB 1.1

1.1 1.1 1.1 1.1

1.1 1.1 1.1 1.1 1.1

The balanced t r a n s l o e a t i o n is also present in the m a t e r n a l g r a n d father. One of the m o t h e r ' s two sisters has a n o r m a l karyotype. The other one could n o t be examined.

Dermatoglyphies Dermatoglyphics are r a t h e r u n r e m a r k a b l e in both patients. Case 1. N o r m a l creases. Axial triradii : t. Fingers : 8 u l n a r loops, 2 radial loops. Presence of a n extra flexion crease on the first p h a l a n x of all fingers. Case 2. N o r m a l creases. Axial triradii: t a n d t ' " on the left, t on the right. H y p o t h e n a r i a n radial ]oop on the left. F i n g e r p a t t e r n s i m m a t u r e .

Fig. 3. Comparison of the rearranged chromosomes of patient No. 1 with those of patient No. 2 and her translocated mother. The diagram indicating the segments for which each patient is trisomie shows that the overlapping segment is small and corresponds to bands q31q32

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C. Turleau et al. Discussion

The 2 patients reported here are strikingly similar. Both had a low birth weight (for a normal length) and remained hypotrophic and doliehomorphic. Their craniofacial dysmorphia is almost identical and includes dolichocephaly, deeply set eyes, narrow, horizontal palpebral fissures, a beaked nose, a small, round, receding chin with an overlapping upper lip, a small well designed mouth and slightly low set ears. The fingers are long with a remarkable clench. Dermatoglyphics have no particular feature. The toes are also long. A few differences do exist: microcephaly, epicanthal folds and strabismus in the first patient, who also had pylorie stenosis and a transitory heart defect; 13 dorsal vertebrae and 13 ribs in the second patient. Psychomotor retardation seems more pronounced in the first patient. This identity of phenotypic expression is probably due to trisomy for a very short segment of 9% As shown in Fig. 3, the region which is trisomic in both patients is the q31q32 region. Trisomy for the remaining segments in each patient respectively does not seem to have had a major phenotypic expression. I t must also be noted that partial monosomy for 4q in the second patient does not appear to have modified the clinical picture significantly. Because of its secondary constriction, structural rearrangements of chromosome 9 m a y well occur differently than for other chromosomes. I t is indeed noteworthy that in both patients there is an anomaly of the secondary constricrich.

We are not aware of other reports of partial trisomy 9q. The well documented trisomy 9p cannot be considered here (Rethor6 et al., 1970; Turleau et al., 1974). The only observations to which our patients are to be compared are observations of trisomy 9 : 3 are mixoploids (Haslam et al., 1973 ; Schinzel et al., 1974 ; Bowen et al., 1974), and 1 is homogeneous (Feingold and Atkins, 1973). Relevant clinical features of these observations and of the 2 patients reported here appear in Table 2. Although the partial 9q trisomy syndrome does not resemble trisomy 9 very closely (whether in mosaic or not), some features are common: a low birth weight and poor thriving, deeply set eyes, prominent maxilla and receding mandible. Limitation of hip motion and malformation of the knees, which appear to be important symptoms of trisomy 9, are not part of the trisomy 9q syndrome (nor of trisomy 9). Likewise, hypoplasia of the external genitalia, found in trisomy 9, is not present in our first patient. I t is in fact difficult to single out the symptoms specific of trisomy 9q from the clinical picture due to trisomy 9. The same holds true for trisomy 9p. The question whether the phenotypic expression of trisomy for a given chromosome segment is the same if this segment is part of a transloeation, or if it is part of a chromosome trisomic in toto, remains difficult to answer. A remarkable feature of the observations presented here is t h a t the chromosome segment responsible for the syndrome of partial trisomy 9q is probably very small. This is not overlooking t h a t the trisomy 21 syndrome is due solely to trisomy for the distal extremity of chromosome 21 (the q22 region). Trisomy for the remaining part of chromosome 21 does not result in major phenotypic disturbance (Dutrillaux et al., 1973; Sinct et al., 1975).

