American Journal of Medical Genetics 38532-534 (1991)
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Interstitial 15q Deletion Without a Classic Prader-Willi Phenotype Francisco Galan, Maria Soledad Aguilar, Juan Gonzalez, Fernando Clemente, Rafael Sanchez, Manuel Tapia, and Manuel Moya Secci6n de Genetica, Departamento de Pediatria, Universidad de Alicante (F.G., M.S.A., M.M.), and Servicio de Pediatria, Hospital S.V.S. (J.G., F.C., R.S., M.T.), Alicante, Spain We report on a newborn boy with pronounced hypotonia, cryptorchidism, minor facial anomalies, congenital heart defect, neurologic anomaly, deafness, renal anomaly, and bifid uvula. The patient has a de novo proximal interstitial deletion of chromosome 15 reaching to band q14,larger than that usually seen in Prader-Willi and Angelman syndromes.
It was the fourth pregnancy of a healthy 33-year-old woman. Her husband was 43 years old, and they were not consanguineous. At birth, the patient was severely hypotonic and pale and had lymphedema mainly in the scrotum and on the hands and back. The Apgar scores were 5 and 8 at 1 and 5 min, respectively. Somatic measurements were: birth weight 2,560 g (3rd centile), head circumference (OFC) 35 cm (50th-75th centile), length 48 cm (10th-25th centile). He had cranial asymmetry, prominent eyes, apparent hypertelorism, anteverted nostrils, long upper lips, apparently low-set ears KEY WORDS: proximal chromosome 15 dele(Fig. 11, highly arched palate, bifid uvula, right cryption, del(l5q), bifid uvula torchidism, a heart murmur, a n enlarged right kidney, a n irregular sacral furrow, and 2 cafk-au-lait spots (2 x 1 cm) on the abdomen. Funduscopy was normal. He had INTRODUCTION severe hypotonia, with absence of the suck reflex and Human chromosome 15 is one of the most polymorphic decreased Moro reflex. chromosomes [Chen et al., 1981; Brookwell and Veleba, Results of laboratory tests performed were normal, 19871. It is often implicated in the formation of super- except for anemia (Hb 11 mg/dl) requiring transfusion. numerary bisatellited chromosomes [Wisniewski and After transfusion the heart murmur persisted, and pulDoherty, 1985;Buckton et al., 19851,and it is implicated monary valve stenosis was diagnosed. in Prader-Willi syndrome (PWS) and Angelman synRenal ultrasound study and intravenous pyelography drome [Mattei et al., 1983, 1984; Magenis et al., 19871. at age 1 month showed dilatation of the collecting sysApproximately one-half of PWS cases have a n intersti- tem. Cranial ultrasound study and axial tomography tial deletion of the proximal 15q region [Ledbetter et al., showed cortical brain atrophy, with enlarged lateral 19821involving bands q l l to q13. Twenty-four patients ventricles. Periodic electroencephalograms showed a with proximal 15q deletions but without typical PWS diffuse slow activity, mainly in the occipital areas. At phenotype have been reported [Herva and Vuorinen, age 10 months, hypotonicity and paleness persisted. At 1980; Duckett and Roberts, 1981; Pauli et al., 1983; that time, he weighed 8,700 g (10th centile) and had a n Schwartz et al., 1985; Greenberg and Ledbetter, 1987; OFC of 49.5 cm (97th centile), chest circumference of Kaplan et al., 1987; Magenis et al., 19871. Apart from 46.5 cm (10th centile), and length of 75.5 cm (75th censome PWS manifestations, these patients have addi- tile). Auditory evoked responses showed bilateral heartional malformations. We describe a new case of proxi- ing deficiency of conductive type. mal 15q deletion with striking similarity to 4 other At age 2 years, hypotonia was slowly decreasing, with published cases with proximal 15q deletion reaching to better neck control and attempts to sit. Somatic meaband q14-ql5. surements were weight 12,600 g (50th centile), length 86.5 cm (50th centile), and OFC 53 cm (50th centile). CLINICAL REPORT Denver test showed normal oculomotor coordination Our patient, a newborn male, was born after a 34 week and sociability. Speech is a t the echolalic stage, and gestation by cesarean section because of placenta previa. primitive reflexes have disappeared. GTG-banded chromosomes of phytohemagglutinin Fkceived for publication June 21, 1989; revision received June (PHA)-stimulated lymphocytes showed a n interstitial 26, 1990. deletion of chromosome 15 (Fig. 2). To achieve better Address reprint requests to Dr. Francisco Galiin, Seccion de Genetica, Departamento de Pediatria, Facultad de Medicina, definition of the banding pattern, the chromosome study was repeated and the 72 h r cultures were exposed to Apartado 374, 03080 Alicante, Spain.
