American Journal of Medical Genetics 111:401– 404 (2002)
Clinical Report Tetrasomy Y by Structural Rearrangement: Clinical Report Martin DesGroseilliers,1,2 Emmanuelle Lemyre,2,3,4 Louis Dallaire,2,3,4 and Nicole Lemieux1,2,5* 1
De´partement de Pathologie et Biologie Cellulaire, Universite´ de Montre´al, Montre´al, Canada Centre de Recherche, Hoˆpital Ste-Justine, Montre´al, Canada 3 De´partement de Pe´diatrie, Faculte´ de Me´decine, Universite´ de Montre´al, Montre´al, Canada 4 Service de Ge´ne´tique Me´dicale, Hoˆpital Ste-Justine, Montre´al, Canada 5 De´partement de Pathologie, Hoˆpital Ste-Justine, Montre´al, Canada 2
Poly-Y karyotypes, except for 47,XYY, are rare events in humans. For instance, Y chromosome tetrasomy has been reported 10 times, 2 of which were by structural rearrangement. We present a 2-year-and4-month-old boy who was referred for cytogenetic assessment because of global psychomotor delay. The GTG- and CBGbanded karyotypes on PHA-stimulated lymphocytes showed two cell populations, one of them contained two identical isodicentric Y chromosomes, which was seen in 93% of metaphases analyzed, and a 45,X cell line (7%). This was confirmed by FISH with probes DYZ3 (recognizing the centromeric region of the Y chromosome), 91H4.5 (recognizing Yp11.2), and DYZ1 (recognizing Y heterochromatin in Yq12). The breakpoint has occurred near the telomeric end of the heterochromatic region. Therefore, the karyotype is mos 47,X,idic(Y)(q12)x2/ 45,X. This is the second time that such a karyotype has been reported. This chromosomal anomaly was formed most likely by a U-type exchange. Clinical features included speech delay, short stature, brachycephaly, large ears, bilateral epicanthal folds, hypertelorism, delayed teeth eruption, bilateral radio-ulnar synostosis, bilateral fifth finger
Grant sponsor: Re´seau de Me´decine Ge´ne´tique Applique´eFRSQ. *Correspondence to: Nicole Lemieux, De´partement de Pathologie et Biologie Cellulaire, Faculte´ de Me´decine, Universite´ de Montre´al, C.P. 6128, Succ. Centre-Ville, Montre´al, Que´bec, H3C 3J7, Canada. E-mail: [email protected]
Received 21 June 2000; Accepted 14 April 2002 DOI 10.1002/ajmg.10591
ß 2002 Wiley-Liss, Inc.
clinodactyly, normal external genitalia, and impulsive behavior. The father had normal phenotype and karyotype. A review of the tetrasomy Y patients is presented. All patients with Y chromosome tetrasomy exhibit some degree of mental retardation, various skeletal abnormalities, and facial dysmorphism. Nevertheless, the correlation between karyotype and phenotype is not yet well defined since few cases have been reported. This clinical report will be helpful in defining the phenotypic range associated with tetrasomy Y. ß 2002 Wiley-Liss, Inc. KEY WORDS: tetrasomy Y; isodicentric Y; psychomotor delay; FISH; sex chromosomes
INTRODUCTION The addition or loss of a sex chromosome (X or Y) in a normal female or male chromosome constitution results either in Turner syndrome (45,X), trisomy X (47,XXX), disomy Y (47,XYY), or Klinefelter syndrome (47,XXY). These syndromes are quite frequent, with a 1/500 incidence [Jones, 1997]. Among poly-Y karyotypes, 47,XYY is the most common, with an incidence of 1/840 [Jones, 1997]. On the other hand, the cases with more than one supernumerary gonosome are much rarer. For example, trisomy and tetrasomy Y have been reported in the literature 20 and 10 times, respectively. No pentasomy Y has been reported. Among the 10 reported cases of tetrasomy Y, 2 are by structural rearrangement [Kyriakakos et al., 1995; Jenderny et al., 1998] involving two copies of an isodicentric Y chromosome. The case of Jenderny et al.  had 0.7% of tetrasomy Y within a mosaic. Therefore, this case will not be considered as an isodicentric Y patient. In this report, we describe a patient with two isodicentric Y chromosomes and global psychomotor delay.