Partial Trisomy 9q: A New Syndrome

241

Comparing partial trisomies with complete trisomies should prove e x t r e m e l y i m p o r t a n t for the u n d e r s t a n d i n g of the organization of genetic material w i t h i n the chromosome. Matching such organization, as deduced from clinical observations, with the visible organization revealed b y chromosome b a n d i n g m i g h t well hold m a j o r surprises in store. This work was supported by the C.N.R.S.: ER 149 and RCP 84.

References Bowen, P., Ying, K. L., Chung, G. S. H.: Trisomy 9 mosaicisnl in a newborn infant with multiple malformations. J. Pedlar. 85, 95 97 (1974) Caspersson, T., Zech, L., Johnsson, C., Modest, E. J. : Identification of human chromosomes by DNA reacting fluorescing agents. Chromosoma (Berl.) 30, 215--227 (1970) Dutrillaux, B.: Nouveau syst~me de marquage chromosomique: les bandes T. Chromosoma (Berl.) 41, 395--402 (1973) Dutrillaux, B. : Sur la nature et l'origine des chromosomes humains. ~onographies des Annales de G~n~tique. Expansion Scientifique Ed., pp. 102 (1975) Dutrillaux, B., Jonasson, J., Lauren, K., Lejeune, J., Lindsten, J., Petersen, G. B., SaldanaGarcia, P. : An unbalanced 4q/21q tranlocation identified by the ~ but not by the G and Q chromosome banding techniques. Ann. G~n6t. 16, 11--16 (1973) Dutrillaux, B., Lejeune, J. : Sur une nouvelle technique d'analyse du caryotype humain. C. R. Acad. Sci. (Paris) 272, 2638--2640 (1971) Feingo]d, 5I, Atkins, L. : A case of trisomy 9. J. reed. Genet. 10, 184--187 (1973) Finaz, C., Grouchy, J. de: Identification of individual chromosomes in the human karyotypc by their banding pattern after proteolytic digestion. Humangenetik 15, 249--252 (1972) Haslam, 1~. H. A., Broske, S. P., Moore, C. M., Thomas, G. H., Neill, C. A. : Trisomy 9 mosaicism with multiple congenital anomalies. J. reed. Genet. 10, 180 184 (1973) Latt, S. A. : Localisation of sister chromatid exchanges in hmnan chromosomes. Science 185, 74--76 (1974) Rethor4, M. O., Larget-Piet, L., Abonyi, D., Boeswillwald, 3/[., Berger, 1~., Carpentier, S., Crnveiller, J., Dutrillaux, B., Lafourcade, J., Penneau, 1~'I.,Lejeune, J. : Sur quatre cas de trisomie pour le bras court du chromosome 9. !ndividualisation d'une nouvelle entit~ morbide. Ann. G6n~t. 13, 217--232 (1970) Schinzel, A., Hayashi, K., Schmid, W.: Mosaic-trisomy and pericentric inversion of chromosome 9 in a malformed boy. Humangenetik 25, 171--177 (1974) Sinet, P. M., Couturier, J., Dutrillaux, B., Poissonnier, M., Raoul, 0., Rethor4, M. O., Allard, D., Lejeune, J., J4rSme, H. : Trisomie 21 et superoxyde dismutase. Tentative de localisation sur ]a sous bande 21q 22.1. (in press, 1975) Turlcau, C., Grouchy, J. de., Chavin-Colin, F., Roubin, M., Langmaid, H.: Trisomie 9p: deux nouvel!es observations. Ann. G6n6t. 17, 167 174 (1974) Yunis, J. J., Roldan, L., Yasmineh, W. G., Lee, J. C. : Staining of satellite DNA in metaphase chromosomes. Nature (Loud.) 2;11, 532--533 (1971) Dr. Catherine Turleau Clinique de G4n4tique M:6dieale et Unitg de Recherche I.N.S.E.R.M. (U12) HSpital des Enfants MMades 149, rue de S~vres Paris, France

Partial trisomy 9q: a new syndrome.

Two unrelated patients with a strikingly similar phenotype (low birth weight and poor thriving; mental retardation; dolichocephaly; beaked nose; deepl...
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