o 1991 Wiley-Liss, Inc.
Interstitial 15q Deletion
533
Fig. 1. Patient’s photographs.
ethidium bromide (10 pg/ml) 2 h r before conventional harvest [Ikeuchi, 19841. The study of the GTG-banded elongated chromosomes obtained by this technique allowed us to determine that the deletion extended from bands q l l or q12 to band q14. Both parents had normal chromosomes. Study of chromosome polymorphisms with DA/DAPI and CBG banding showed paternal origin of the deleted chromosome 15.
DISCUSSION Available data suggest that deletions of proximal 15q region can be divided into 2 groups according to the cytogenetic characteristics and clinical manifestations: group 1: proximal 15q deletions (qll-q13) with classical PWS phenotype and group 2: proximal 15q deletions with nonclassical PWS phenotype. In the second group there is a great clinical variability: There are some patients [Schwartz et al., 1985; Greenberg and Ledbetter, 19871with the same chromosome anomaly found in group 1but without classic PWS and without a characteristic common phenotype. There are also some patients with apparently the same deletion but with the Angelman syndrome [Kaplan et al., 1987; Magenis et al., 19871.
The most convincing hypothesis for this great clinical variability suggests that PWS and Angelman syndrome could be caused by two mechanisms: a combination of abnormal alleles found in a homozygous state (a recessive-like disorder) or a 15q deletion in which abnormal alleles could be present on the cytogenetically normal chromosome 15 in a hemizygous state (a deletion syndrome), leading to different phenotypes [Donlon, 19881. There are 4 cases in group 2 [Herva and Vuorinen, 1980; Duckett and Roberts, 1981; Pauli e t al., 1983; Schwartz et al., 19851 and the present case with these common characteristics: The deleted segment is larger (reaching to bands q14-ql5) than in other proximal 15q deletions, and the clinical picture shows a n “expanded” PWS with striking similarities: Some PWS manifestations (515) (such as neonatal hypotonia and genital anomalies) and other findings not usually seen in the syndrome (cardiac [5/5], renal [5/5] and neurologic [4/5] abnormalities; bifid uvula [3/5]; and auditory disfunction [2/21). Nevertheless, we cannot exclude the phenotypic influence of the concomitant chromosome anomalies present in some of these cases. Due to the small number of reported cases with similar 15q deletions, we do not have precise information about psychomotor development of these patients. We would be interested in contacting other authors with similar cases and exchanging information about the psychophysical evolution of our patients.
REFERENCES Brookwell R, Veleba A (1987):Proximal 15q variant with normal phenotype in three unrelated individuals. Clin Genet 31:311-314. Buckton KE, Spowart G, Newton MS, Evans HJ (1985): Forty four probands with an additional “marker” chromosome. Hum Genet 69:353-370. Chen TR, Kao ML, Marks J , Chen YY (1981):Polymorphic variants in human chromosome 15. Am J Med Genet 951-66.
Fig. 2. GTG-banded chromosomes 15 of the patient and a scheme of the deletion, showing the breakpoints.
