- Email: [email protected]
46,XY Mosaicism
Short Stature, Type E Brachydactyly, Exostoses, Gynecomastia, and Cryptorchidism in a Patient with 47,XYY/45,X/46,XY Mosaicism ALEXANDRA MONASTIRLI, MD; GEORGIA STEPHANOU, PHD; SOPHIA GEORGIOU, MD; CONSTANTINOS ANDRIANOPOULOS, MSC; EFI PASMATZI, MD; ELIZABETH CHRONI, MD, PHD; AGGELIKI KATRIVANOU, MD; PANAGIOTIS DIMOPOULOS, MD, PHD; NIKOS A. DEMOPOULOS, PHD; DIONYSIOS TSAMBAOS, MD, PHD
ABSTRACT: We report a 72-year-old male patient with a 47,XYY/45,X/46,XY mosaicism associated with short stature, exostoses, type E brachydactyly, gynecomastia, cryptorchidism, mild mental retardation, and a paranoid personality and conversion disorder. Since his prevalent cell line was 47,XYY (about 75%), our patient could be karyotypically classified as a case of 47,XYY syndrome.
In view of the striking similarity of the clinical features of this case and those of a XYY case previously reported by Ikegawa et al (1992), it seems reasonable to suggest that these patients are representatives of a novel syndrome with a XYY karyotype. KEY INDEXING TERMS: Short stature; Cryptorchidism; Exostoses; Gynecomastia; XYY. [Am J Med Sci 2005;329(4):208–210.]
P
tary school. Family history was negative for mental retardation and antisocial behavior. On examination, the patient had short stature; his height was 143 cm with a sitting height of 88 cm and an arm span of 137 cm. His weight was 97 kg. The patient revealed a bilateral gynecomastia and cryptorchidism, whereas his penis measured 4.4 cm in length. Facial and axillary hair were sparse but pubic hair was normal. Apart from an increase in the serum levels of glucose (147 mg/dL) and uric acid (10.5 mg/dL), all results of hematologic, biochemical, and serologic investigations were within normal limits. The findings of neurologic, neurophysiologic, ophthalmologic, and cardiologic examinations were unremarkable. On psychiatric examination, the patient revealed features of mild mental retardation and a paranoid personality disorder with traits of pervasive suspiciousness and paranoid ideation (Axis II, DSMIV).5 Additionally, symptoms of a conversion disorder (Axis I, DSM-IV) were identified, causing impairment of his social and global functioning. Radiographic investigation demonstrated a bilateral shortening of all metacarpal bones and an exostosis at the anterior aspect of the distal epiphysis of both tibiae. Genetic investigation with conventional G-banding in 118 metaphases of peripheral blood lymphocytes revealed a 47,XYY[88]/ 45,X[3]/46,XY[27] mosaicism with the following cell percentage: 47,XYY ⫽ 74.58%; 46,XY ⫽ 22.88%; 45,X ⫽ 2.54%. In addition, 520 nuclei in interphase lymphocytes were evaluated by fluorescent in situ hybridization (FISH) analysis using a biotin-labeled chromosome Y a-Satellite probe (DYZ3, Oncor). 60.76% of cells showed two hybridization signals, 35.38% showed only one, and 3.85% did not show any hybridization signal at all. FISH analysis confirmed the variation in the number of Y chromosomes. A 60-year-old healthy male subject served as control. Interphase FISH analysis of 2000 nuclei revealed only 0.30% of nuclei with two hybridization signals, 99.35% with one, and 0.35% with no hybridization signal, documenting a clear difference in chromosome Y hyper- and hypodiploidy, as compared with the respective values of the patient.
