American Journal of Medical Genetics 41:267-268 (1991)
Letter to the Editor
Isodicentric Xq in Klinefelter Syndrome To the Editor: Richer et al. [19891reported on a man with Klinefelter syndrome (KS) and isochromosome Xq. This has suggested the existence of a specific isochromosome Xq KS presenting with a lack of height increase. This observation seems substantiated by several reported patients [Donlan et al., 1987; Gardiner et al., 1978; Geneix et al., 1983; Kalousek et al., 1978; Kleczkowska et al., 1988; Ponzio et al., 1980; Richer et al., 1989; Trunca et al., 1979; Zang et al., 1969; Table I], although this point should be judged comparing the patients to their parents and sibs. In fact, a nonmosaic i(Xq) KS man [Kleczkowskaet al., 19881with an increased height (198 cm) has questioned the existence of a distinct phenotype associated with this rare cytogenetic variant of KS [F'ryns et al., 19901. We report here the clinical, hormonal, and cytogenetic data of a man with KS due to an isodicentric Xq, a hitherto undescribed chromosome complement which widens the genotypic spectrum of this syndrome.
CLINICAL REPORT M.M., a 27-year-old man, was evaluated for infertility. He weighed 75 kg and measured 178 cm. He was taller than his father (168 cm) and mother (157 cm). His span was 180 cm. He had normal secondary sexual characteristics, small atrophic testes, and no gynecomastia. Dermatoglyphics showed the right hand with fingertip pattern 1-2 whorl and 3-5 ulnar loop, I3 and I4 distal loop, and t and the left hand with fingertip pattern 1 whorl and 2-5 ulnar loop, I4 distal loop, and t. Puberty occurred a t 14 years and organic function with ejaculation began at 16 years. His libido was high. He had an infantile personality and I.&. was 80 (WAIS developmental scale). Semen volume was normal. Four samples showed azoospermia, normal levels of acid phosphates and fructose and, no cells of the spermatogenetic line. Hormonal investigations showed elevated levels of basal plasma FSH (92.2 mU.I./ml) (normal range 5-20 mUI/ml) and LH (59.0 mUI/ml) (normal range 5-20 mUI/ml), while testosterone levels were slightly reduced (0.98 ng/ml) (normal range 2.8-8.2 ng/ml). Received for publication October 29,1990; revision received January 28, 1991. Address reprint requests to Dr. L. Zelante, Servizio di Genetica Medica, Ospedale CSS, 1-71013 San Giovanni Rotondo, Foggia, Italy.
0 1991 Wiley-Liss, Inc.
Chromosome analyses were performed on peripheral blood lymphocytes and from skin fibroblasts, with similar results. All cells examined had an extra isodicentric X chromosome interpreted as idic(X) (pter + q22::q22 -+ pter) (Fig. 1).The pattern of DNA replication was studied by adding BrdU 7 hours before fixation. The idic(Xq) invariably was late replicating. The parents had normal chromosomes.
DISCUSSION Different observations of patients with iso(Xq) and a patient with 47,X,del(Xp)Y [F'ryns, 19821have substantiated the fact that the addition of Xq material results in azoospermia and hormonal changes of KS. This seems the case also in partial addition of Xq as suggested by a man with 47,X,del(Xq),Y[Patil et al., 19811. The present patient with an idic(Xq) and KS had duplication of Xp and partial duplication of Xq. This abnormal chromosome could have originated from an isochromatid break in the G2 phase, followed by fusion of the broken sister chromatids or from breakage in the G1 phase
a
b
GAG
0FO
C
d
RBG
CBG
Fig. 1 Partial karyotype of normal (at left) and isodicentricX chromosome (at right) of four selected cells from the patient a) GAG bands, b) QFQ bands, c) RBG bands, and d) CBG bands.
268
Zelante et al. TABLE I. Reported Cases of Klinefelter syndrome With Isochromosome Xu Height Case ____ 1 2 3 4 5 6 7 8 9 10 11 12
Authors
Age
(cm)
Zang et al., 1969 Gardiner et al., 1978 McDermott, 1978 Kalousek e t al., 1978 Trunca et al., 1979 Ponzio et al., 1980 Geneix et al., 1981 Donlan e t al., 1987 Kleczkowska et al., 1988 Kleczkowska e t al., 1988 Richer et al., 1989 Present case
44 36 ? 24 32 33 31 17 28 18 30 27
176 165 163 166 ? 168 166 160 198 164.5 165 178
and fusion of broken ends during or after replication [Dewalds, 19831. This patient had tall stature similar to that of a few known KS patients with a structurally rearranged extra X chromosome. He has three copies of Xp and three copies of Xq. The delineation of a specific Xq KS with lack of height increase was based on the presence of three copies of Xq with a single copy of Xp. The increased height in our case gives support to the fact that extra Xp material might be causally associated with height increase.