Donlon TA (1988):Similar molecular deletions on chromosome 15q11.2 are encountered in both the Fi-ader-Willi and Angelman syndromes. Hum Genet 80:322-328. Duckett DP, Roberts SH (1981):Adjacent 2 meiotic disjunction. Report
534
Galan et al.
of a case resulting from a familial 13q;15q balanced reciprocal translocation and review of the literature. Hum Genet 58:377-386. Greenberg F, Ledbetter DH (1987):Deletions of proximal 15q without Prader-Willi syndrome. Am J Med Genet 28:813-820. Herva R, Vuorinen 0 (1980):Congenital heart disease with del (15q) mosaicism. Clin Genet 17:26-28. Ikeuchi T (1984):Inhibitory effect of ethidium bromide on mitotic chromosome condensation and its application to high-resolution chromosome banding. Cytogenet Cell Genet 38:56-61. Kaplan LC, Wharton R, Elias E, Mandell F, Donlon T, Latt SA (1987): Clinical heterogeneity associated with deletions in the long arm of chromosome 15:Report of 3 new cases and their possible genetic significance. Am J Med Genet 28:45-53. Ledbetter DH, Mascarello JT, Riccardi VM, Harper VD, Airhard SD, Strobe1 R J (1982):Chromosome 15 abnormalities and the PraderWilli syndrome: A follow-up report of 40 cases. Am J Hum Genet 34278-285. Magenis RE, Brown MG, Lacy Da, Budden S, La Franchi S (1987):Is
Angelman syndrome an alternate result ofdel(15q)(qllq13)?Am J Med Genet 28:829-838. Mattei JF, Mattei MG, Giraud F (1983):Prader-Willi syndrome and chromosome 15. A clinical discussion of 20 cases. Hum Genet 64:356-362. Mattei MG, Souiah N,Mattei JF (1984):Chromosome 15 anomalies and the Prader-Willi syndrome: Cytogenetic analysis. Hum Genet 66:313-334. Pauli RM, Meisner LF, Szmanda RJ (1983):“Expanded” Prader-Willi syndrome in a boy with an unusual 15q chromosomedeletion.Am J Dis Child 137:1087-1989. Schwartz S, Max SR, Panny SR, Cohen MM (1985):Deletions of proximal 15 q and non-classical Prader-Willi syndrome phenotypes. Am J Med Genet 20:255-263. Wisniewski LP, Doherty RA (1985): Supernumerary microchromosomes identified as inverted duplications of chromosome 1 5 A report of three cases. Hum Genet 69:161-163.
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Interstitial 15q Deletion Without a Classic Prader-Willi Phenotype Francisco Galan, Maria Soledad Aguilar, Juan Gonzalez, Fernando Clemente, Rafael Sanchez, Manuel Tapia, and Manuel Moya Secci6n de Genetica, Departamento de Pediatria, Universidad de Alicante (F.G., M.S.A., M.M.), and Servicio de Pediatria, Hospital S.V.S. (J.G., F.C., R.S., M.T.), Alicante, Spain We report on a newborn boy with pronounced hypotonia, cryptorchidism, minor facial anomalies, congenital heart defect, neurologic anomaly, deafness, renal anomaly, and bifid uvula. The patient has a de novo proximal interstitial deletion of chromosome 15 reaching to band q14,larger than that usually seen in Prader-Willi and Angelman syndromes.