atients with a 47,XYY karyotype tend to be tall and thin, are often affected by severe nodulocystic acne,1,2 may have small or undescended testicles3 and are not at increased risk of mental retardation, although they may have speech delay, educational difficulties, and hyperactivity.4 We report herein a male patient with a 47,XYY/45,X/ 46,XY mosaicism (with 47,XYY being the prevalent cell line) associated with short stature, exostoses, type E brachydactyly, gynecomastia, cryptorchidism, mild mental retardation, and a paranoid personality and conversion disorder. Case Report A 72-year-old man was admitted to the Department of Dermatology, University of Patras with an acute relapse of his chronic plaque psoriasis. He was the only product of the first and uncomplicated pregnancy of unrelated parents. He was born by vaginal delivery at term; data on birth weight and body length at birth were unavailable. The paternal and maternal ages at birth were 23 years and 18 years, respectively. The patient’s short stature and brachydactyly became evident in the first years of elemen-
From the Departments of Dermatology (AM, SG, EP, DT), Neurology (EC), Psychiatry (AK), and Radiology (PD), and the Division of Genetics, Cell and Developmental Biology (GS, CA, NAD), University of Patras, Patras, Greece. Submitted July 23, 2004; accepted November 19, 2004. Correspondence: A. Monastirli, MD, Department of Dermatology, School of Medicine, University of Patras, P.O. Box 1413, Rio-Patras 265 04, Greece. (E-mail: [email protected])
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Discussion We report a 47,XYY/45,X/46,XY mosaicism with 47,XYY being the prevalent cell line and 45,X cells restricted to a very low percentage. It is possible for such a mosaic to arise as a consequence of various genetic changes resulting in the formation of aneuploid cells. A nondisjunction of chromosome Y at the second meiotic division of the paternal germ cells followed by loss of the same chromosome in somatic cells could result in this mosaic. In addition, mitotic nondisjunction in the early zygotic cleavages could also produce a 47,XYY /45,X or 47,XYY/45,X/46,XY mosaic.6 It is equally possible that an early mitotic nondisjunction could also lead to varying percentage of cells in different tissues. However, our observation is based on the examination of a single tissue, since the patient refused to undergo a skin biopsy that would enable us to investigate at least one additional tissue (skin fibroblasts). Since the original report on the positive correlation of aging and aneuploidy in human peripheral lymphocytes,7 this finding has been verified by various authors in metaphase and mesophase cells.8 –10 Thus, one could argue that the karyotypic findings in our patient are associated with this age. However, at least with regard to mesophase nucleus analysis, the percentage of his Y aneuploid cells (hyper- and hypodiploid) is much higher than that observed in men older than 50 years, in which an effect of age for Y chromosome reciprocal gain and loss as well as a nonsignificant trend to Y hyperdiploid (0.48%) and hypodiploid (0.72%) nuclei have been identified.10 In addition, the Y hyperdiploid (0.30%) and hypodiploid (0.35%) percentages observed in mesophase cells of the control adult are in accordance with the results presented in the last referred study and are much lower than those determined in our patient. Thus, it seems reasonable to suggest that the karyotypic findings in the latter cannot be attributed to the effect of aging. Although there is no direct evidence in the literature about the correlation of Y aneuploidy rate in mesophase with that in metaphase cells, our results demonstrate a good agreement of the different cell line percentages in both mesophase and metaphase cells. However, previously published data suggested that there is a relationship between metaphases lacking the Y chromosome and Y micronucleation in peripheral human lymphocytes and that the effects underlying this observation are age-related.11 In a phenotypic female 45,X/46,XY/47,XYY mosaic with gonadoblastoma, chromosome analysis reportedly showed prevalence of 45,X cells (61.8%) in the blood of the patient and of 46,XY cells (56.2%) in gonadoblastoma.12 Interestingly, the clinical features of this patient included a type E1 brachydactyly, cubitus valgus, deep hair line, melanocytic nevi, and enlarged clitoris. Wilson et al13 presented THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