REFERENCES Dewald GW (1983): Isodicentric X chromosome in humans: Origin, segregation behavior, and replication band patterns. In Sandberg AA (ed): “Cytogenetics of the Mammalian X Chromosome, Part A, Basic Mechanism of X Chromosome Behavior”. New York: Alan R Liss, pp 405-426. Donlan MA, Dolan CR, Metcalf MJ, Bradley CM, Salk D (1987): Trisomy Xq in a male: The isochromosome X Klinefelter syndrome. Am J Med Genet 27:189-194. Fryns J P (1982): Klinefelter syndrome and the Xqll-22 region. Clin Genet 20:237. Fryns JP, Kleczkowska A, Steeno 0 (1990): Isochromosome Xq in Klinefelter syndrome. Am J Med Genet 36:365. Gardiner A, Brown MM, Gray J E (1978): Unusual chromosome variant in Klinefelter’s syndrome. Br Med J 21123. Geneix A, Janny L, Perissel B, Hermabassiere J, Loubier R, Malet P (1983): 47,X,iso(Xq),Y karyotype. A new case. Pathologica 75425428.
Weight (kg) 84 ? 53
Karyotype Xi(Xq)Y Xi(Xq)Y Xi(Xa)Y
57 60 89 57 59 75
Xi(Xq)Y Xi(Xq)Y XXY/XXi(Xa)Y Xi(Xq)Y Xidic(Xq)Y
Kalousek D, Cushman Biddle CJ, Rudner M, Arronet GH, Fraser FC (1978): 47,X,i(Xq),Y karyotype in Klinefelter’s syndrome. Hum Genet 43:107-110. Kleczkowska A, Fryns JP, Van den Berghe H (1988): X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet 80:16-22 Patil SR, Bartley JA, Hanson W (1981): Association of the X chromosomal region qll-22 and Klinefelter syndrome. Clin Genet 19:342-346. Ponzio G, De Marchi M, Gallone G, Fonzo D, Carbonara A 0 (1980): A case of Klinefelter’s syndrome with 47,XXXq)Y karyotype. J Med Genet 17:152-155. Richer CL, Bleau G, Chapdelaine A, Murer-Orlando M, Lemieux N, Cadotte M (1989): A man with isochromosome Xq Klinefelter syndrome with lack of height increase and normal androgenization. Am J Med Genet 3242-44. Trunca C, Roginsky M, Ugrinsky C, Milson J (1979): 47,X,i(Xq),Y:An unusual chromosome complement associated with the Klinefelter syndrome. Am J Hum Genet 31:113A (abstract). Zang KD, Singer H, Loeffler L, Souvatzoglou A., Halbfass J, Mehnert H (1969): Klinefelter-Syndrom mit dem Chromosomensatz 47,XXpiY [sic]. Eine neue genetische Variante des Syndroms. Klin Wochenschr 47:237-244.
LeoDoldo Zelante Savino Calvano Servizio di Genetica Medica Ospedale CCS San Giovanni Rotondo, Italy Bruno Dallapiccola Cattedra di Genetica Umana I1 Universita di Roma, Italy
Letter to the Editor
Isodicentric Xq in Klinefelter Syndrome To the Editor: Richer et al. [19891reported on a man with Klinefelter syndrome (KS) and isochromosome Xq. This has suggested the existence of a specific isochromosome Xq KS presenting with a lack of height increase. This observation seems substantiated by several reported patients [Donlan et al., 1987; Gardiner et al., 1978; Geneix et al., 1983; Kalousek et al., 1978; Kleczkowska et al., 1988; Ponzio et al., 1980; Richer et al., 1989; Trunca et al., 1979; Zang et al., 1969; Table I], although this point should be judged comparing the patients to their parents and sibs. In fact, a nonmosaic i(Xq) KS man [Kleczkowskaet al., 19881with an increased height (198 cm) has questioned the existence of a distinct phenotype associated with this rare cytogenetic variant of KS [F'ryns et al., 19901. We report here the clinical, hormonal, and cytogenetic data of a man with KS due to an isodicentric Xq, a hitherto undescribed chromosome complement which widens the genotypic spectrum of this syndrome.