It was the fourth pregnancy of a healthy 33-year-old woman. Her husband was 43 years old, and they were not consanguineous. At birth, the patient was severely hypotonic and pale and had lymphedema mainly in the scrotum and on the hands and back. The Apgar scores were 5 and 8 at 1 and 5 min, respectively. Somatic measurements were: birth weight 2,560 g (3rd centile), head circumference (OFC) 35 cm (50th-75th centile), length 48 cm (10th-25th centile). He had cranial asymmetry, prominent eyes, apparent hypertelorism, anteverted nostrils, long upper lips, apparently low-set ears KEY WORDS: proximal chromosome 15 dele(Fig. 11, highly arched palate, bifid uvula, right cryption, del(l5q), bifid uvula torchidism, a heart murmur, a n enlarged right kidney, a n irregular sacral furrow, and 2 cafk-au-lait spots (2 x 1 cm) on the abdomen. Funduscopy was normal. He had INTRODUCTION severe hypotonia, with absence of the suck reflex and Human chromosome 15 is one of the most polymorphic decreased Moro reflex. chromosomes [Chen et al., 1981; Brookwell and Veleba, Results of laboratory tests performed were normal, 19871. It is often implicated in the formation of super- except for anemia (Hb 11 mg/dl) requiring transfusion. numerary bisatellited chromosomes [Wisniewski and After transfusion the heart murmur persisted, and pulDoherty, 1985;Buckton et al., 19851,and it is implicated monary valve stenosis was diagnosed. in Prader-Willi syndrome (PWS) and Angelman synRenal ultrasound study and intravenous pyelography drome [Mattei et al., 1983, 1984; Magenis et al., 19871. at age 1 month showed dilatation of the collecting sysApproximately one-half of PWS cases have a n intersti- tem. Cranial ultrasound study and axial tomography tial deletion of the proximal 15q region [Ledbetter et al., showed cortical brain atrophy, with enlarged lateral 19821involving bands q l l to q13. Twenty-four patients ventricles. Periodic electroencephalograms showed a with proximal 15q deletions but without typical PWS diffuse slow activity, mainly in the occipital areas. At phenotype have been reported [Herva and Vuorinen, age 10 months, hypotonicity and paleness persisted. At 1980; Duckett and Roberts, 1981; Pauli et al., 1983; that time, he weighed 8,700 g (10th centile) and had a n Schwartz et al., 1985; Greenberg and Ledbetter, 1987; OFC of 49.5 cm (97th centile), chest circumference of Kaplan et al., 1987; Magenis et al., 19871. Apart from 46.5 cm (10th centile), and length of 75.5 cm (75th censome PWS manifestations, these patients have addi- tile). Auditory evoked responses showed bilateral heartional malformations. We describe a new case of proxi- ing deficiency of conductive type. mal 15q deletion with striking similarity to 4 other At age 2 years, hypotonia was slowly decreasing, with published cases with proximal 15q deletion reaching to better neck control and attempts to sit. Somatic meaband q14-ql5. surements were weight 12,600 g (50th centile), length 86.5 cm (50th centile), and OFC 53 cm (50th centile). CLINICAL REPORT Denver test showed normal oculomotor coordination Our patient, a newborn male, was born after a 34 week and sociability. Speech is a t the echolalic stage, and gestation by cesarean section because of placenta previa. primitive reflexes have disappeared. GTG-banded chromosomes of phytohemagglutinin Fkceived for publication June 21, 1989; revision received June (PHA)-stimulated lymphocytes showed a n interstitial 26, 1990. deletion of chromosome 15 (Fig. 2). To achieve better Address reprint requests to Dr. Francisco Galiin, Seccion de Genetica, Departamento de Pediatria, Facultad de Medicina, definition of the banding pattern, the chromosome study was repeated and the 72 h r cultures were exposed to Apartado 374, 03080 Alicante, Spain.
o 1991 Wiley-Liss, Inc.
Interstitial 15q Deletion
533
Fig. 1. Patient’s photographs.
ethidium bromide (10 pg/ml) 2 h r before conventional harvest [Ikeuchi, 19841. The study of the GTG-banded elongated chromosomes obtained by this technique allowed us to determine that the deletion extended from bands q l l or q12 to band q14. Both parents had normal chromosomes. Study of chromosome polymorphisms with DA/DAPI and CBG banding showed paternal origin of the deleted chromosome 15.
DISCUSSION Available data suggest that deletions of proximal 15q region can be divided into 2 groups according to the cytogenetic characteristics and clinical manifestations: group 1: proximal 15q deletions (qll-q13) with classical PWS phenotype and group 2: proximal 15q deletions with nonclassical PWS phenotype. In the second group there is a great clinical variability: There are some patients [Schwartz et al., 1985; Greenberg and Ledbetter, 19871with the same chromosome anomaly found in group 1but without classic PWS and without a characteristic common phenotype. There are also some patients with apparently the same deletion but with the Angelman syndrome [Kaplan et al., 1987; Magenis et al., 19871.
