American Journal of Medical Genetics 37:62-64 (1990)
De Novo (15;21) Unbalanced Translocation of Paternal Origin in a Girl With Prader-Willi Syndrome C. Cuoco, M.P. Bicocchi, D. Granata, P. Mezzano, and G. Serra Laboratorio di Citogenetica, Istituto G. Gaslini (C.C., M.P.B., D.G.) and Istituto di Puericultura e Medicina Neonatale L. Gaslini, Universita di Genova (P.M., G.S.), Genova, Italy
We describe a 3-month-oldgirl with PraderWilli syndrome and a de novo unbalanced This rekaryotype 45,XX,t(15;21)(q13;q22.3). arrangement, resulting in monosomy for the pericentromeric region of chromosome 15 and a virtual monosomy for the 21q distal band, had a paternal origin as demonstrated by Q and NOR staining.
centile). Physical examination showed a peculiar face with small nose, micrognathia and thin hair; the facial appearance was strikingly reminiscent of PWS. The skin was hypothermic and marbled. She was hypotonic, slow to feed because of an inefficient suck reflex, with slow tendon reflexes, somnolence, and absence of common neonatal automatisms. A CT scan showed enlargement of ventricular and subaracnoid spaces and signs of cerebral atrophy. During a follow-upexamination a t age 3 months (Fig. 1)she continued to show severe hypoKEY WORDS: chromosome 15, unbalanced tonia and joint laxity. At age 2 years the proposita had translocation the following anthropometric measurements: weight 13.5 kg (>loth centile), length 88 cm (>loth centile), OFC 46 cm (loth + der(2l),t(15;21)(q13;q22.3).C-banding and DA/DAPI staining excluded an inactive centromere of the translocated chromosome 15. The same chromosome abnormality was also present in fibroblasts. Both parents’ chroReceived for publication September 14, 1989; revision received mosomes were normal. The paternal origin of the November 6, 1989. translocated chromosome was ascertained by NOR and Address reprint requests to Dr. Cristina Cuoco, Laboratorio di Q staining. The short arm variants of acrocentric chroCitogenetica, Istituto G. Gaslini, Via 5 Maggio, 39,16148 Genova, mosomes were identified by sequential staining with Q Italy. 0 1990 Wiley-Liss, Inc.
Unbalanced (15;21)Tkanslocation in P W S
Fig. 1. The proposita at 3 months.
banding and silver staining of the nucleolar organising regions (NOR). The normal chromosome 21 of the proposita, with consistent NOR positivity but no bright fluorescence after Q banding, was similar to a maternal chromosome 21. The short arm of the translocated 21 showed a very weak NOR staining and absence of bright fluorescence of satellites by Q banding and appeared identical with a father’s 21.
DISCUSSION In our case no loss of chromosome 21 material was identified in the translocated chromosome. Several authors have stressed that in PWS patients with either balanced or unbalanced translocations, the long arm of chromosome 15 is in most cases transposed to the telomere of another chromosome [Duckett and Roberts, 1981; F’raccaro et al., 1983; Mattei et al., 1984; Elder et al., 19851. Furthermore, in 2 cases [Lejeune et al., 1979; Greenberg et al., 19871 a jumping translocation was found with the long arm of chromosome 15 transposed in different cells to different chromosomes. DNA sequence homology at the 15q11.2-ql2 region could explain its propensity to interact with telomeric regions of other chromosomes. Regarding the parental origin of the cytogenetic abnormality in PWS patients, Butler et al., [1986] documented a consistent paternal origin in 13 informative interstitial deletions of chromosome 15. This is also the case of our patient as demonstrated by satellite polymorphisms. This preferential derivation is in contrast to cases of inv dup (151, where the involved region of chromosome 15 is the same. In fact, most of these extra chromosomes originate by a U type ex-
63
Fig. 2. The proposita at 2 years.
change during the first maternal meiotic division [Maraschio et al., 19811. Although the cause of PWS is still unclear, the recent report of Lubinsky et al. 119871 of familial occurrence of PWS in cytogenetically normal patients favours the hypothesis of autosomal recessive inheritance. The loss of gene function as a consequence of an interstitial deletion or, rarely, of a translocation or inversion would give rise to PWS in those heterozygous who became hemizygous because of the 15q chromosomal abnormality. This hypothesis also explains the lack of the PWS manifestations in some patients with proximal 15q deletion [Smith et al., 19831;in fact, these subjects probably were not heterozygous for the PWS gene.