one patient with 45,X/46,XY/47,XYY mosaic who was reared as a female, in whom chromosome analysis demonstrated two cell lines (46,XY and 47,XYY) in blood culture and one cell line (45,X) in the skin, constituting a three-cell line mosaicism that was also observed in each gonad of the patient. The clinical features of this patient included obesity and clitoris enlargement. Two cases with 45,X/46,XY/ 47,XYY mosaicism were reported in an international survey of prenatally diagnosed mosaicism.14 Rubin et al15 described a case in which three different cell lines— 45,X, 46,XY, and 47,XYY—were observed in different fetal tissues. The newborn child was phenotypically male with a 46,XY/47,XYY karyotype in peripheral blood lymphocytes and foreskin. Kreft et al16 reported a 62-year-old man with gynecomastia and hypergonadotropic hypogonadism in whom a 45,X/46,XY/47,XYY mosaicism was observed in skin fibroblasts (4%/90%/6%) and a 45,X/46,XY mosaicism (10%/90%) in blood lymphocytes. The association of exostoses and type E brachydactyly with XYY karyotype has previously been reported in two male patients.17,18 Ikegawa et al19 described an 18-year-old man with an 47,XYY karyotype, disproportionate short stature, type E brachydactyly, exostoses of both tibiae, hypogonadism, bilateral gynecomastia, and cryptorchidism. The anatomical features of their case and those of the patient reported here are almost identical. However, the intelligence and personality of their patient were normal, whereas our patient revealed a mild mental retardation and a paranoid personality and conversion disorder. Since in our case the prevalent cell line is 47,XYY (about 75%), our patient could be classified as a case of 47,XYY syndrome showing an unusual overall phenotypic pattern. In view of the striking similarity of the clinical features of the XYY case reported by Ikegawa et al and those of the case presented here, it seems reasonable to suggest that these patients represent a novel syndrome with a XYY karyotype. References 1. Voorhees JJ, Wilkins J Jr, Hayes E, et al. The XYY syndrome in prisoners and outpatients with cystic acne. Birth Defects Orig Artic Ser 1971;7:186 –92. 2. Grumbach MM, Conte FA. Disorder of sex differentiation. In Wilson JD, Foster DW (editors). Williams textbook of endocrinology. Philadelphia (PA): WB Saunders; 1992. p 905. 3. Buyse ME. Q Chromosome X, Chromosome XYY. In birth defects encyclopedia. Cambridge (MA): Blackwell Scientific Publications; 1990. p 400 –1. 4. Linden MG, Bender BG, Robinson A. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996;87: 468 –75. 5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994. 6. Levitan M, Montagu A. Textbook of human cytogenetics. New York (NY): Oxford University Press; 1971. p 102–5.
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47,XYY/45,X/46,XY Mosaicism
7. Jacobs PA, Court Brown WM, Kalousek DK. Distribution of human chromosome counts in relation to age. Nature 1961;191:1178 – 80. 8. Richard F, Aurias A, Couturier J, et al. Aneuploidy in human lymphocytes: an extensive study of eight individuals of various ages. Mutat Res 1993;295:71– 80. 9. Guttenbach M, Schakowski R, Schmid M. Aneuploidy and ageing: sex chromosome exclusion into micronuclei. Hum Genet 1994;94:295– 8. 10. Catalan J, Surralles J, Falck GC, et al. Segregation of sex chromosomes in human lymphocytes. Mutagenesis 2000;15: 251–5. 11. Nath J, Tucker J, Hando J. Y chromosome aneuploidy, micronuclei, kinetochores and aging in men. Chromosoma 1995;103:725–31. 12. Osztovics M, Ivady G, Ruzicska P, et al. 45,X/46,XY/ 47,XYY mosaicism in a phenotypic female with gonadoblastoma. Acta Paediatr Acad Sci Hung 1974;15:295–9. 13. Wilson MG, Ebbin AJ, Shinno NW, et al. Sex chromosome mosaicism of X/XY or X/XY/XYY. Birth Defects Orig Artic Ser 1975;5:255– 66.
210
14. Change HJ, Clark RD, Bachman H. The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet 1990;46:156 – 67. 15. Rubin CH, Williams J, Wang BB. Discrepancy in mosaic findings between chorionic villi and amniocytes: a diagnostic dilemma involving 45,X, 46,XY and 47,XYY cell lines. Am J Med Genet 1993;1:457–9. 16. Kreft B, Greiwe M, Schwinger E, et al. Chromosomenmosaik 45,X,/46,XY/ 47,XYY als Ursache eines im höheren Lebensalter festgestellten hypergonadotropen Hypogonadismus. Dtsch Med Wschr 1995;120:1114 –7. 17. Balodimos MC, Lisco H, Irwin I, et al. XYY karyotype in a case of familial hypogonadism. J Clin Endocrinol Metab 1966;26:443–52. 18. Vigi V, Volpato S, Zardini V, et al. XYY in a ten-year-old child with aggressive behavior. Ann Genet 1969;12:202–3. 19. Ikegawa S, Nagano A, Kurokawa T. Disproportionate short stature, type E brachydactyly and exostoses of tibiae in a patient with an XYY karyotype: a “new” syndrome? Clin Dysmorphol 1992;1:217–9.