The most convincing hypothesis for this great clinical variability suggests that PWS and Angelman syndrome could be caused by two mechanisms: a combination of abnormal alleles found in a homozygous state (a recessive-like disorder) or a 15q deletion in which abnormal alleles could be present on the cytogenetically normal chromosome 15 in a hemizygous state (a deletion syndrome), leading to different phenotypes [Donlon, 19881. There are 4 cases in group 2 [Herva and Vuorinen, 1980; Duckett and Roberts, 1981; Pauli e t al., 1983; Schwartz et al., 19851 and the present case with these common characteristics: The deleted segment is larger (reaching to bands q14-ql5) than in other proximal 15q deletions, and the clinical picture shows a n “expanded” PWS with striking similarities: Some PWS manifestations (515) (such as neonatal hypotonia and genital anomalies) and other findings not usually seen in the syndrome (cardiac [5/5], renal [5/5] and neurologic [4/5] abnormalities; bifid uvula [3/5]; and auditory disfunction [2/21). Nevertheless, we cannot exclude the phenotypic influence of the concomitant chromosome anomalies present in some of these cases. Due to the small number of reported cases with similar 15q deletions, we do not have precise information about psychomotor development of these patients. We would be interested in contacting other authors with similar cases and exchanging information about the psychophysical evolution of our patients.
REFERENCES Brookwell R, Veleba A (1987):Proximal 15q variant with normal phenotype in three unrelated individuals. Clin Genet 31:311-314. Buckton KE, Spowart G, Newton MS, Evans HJ (1985): Forty four probands with an additional “marker” chromosome. Hum Genet 69:353-370. Chen TR, Kao ML, Marks J , Chen YY (1981):Polymorphic variants in human chromosome 15. Am J Med Genet 951-66.
Fig. 2. GTG-banded chromosomes 15 of the patient and a scheme of the deletion, showing the breakpoints.
Donlon TA (1988):Similar molecular deletions on chromosome 15q11.2 are encountered in both the Fi-ader-Willi and Angelman syndromes. Hum Genet 80:322-328. Duckett DP, Roberts SH (1981):Adjacent 2 meiotic disjunction. Report
534
Galan et al.
of a case resulting from a familial 13q;15q balanced reciprocal translocation and review of the literature. Hum Genet 58:377-386. Greenberg F, Ledbetter DH (1987):Deletions of proximal 15q without Prader-Willi syndrome. Am J Med Genet 28:813-820. Herva R, Vuorinen 0 (1980):Congenital heart disease with del (15q) mosaicism. Clin Genet 17:26-28. Ikeuchi T (1984):Inhibitory effect of ethidium bromide on mitotic chromosome condensation and its application to high-resolution chromosome banding. Cytogenet Cell Genet 38:56-61. Kaplan LC, Wharton R, Elias E, Mandell F, Donlon T, Latt SA (1987): Clinical heterogeneity associated with deletions in the long arm of chromosome 15:Report of 3 new cases and their possible genetic significance. Am J Med Genet 28:45-53. Ledbetter DH, Mascarello JT, Riccardi VM, Harper VD, Airhard SD, Strobe1 R J (1982):Chromosome 15 abnormalities and the PraderWilli syndrome: A follow-up report of 40 cases. Am J Hum Genet 34278-285. Magenis RE, Brown MG, Lacy Da, Budden S, La Franchi S (1987):Is
Angelman syndrome an alternate result ofdel(15q)(qllq13)?Am J Med Genet 28:829-838. Mattei JF, Mattei MG, Giraud F (1983):Prader-Willi syndrome and chromosome 15. A clinical discussion of 20 cases. Hum Genet 64:356-362. Mattei MG, Souiah N,Mattei JF (1984):Chromosome 15 anomalies and the Prader-Willi syndrome: Cytogenetic analysis. Hum Genet 66:313-334. Pauli RM, Meisner LF, Szmanda RJ (1983):“Expanded” Prader-Willi syndrome in a boy with an unusual 15q chromosomedeletion.Am J Dis Child 137:1087-1989. Schwartz S, Max SR, Panny SR, Cohen MM (1985):Deletions of proximal 15 q and non-classical Prader-Willi syndrome phenotypes. Am J Med Genet 20:255-263. Wisniewski LP, Doherty RA (1985): Supernumerary microchromosomes identified as inverted duplications of chromosome 1 5 A report of three cases. Hum Genet 69:161-163.