REFERENCES Butler MG, Meaney FJ, Palmer CG (1986): Clinical and cytogenetic survey of 39 individual with Prader-Labhart-Willi syndrome. Am J Med Genet 23:793-809. Duckett DP, Roberts SH (1981): Adjacent 2 meiotic disjunction translocation and review of literature. Hum Genet 58:377-386. Elder FFB, Nichols MM, Hood OJ, Harrison WR, I11 (1985): Unbalanced translocation (15;17)(q13;~13.3) with apparent Prader-Willi syndrome but without Miller-Dieker syndrome. Am J Med Genet 20519-524. Raccarro M, Zuffardi 0,Buhler E, Schinzel A, Simoni G, Witkowski R, Bonifaci E, Caufin D, Cignacco G, Delendi N, Gargantini I, Losanowa T, Marca L, Ullrich E, Vigi V (1983): Deficiency, transposition, and duplication of one 15q region may be alternatively associated with Prader-Willi (or a similar) syndrome. Analysis of seven cases after varying ascertainment. Hum Genet 64:388-394. Greenberg F, Elder FBF, Ledbetter DH (1987): Neonatal diagnosis of Prader-Willi syndrome and its implications. Am J Med Genet 28:845-856.
Cuocoet al.
64
a
b
YZ 2
I2 3
15
21
der (21) 25 26 1
15
21
d e r (21)
Fig. 3. a: Partial G-banded karyotype of the proposita: normal chromosome 15, normal chromosome 21, and the derivative 21 t(21;15).b: Diagrams ofnormal 15 and 21 chromosomes, showing breakpoints, and of the derivative one.
Ledbetter DH, Mascarello JT, Ricciardi VM, Harper VD, Airhart SD, Strobe1 RJ (1982): Chromosome 15 abnormalities and the PraderWilli syndrome: A follow up report of 40 cases. Am J Hum Genet 34:278-285. Jijeune J, Maunory C, Prieur M, Van den Akker J (1979): TranslocaAnn Genet (Paris) tion sauteuse (5~;15q),(8q;15q),(l2q;15q). 22:210-213. Lubinsky M, Zellweger H, Greenswag L, Larson G, Hansmann I, Ledbetter D (1987): Familial Prader-Willi syndrome with apparent normal chromosomes. Am J Med Genet 28:37-43.
Marasehio P, Zuffardi 0,Bernardi F, Bozzola M, De Paoli C, Fonatsch C, Flatz DS, Ghersini L, Gimelli G, Loi M, Lorini R, Peretti D, Poloni L, Tonetti D, Vanni R, Zamboni G (1981): Preferential maternal derivation in inv dup (15).Analysis of eight new cases. Hum Genet 57:345-350. Mattei MG, Souiah N, Mattei JF (1984): Chromosome 15 anomalies and the Prader-Willi syndrome: Cytogenetic analysis. Hum Genet 66313-334. Smith A, Murray R, Den Dulk G (1983):Familial deletion. Ann Genet (Paris) 26:91-93.
De Novo (15;21) Unbalanced Translocation of Paternal Origin in a Girl With Prader-Willi Syndrome C. Cuoco, M.P. Bicocchi, D. Granata, P. Mezzano, and G. Serra Laboratorio di Citogenetica, Istituto G. Gaslini (C.C., M.P.B., D.G.) and Istituto di Puericultura e Medicina Neonatale L. Gaslini, Universita di Genova (P.M., G.S.), Genova, Italy
We describe a 3-month-oldgirl with PraderWilli syndrome and a de novo unbalanced This rekaryotype 45,XX,t(15;21)(q13;q22.3). arrangement, resulting in monosomy for the pericentromeric region of chromosome 15 and a virtual monosomy for the 21q distal band, had a paternal origin as demonstrated by Q and NOR staining.
centile). Physical examination showed a peculiar face with small nose, micrognathia and thin hair; the facial appearance was strikingly reminiscent of PWS. The skin was hypothermic and marbled. She was hypotonic, slow to feed because of an inefficient suck reflex, with slow tendon reflexes, somnolence, and absence of common neonatal automatisms. A CT scan showed enlargement of ventricular and subaracnoid spaces and signs of cerebral atrophy. During a follow-upexamination a t age 3 months (Fig. 1)she continued to show severe hypoKEY WORDS: chromosome 15, unbalanced tonia and joint laxity. At age 2 years the proposita had translocation the following anthropometric measurements: weight 13.5 kg (>loth centile), length 88 cm (>loth centile), OFC 46 cm (loth + der(2l),t(15;21)(q13;q22.3).C-banding and DA/DAPI staining excluded an inactive centromere of the translocated chromosome 15. The same chromosome abnormality was also present in fibroblasts. Both parents’ chroReceived for publication September 14, 1989; revision received mosomes were normal. The paternal origin of the November 6, 1989. translocated chromosome was ascertained by NOR and Address reprint requests to Dr. Cristina Cuoco, Laboratorio di Q staining. The short arm variants of acrocentric chroCitogenetica, Istituto G. Gaslini, Via 5 Maggio, 39,16148 Genova, mosomes were identified by sequential staining with Q Italy. 0 1990 Wiley-Liss, Inc.
Unbalanced (15;21)Tkanslocation in P W S
Fig. 1. The proposita at 3 months.
banding and silver staining of the nucleolar organising regions (NOR). The normal chromosome 21 of the proposita, with consistent NOR positivity but no bright fluorescence after Q banding, was similar to a maternal chromosome 21. The short arm of the translocated 21 showed a very weak NOR staining and absence of bright fluorescence of satellites by Q banding and appeared identical with a father’s 21.