April 2005 Volume 329 Number 4
ABSTRACT: We report a 72-year-old male patient with a 47,XYY/45,X/46,XY mosaicism associated with short stature, exostoses, type E brachydactyly, gynecomastia, cryptorchidism, mild mental retardation, and a paranoid personality and conversion disorder. Since his prevalent cell line was 47,XYY (about 75%), our patient could be karyotypically classified as a case of 47,XYY syndrome.
In view of the striking similarity of the clinical features of this case and those of a XYY case previously reported by Ikegawa et al (1992), it seems reasonable to suggest that these patients are representatives of a novel syndrome with a XYY karyotype. KEY INDEXING TERMS: Short stature; Cryptorchidism; Exostoses; Gynecomastia; XYY. [Am J Med Sci 2005;329(4):208–210.]
P
tary school. Family history was negative for mental retardation and antisocial behavior. On examination, the patient had short stature; his height was 143 cm with a sitting height of 88 cm and an arm span of 137 cm. His weight was 97 kg. The patient revealed a bilateral gynecomastia and cryptorchidism, whereas his penis measured 4.4 cm in length. Facial and axillary hair were sparse but pubic hair was normal. Apart from an increase in the serum levels of glucose (147 mg/dL) and uric acid (10.5 mg/dL), all results of hematologic, biochemical, and serologic investigations were within normal limits. The findings of neurologic, neurophysiologic, ophthalmologic, and cardiologic examinations were unremarkable. On psychiatric examination, the patient revealed features of mild mental retardation and a paranoid personality disorder with traits of pervasive suspiciousness and paranoid ideation (Axis II, DSMIV).5 Additionally, symptoms of a conversion disorder (Axis I, DSM-IV) were identified, causing impairment of his social and global functioning. Radiographic investigation demonstrated a bilateral shortening of all metacarpal bones and an exostosis at the anterior aspect of the distal epiphysis of both tibiae. Genetic investigation with conventional G-banding in 118 metaphases of peripheral blood lymphocytes revealed a 47,XYY[88]/ 45,X[3]/46,XY[27] mosaicism with the following cell percentage: 47,XYY ⫽ 74.58%; 46,XY ⫽ 22.88%; 45,X ⫽ 2.54%. In addition, 520 nuclei in interphase lymphocytes were evaluated by fluorescent in situ hybridization (FISH) analysis using a biotin-labeled chromosome Y a-Satellite probe (DYZ3, Oncor). 60.76% of cells showed two hybridization signals, 35.38% showed only one, and 3.85% did not show any hybridization signal at all. FISH analysis confirmed the variation in the number of Y chromosomes. A 60-year-old healthy male subject served as control. Interphase FISH analysis of 2000 nuclei revealed only 0.30% of nuclei with two hybridization signals, 99.35% with one, and 0.35% with no hybridization signal, documenting a clear difference in chromosome Y hyper- and hypodiploidy, as compared with the respective values of the patient.