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CLINICAL REPORT This 2-year-and-4-month-old boy was assessed in our medical genetics clinic because of global psychomotor delay. His family history was negative for mental retardation, malformations, or multiple miscarriages. The propositus had one healthy brother. His past medical history revealed uncomplicated pregnancy and delivery. The birth weight was 3.333 kg. The Apgar score was 91, 105, 1010. The neonatal period was significant for meconium aspiration requiring oxygen therapy. He had an atrioseptal defect, which closed spontaneously, bilateral radio-ulnar synostosis, bilateral fifth finger clinodactyly, premature closure of the anterior fontanel. His development history revealed global moderate psychomotor retardation. He walked at 19 months of age, was unable to climb stairs and to hop at almost 2.5 years old. At that age, he spoke only four words. He also had impulsive behavior. On physical examination, his weight was 12.7 Kg (50th centile), length was 85.6 cm (10th centile). He had brachycephaly, bilateral epicanthal folds, hypertelorism, bulbous nose with small nostrils, long philtrum, thin upper lip, pointed chin, delayed teeth eruption, and large ears. The extremities showed bilateral radio-ulnar synostosis. On neurological examination, the tone and deep tendon reflexes were increased, especially on the left side. On the left thigh, he had a 5.5 cm 2.1 cm cafe´-au-lait spot. Plasma amino acids, urine organic acids, lactate, pyruvate, and cerebral CT scan were normal. Blood for karyotype was drawn. Chromosome Preparation and Fluorescence In Situ Hybridization (FISH) Peripheral blood lymphocytes were cultured in RPMI 1640. After fixation, the chromosome preparations were G- and C-banded (GTG and CBG) according to the classic protocols [Seabright, 1971; Sumner, 1972]. FISH and detection with probe 91H4.5 (biotin-labeled) were performed as described by Lemieux et al. . FISH and detection using probes DYZ3 and DYZ1 (both digoxigenin-labeled) were performed as suggested by the manufacturer (Oncor, Gaithersberg, MD). Finally, FISH and detection using Telomere PNA Probe/FITC (Dako, Mississauga, ON) were done according to the Dako protocol with minor modifications. Chromosomes were counterstained with propidium iodide before visualizing. DNA Probes The DNA probes DYZ3 and DYZ1 (Oncor) are Y chromosome alphoid centromere-specific sequences and Y chromosome heterochromatin-specific (Yq12), respectively. Probe 91H4.5 is a 4.5 kb HindIII fragment cloned in pTZ18R of the DYZ4/DYZ5 repeat locus, located in the mid region of the Y short arm in Yp11.2 [Tyler-Smith et al., 1988] (Fig. 1A). Telomere PNA Probe/FITC detects all telomeres using a fluorescein-conjugated peptide nucleic acid (PNA) probe (Dako). RESULTS The GTG-banded karyotypes showed mosaicism for two cell lines. Of the 132 metaphases analyzed from two
Fig. 1. Schematic illustration of (A) normal and (B) isodicentric Y chromosomes with location of probes 91H4.5 (Yp11.2), DYZ3 (centromeric region), and DYZ1 (Yq12). Partial karyotypes of the patient in (C) GTG and (D) CBG banding (arrows), showing the two idic(Y). FISH with probes (E) DYZ3, (F) 91H4.5, (G) DYZ1, displaying the isodicentric nature of the rearranged Y chromosomes, and the (H) Telomere PNA Probe (arrows), which favors the U-type exchange as the mechanism of formation.
independent cultures, 9 were 45,X. The predominant cell line (123/132) contained 47 chromosomes with two identical and unusual Y chromosomes (Fig. 1C). CBG banding (Fig. 1D) revealed two isodicentric Y chromosomes: the thick C-band in the center of the rearranged chromosomes indicates that the breakpoint occurred near the telomeric end of the Y long arms. With GTG
Tetrasomy Y by Structural Rearrangement
and CBG bandings, only one primary constriction was visible in all cells analyzed, which probably means that each Y chromosomes possesses only one active centromere, the other being inactivated. The rearranged Ys are idic(Y) with duplication of the short arms, centromere, and the proximal portion of the long arms. FISH with probes DYZ3 (Fig. 1E), 91H4.5 (Fig. 1F), and DYZ1 (Fig. 1G) gave signals in the expected positions as illustrated in Figure 1B. Therefore, the structure of these rearranged Y chromosomes was confirmed. Thus, the karyotype is 47,X,idic(Y)(q12)x2/ 45,X. FISH with Telomere PNA Probe/FITC (Fig. 1H) gave signals at the telomeric ends of all chromosomes, including both rearranged Y chromosomes. None of the 25 mitoses analyzed showed FISH signals in the middle of the isodicentric Ys. The karyotype of the father was normal. DISCUSSION Among the three types of poly-Y complement, 47,XYY is by far the more frequent and the best characterized. Trisomy and tetrasomy of Y chromosome are much less frequent, with 20 and 10 reported cases, respectively. Among trisomy Y cases, 13 were nonmosaic or had a 48,XYYY major cell line (86% or more). Of the 10 reported cases of tetrasomy Y, 4 of them—Hunter and Quaife  (1.25%), Gigliani et al.  (4%), Pincheira et al.  (1.1%), Jenderny et al.  (0.7%)—present a very low proportion of cells bearing four Y chromosomes. For that reason, these cases will not be considered for discussion of the tetrasomy Y phenotype. Those from Van den Berghe et al.  (86%), Plauchu et al.  (96.7%), and Kyriakakos et al.  (93.5%) are cases with tetrasomy Y representing the major cell line within a mosaic. Finally, the cases reported by Sirota et al. , Noe¨l et al. , and Shanske et al.  are nonmosaic cases. While no pentasomy Y has been reported, Das et al.  have reported a 49,XXYYY patient. The clinical description of our case and the other cases of tetrasomy Y share some common features. Psychomotor delay, skeletal abnormalities, and facial dysmorphism are reported in every case. Psychomotor delay is variable and ranges from speech delay to severe mental retardation. Hypotonia is also reported in two cases. The features of facial dysmorphism are variable among cases: facial asymmetry, hypertelorism, micrognatia, low-set ears, bilateral lop ears, and epicanthal folds are reported, among others. Skeletal abnormalities include anomaly of the elbows (radio-ulnar synostosis and malformation; three cases) and of the fingers (including clinodactyly and brachydactyly; four cases), head asymmetry (three cases), scoliosis (three cases), and spina bifida (three cases). Delayed dental eruption (three cases) is also reported. Among tetrasomy Y, the patients’ stature is not consistent: one is tall, four are within normal range, and two are short. Still, because the number of reported cases is small, this observation may be biased. It is of note that four of the five patients whose behaviors were reported had moderate (one case), violent (one case), or impulsive behavior (two cases).