DISCUSSION In our case no loss of chromosome 21 material was identified in the translocated chromosome. Several authors have stressed that in PWS patients with either balanced or unbalanced translocations, the long arm of chromosome 15 is in most cases transposed to the telomere of another chromosome [Duckett and Roberts, 1981; F’raccaro et al., 1983; Mattei et al., 1984; Elder et al., 19851. Furthermore, in 2 cases [Lejeune et al., 1979; Greenberg et al., 19871 a jumping translocation was found with the long arm of chromosome 15 transposed in different cells to different chromosomes. DNA sequence homology at the 15q11.2-ql2 region could explain its propensity to interact with telomeric regions of other chromosomes. Regarding the parental origin of the cytogenetic abnormality in PWS patients, Butler et al., [1986] documented a consistent paternal origin in 13 informative interstitial deletions of chromosome 15. This is also the case of our patient as demonstrated by satellite polymorphisms. This preferential derivation is in contrast to cases of inv dup (151, where the involved region of chromosome 15 is the same. In fact, most of these extra chromosomes originate by a U type ex-
63
Fig. 2. The proposita at 2 years.
change during the first maternal meiotic division [Maraschio et al., 19811. Although the cause of PWS is still unclear, the recent report of Lubinsky et al. 119871 of familial occurrence of PWS in cytogenetically normal patients favours the hypothesis of autosomal recessive inheritance. The loss of gene function as a consequence of an interstitial deletion or, rarely, of a translocation or inversion would give rise to PWS in those heterozygous who became hemizygous because of the 15q chromosomal abnormality. This hypothesis also explains the lack of the PWS manifestations in some patients with proximal 15q deletion [Smith et al., 19831;in fact, these subjects probably were not heterozygous for the PWS gene.
REFERENCES Butler MG, Meaney FJ, Palmer CG (1986): Clinical and cytogenetic survey of 39 individual with Prader-Labhart-Willi syndrome. Am J Med Genet 23:793-809. Duckett DP, Roberts SH (1981): Adjacent 2 meiotic disjunction translocation and review of literature. Hum Genet 58:377-386. Elder FFB, Nichols MM, Hood OJ, Harrison WR, I11 (1985): Unbalanced translocation (15;17)(q13;~13.3) with apparent Prader-Willi syndrome but without Miller-Dieker syndrome. Am J Med Genet 20519-524. Raccarro M, Zuffardi 0,Buhler E, Schinzel A, Simoni G, Witkowski R, Bonifaci E, Caufin D, Cignacco G, Delendi N, Gargantini I, Losanowa T, Marca L, Ullrich E, Vigi V (1983): Deficiency, transposition, and duplication of one 15q region may be alternatively associated with Prader-Willi (or a similar) syndrome. Analysis of seven cases after varying ascertainment. Hum Genet 64:388-394. Greenberg F, Elder FBF, Ledbetter DH (1987): Neonatal diagnosis of Prader-Willi syndrome and its implications. Am J Med Genet 28:845-856.
Cuocoet al.
64
a
b
YZ 2
I2 3
15
21
der (21) 25 26 1
15
21
d e r (21)
Fig. 3. a: Partial G-banded karyotype of the proposita: normal chromosome 15, normal chromosome 21, and the derivative 21 t(21;15).b: Diagrams ofnormal 15 and 21 chromosomes, showing breakpoints, and of the derivative one.
Ledbetter DH, Mascarello JT, Ricciardi VM, Harper VD, Airhart SD, Strobe1 RJ (1982): Chromosome 15 abnormalities and the PraderWilli syndrome: A follow up report of 40 cases. Am J Hum Genet 34:278-285. Jijeune J, Maunory C, Prieur M, Van den Akker J (1979): TranslocaAnn Genet (Paris) tion sauteuse (5~;15q),(8q;15q),(l2q;15q). 22:210-213. Lubinsky M, Zellweger H, Greenswag L, Larson G, Hansmann I, Ledbetter D (1987): Familial Prader-Willi syndrome with apparent normal chromosomes. Am J Med Genet 28:37-43.
Marasehio P, Zuffardi 0,Bernardi F, Bozzola M, De Paoli C, Fonatsch C, Flatz DS, Ghersini L, Gimelli G, Loi M, Lorini R, Peretti D, Poloni L, Tonetti D, Vanni R, Zamboni G (1981): Preferential maternal derivation in inv dup (15).Analysis of eight new cases. Hum Genet 57:345-350. Mattei MG, Souiah N, Mattei JF (1984): Chromosome 15 anomalies and the Prader-Willi syndrome: Cytogenetic analysis. Hum Genet 66313-334. Smith A, Murray R, Den Dulk G (1983):Familial deletion. Ann Genet (Paris) 26:91-93.