atients with a 47,XYY karyotype tend to be tall and thin, are often affected by severe nodulocystic acne,1,2 may have small or undescended testicles3 and are not at increased risk of mental retardation, although they may have speech delay, educational difficulties, and hyperactivity.4 We report herein a male patient with a 47,XYY/45,X/ 46,XY mosaicism (with 47,XYY being the prevalent cell line) associated with short stature, exostoses, type E brachydactyly, gynecomastia, cryptorchidism, mild mental retardation, and a paranoid personality and conversion disorder. Case Report A 72-year-old man was admitted to the Department of Dermatology, University of Patras with an acute relapse of his chronic plaque psoriasis. He was the only product of the first and uncomplicated pregnancy of unrelated parents. He was born by vaginal delivery at term; data on birth weight and body length at birth were unavailable. The paternal and maternal ages at birth were 23 years and 18 years, respectively. The patient’s short stature and brachydactyly became evident in the first years of elemen-
From the Departments of Dermatology (AM, SG, EP, DT), Neurology (EC), Psychiatry (AK), and Radiology (PD), and the Division of Genetics, Cell and Developmental Biology (GS, CA, NAD), University of Patras, Patras, Greece. Submitted July 23, 2004; accepted November 19, 2004. Correspondence: A. Monastirli, MD, Department of Dermatology, School of Medicine, University of Patras, P.O. Box 1413, Rio-Patras 265 04, Greece. (E-mail: [email protected])
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April 2005 Volume 329 Number 4
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Discussion We report a 47,XYY/45,X/46,XY mosaicism with 47,XYY being the prevalent cell line and 45,X cells restricted to a very low percentage. It is possible for such a mosaic to arise as a consequence of various genetic changes resulting in the formation of aneuploid cells. A nondisjunction of chromosome Y at the second meiotic division of the paternal germ cells followed by loss of the same chromosome in somatic cells could result in this mosaic. In addition, mitotic nondisjunction in the early zygotic cleavages could also produce a 47,XYY /45,X or 47,XYY/45,X/46,XY mosaic.6 It is equally possible that an early mitotic nondisjunction could also lead to varying percentage of cells in different tissues. However, our observation is based on the examination of a single tissue, since the patient refused to undergo a skin biopsy that would enable us to investigate at least one additional tissue (skin fibroblasts). Since the original report on the positive correlation of aging and aneuploidy in human peripheral lymphocytes,7 this finding has been verified by various authors in metaphase and mesophase cells.8 –10 Thus, one could argue that the karyotypic findings in our patient are associated with this age. However, at least with regard to mesophase nucleus analysis, the percentage of his Y aneuploid cells (hyper- and hypodiploid) is much higher than that observed in men older than 50 years, in which an effect of age for Y chromosome reciprocal gain and loss as well as a nonsignificant trend to Y hyperdiploid (0.48%) and hypodiploid (0.72%) nuclei have been identified.10 In addition, the Y hyperdiploid (0.30%) and hypodiploid (0.35%) percentages observed in mesophase cells of the control adult are in accordance with the results presented in the last referred study and are much lower than those determined in our patient. Thus, it seems reasonable to suggest that the karyotypic findings in the latter cannot be attributed to the effect of aging. Although there is no direct evidence in the literature about the correlation of Y aneuploidy rate in mesophase with that in metaphase cells, our results demonstrate a good agreement of the different cell line percentages in both mesophase and metaphase cells. However, previously published data suggested that there is a relationship between metaphases lacking the Y chromosome and Y micronucleation in peripheral human lymphocytes and that the effects underlying this observation are age-related.11 In a phenotypic female 45,X/46,XY/47,XYY mosaic with gonadoblastoma, chromosome analysis reportedly showed prevalence of 45,X cells (61.8%) in the blood of the patient and of 46,XY cells (56.2%) in gonadoblastoma.12 Interestingly, the clinical features of this patient included a type E1 brachydactyly, cubitus valgus, deep hair line, melanocytic nevi, and enlarged clitoris. Wilson et al13 presented THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