One adult with tetrasomy Y (aged 30) was described previously with hypogonadism and infertility [Shanske et al., 1998]. All other patients were young boys with normal genitalia. However, this does not eliminate possible infertility or hypogonadism developing at a later age. For example, Van den Berghe et al.  described a 15-year-old boy [49,XYYYY (86%)] with complete absence of spermatogenesis. In addition, four of the five investigated 48,XYYY individuals were infertile (the other case may likely be explained by tissular heterogeneity). In those cases, infertility may be associated with a disturbance of spermatogenesis owing to the number of Y chromosome. Nevertheless, 47,XYY individuals are fertile. It will be very interesting to follow on the development of our patient to see if his chromosomal aberration [idic(Y)(q12)x2] will allow normal spermatogenesis. A review of the clinical picture of the tetrasomy Y patients is presented in Table I. The phenotype of our patient and the patient of Kyriakakos et al.  are consistent with the other cases of tetrasomy Y. In both cases, the breakpoint is in Yq heterochromatin, resulting in a full tetrasomic dose of Y genes. To our knowledge, this is the second time that a patient with tetrasomy Y by structural rearrangement is reported. The other case was described by Kyriakakos et al. . The simplest explanation for the patient’s karyotype (47,X,idic(Y)(q12)x2/45,X) is the formation of an isodicentric Y during the father’s spermatogenesis, followed by a mitotic error early in embryogenesis. The isodicentric could occur either by a U-type exchange or by telomeric associations. In order to clarify this issue, we used the all-telomeres probe to verify if Yq telomeric regions were present or absent in the rearranged chromosomes. These Yq telomeric sequences would be absent in U-type exchange, but present in telomeric associations. Figure 1H clearly shows that only Yp telomeres are present. Therefore, a U-type exchange in paternal meiosis could have generated a 46,X,idic(Y) sperm, followed by postfertilization nondisjunction early in embryogenesis, leading to 47,X,idic(Y)(q12) (93%) and 45,X (7%) cell lines.
TABLE I. Clinical Picture of Tetrasomy Y Patients* Tetrasomy Y phenotype (seven cases) Variable stature (tallb; normal rangea,c,d,e; shortf,g) Psychomotor delay (7/7)a,b,c,d,e,f,g Various skeletal abnormalities (7/7)a,b,c,d,e,f,g Various facial dysmorphism (7/7)a,b,c,d,e,f,g Impulsiveness/violence (4/5)a,b,c,f,g; calme Delayed dental eruption (3/3)b,e,g Infertility (2/2)c,d Hypogonadism (1 adult)c *Nonmosaic tetrasomy Y includes a, b, and c. Mosaic tetrasomy Y includes d, e, f, g. a Sirota et al. . b Noe¨l et al. . c Shanske et al. . d Van den Berghe et al. ; lymphocytes: 86%; fibroblasts: 95.6%. e Plauchu et al. ; lymphocytes: 97%; fibroblasts: 96.1%. f Kyriakakos et al. ; 93.6%. g Present case; 93.2%.
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The proportions of each cell line could reflect selection secondary to differential viability of the monosomy X cells compared to the tetrasomic dose of Y cells. Gonadal mosaicism in the father cannot be rule out. Unfortunately, it was not possible to analyze a second tissue on our patient. The review of tetrasomy Y patients shows that all cases exhibit some degree of mental retardation, various skeletal abnormalities, and facial dysmorphism. Nevertheless, the correlation between karyotype and phenotype is not yet well defined since only a few cases have been reported. This clinical report will be helpful in defining the phenotypic range of the tetrasomy Y patients. ACKNOWLEDGMENTS We thank Fle´che`re Fortin (Universite´ de Montre´al) for her technical support. We are also grateful to TylerSmith et al.  for providing us with probe 91H4.5, as well as Dr. Claude-Lise Richer for critically reading this report. Finally, we thank Jean Le´veille´ and Gaston Lambert, from our department, for their photographic work.
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