one patient with 45,X/46,XY/47,XYY mosaic who was reared as a female, in whom chromosome analysis demonstrated two cell lines (46,XY and 47,XYY) in blood culture and one cell line (45,X) in the skin, constituting a three-cell line mosaicism that was also observed in each gonad of the patient. The clinical features of this patient included obesity and clitoris enlargement. Two cases with 45,X/46,XY/ 47,XYY mosaicism were reported in an international survey of prenatally diagnosed mosaicism.14 Rubin et al15 described a case in which three different cell lines— 45,X, 46,XY, and 47,XYY—were observed in different fetal tissues. The newborn child was phenotypically male with a 46,XY/47,XYY karyotype in peripheral blood lymphocytes and foreskin. Kreft et al16 reported a 62-year-old man with gynecomastia and hypergonadotropic hypogonadism in whom a 45,X/46,XY/47,XYY mosaicism was observed in skin fibroblasts (4%/90%/6%) and a 45,X/46,XY mosaicism (10%/90%) in blood lymphocytes. The association of exostoses and type E brachydactyly with XYY karyotype has previously been reported in two male patients.17,18 Ikegawa et al19 described an 18-year-old man with an 47,XYY karyotype, disproportionate short stature, type E brachydactyly, exostoses of both tibiae, hypogonadism, bilateral gynecomastia, and cryptorchidism. The anatomical features of their case and those of the patient reported here are almost identical. However, the intelligence and personality of their patient were normal, whereas our patient revealed a mild mental retardation and a paranoid personality and conversion disorder. Since in our case the prevalent cell line is 47,XYY (about 75%), our patient could be classified as a case of 47,XYY syndrome showing an unusual overall phenotypic pattern. In view of the striking similarity of the clinical features of the XYY case reported by Ikegawa et al and those of the case presented here, it seems reasonable to suggest that these patients represent a novel syndrome with a XYY karyotype. References 1. Voorhees JJ, Wilkins J Jr, Hayes E, et al. The XYY syndrome in prisoners and outpatients with cystic acne. Birth Defects Orig Artic Ser 1971;7:186 –92. 2. Grumbach MM, Conte FA. Disorder of sex differentiation. In Wilson JD, Foster DW (editors). Williams textbook of endocrinology. Philadelphia (PA): WB Saunders; 1992. p 905. 3. Buyse ME. Q Chromosome X, Chromosome XYY. In birth defects encyclopedia. Cambridge (MA): Blackwell Scientific Publications; 1990. p 400 –1. 4. Linden MG, Bender BG, Robinson A. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996;87: 468 –75. 5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994. 6. Levitan M, Montagu A. Textbook of human cytogenetics. New York (NY): Oxford University Press; 1971. p 102–5.
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47,XYY/45,X/46,XY Mosaicism
7. Jacobs PA, Court Brown WM, Kalousek DK. Distribution of human chromosome counts in relation to age. Nature 1961;191:1178 – 80. 8. Richard F, Aurias A, Couturier J, et al. Aneuploidy in human lymphocytes: an extensive study of eight individuals of various ages. Mutat Res 1993;295:71– 80. 9. Guttenbach M, Schakowski R, Schmid M. Aneuploidy and ageing: sex chromosome exclusion into micronuclei. Hum Genet 1994;94:295– 8. 10. Catalan J, Surralles J, Falck GC, et al. Segregation of sex chromosomes in human lymphocytes. Mutagenesis 2000;15: 251–5. 11. Nath J, Tucker J, Hando J. Y chromosome aneuploidy, micronuclei, kinetochores and aging in men. Chromosoma 1995;103:725–31. 12. Osztovics M, Ivady G, Ruzicska P, et al. 45,X/46,XY/ 47,XYY mosaicism in a phenotypic female with gonadoblastoma. Acta Paediatr Acad Sci Hung 1974;15:295–9. 13. Wilson MG, Ebbin AJ, Shinno NW, et al. Sex chromosome mosaicism of X/XY or X/XY/XYY. Birth Defects Orig Artic Ser 1975;5:255– 66.
210
14. Change HJ, Clark RD, Bachman H. The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet 1990;46:156 – 67. 15. Rubin CH, Williams J, Wang BB. Discrepancy in mosaic findings between chorionic villi and amniocytes: a diagnostic dilemma involving 45,X, 46,XY and 47,XYY cell lines. Am J Med Genet 1993;1:457–9. 16. Kreft B, Greiwe M, Schwinger E, et al. Chromosomenmosaik 45,X,/46,XY/ 47,XYY als Ursache eines im höheren Lebensalter festgestellten hypergonadotropen Hypogonadismus. Dtsch Med Wschr 1995;120:1114 –7. 17. Balodimos MC, Lisco H, Irwin I, et al. XYY karyotype in a case of familial hypogonadism. J Clin Endocrinol Metab 1966;26:443–52. 18. Vigi V, Volpato S, Zardini V, et al. XYY in a ten-year-old child with aggressive behavior. Ann Genet 1969;12:202–3. 19. Ikegawa S, Nagano A, Kurokawa T. Disproportionate short stature, type E brachydactyly and exostoses of tibiae in a patient with an XYY karyotype: a “new” syndrome? Clin Dysmorphol 1992;1:217–9.
April 2005 Volume 329 Number 4