CLINICAL REPORT M.M., a 27-year-old man, was evaluated for infertility. He weighed 75 kg and measured 178 cm. He was taller than his father (168 cm) and mother (157 cm). His span was 180 cm. He had normal secondary sexual characteristics, small atrophic testes, and no gynecomastia. Dermatoglyphics showed the right hand with fingertip pattern 1-2 whorl and 3-5 ulnar loop, I3 and I4 distal loop, and t and the left hand with fingertip pattern 1 whorl and 2-5 ulnar loop, I4 distal loop, and t. Puberty occurred a t 14 years and organic function with ejaculation began at 16 years. His libido was high. He had an infantile personality and I.&. was 80 (WAIS developmental scale). Semen volume was normal. Four samples showed azoospermia, normal levels of acid phosphates and fructose and, no cells of the spermatogenetic line. Hormonal investigations showed elevated levels of basal plasma FSH (92.2 mU.I./ml) (normal range 5-20 mUI/ml) and LH (59.0 mUI/ml) (normal range 5-20 mUI/ml), while testosterone levels were slightly reduced (0.98 ng/ml) (normal range 2.8-8.2 ng/ml). Received for publication October 29,1990; revision received January 28, 1991. Address reprint requests to Dr. L. Zelante, Servizio di Genetica Medica, Ospedale CSS, 1-71013 San Giovanni Rotondo, Foggia, Italy.
0 1991 Wiley-Liss, Inc.
Chromosome analyses were performed on peripheral blood lymphocytes and from skin fibroblasts, with similar results. All cells examined had an extra isodicentric X chromosome interpreted as idic(X) (pter + q22::q22 -+ pter) (Fig. 1).The pattern of DNA replication was studied by adding BrdU 7 hours before fixation. The idic(Xq) invariably was late replicating. The parents had normal chromosomes.
DISCUSSION Different observations of patients with iso(Xq) and a patient with 47,X,del(Xp)Y [F'ryns, 19821have substantiated the fact that the addition of Xq material results in azoospermia and hormonal changes of KS. This seems the case also in partial addition of Xq as suggested by a man with 47,X,del(Xq),Y[Patil et al., 19811. The present patient with an idic(Xq) and KS had duplication of Xp and partial duplication of Xq. This abnormal chromosome could have originated from an isochromatid break in the G2 phase, followed by fusion of the broken sister chromatids or from breakage in the G1 phase
a
b
GAG
0FO
C
d
RBG
CBG
Fig. 1 Partial karyotype of normal (at left) and isodicentricX chromosome (at right) of four selected cells from the patient a) GAG bands, b) QFQ bands, c) RBG bands, and d) CBG bands.
268
Zelante et al. TABLE I. Reported Cases of Klinefelter syndrome With Isochromosome Xu Height Case ____ 1 2 3 4 5 6 7 8 9 10 11 12
Authors
Age
(cm)
Zang et al., 1969 Gardiner et al., 1978 McDermott, 1978 Kalousek e t al., 1978 Trunca et al., 1979 Ponzio et al., 1980 Geneix et al., 1981 Donlan e t al., 1987 Kleczkowska et al., 1988 Kleczkowska e t al., 1988 Richer et al., 1989 Present case
44 36 ? 24 32 33 31 17 28 18 30 27
176 165 163 166 ? 168 166 160 198 164.5 165 178
and fusion of broken ends during or after replication [Dewalds, 19831. This patient had tall stature similar to that of a few known KS patients with a structurally rearranged extra X chromosome. He has three copies of Xp and three copies of Xq. The delineation of a specific Xq KS with lack of height increase was based on the presence of three copies of Xq with a single copy of Xp. The increased height in our case gives support to the fact that extra Xp material might be causally associated with height increase.
REFERENCES Dewald GW (1983): Isodicentric X chromosome in humans: Origin, segregation behavior, and replication band patterns. In Sandberg AA (ed): “Cytogenetics of the Mammalian X Chromosome, Part A, Basic Mechanism of X Chromosome Behavior”. New York: Alan R Liss, pp 405-426. Donlan MA, Dolan CR, Metcalf MJ, Bradley CM, Salk D (1987): Trisomy Xq in a male: The isochromosome X Klinefelter syndrome. Am J Med Genet 27:189-194. Fryns J P (1982): Klinefelter syndrome and the Xqll-22 region. Clin Genet 20:237. Fryns JP, Kleczkowska A, Steeno 0 (1990): Isochromosome Xq in Klinefelter syndrome. Am J Med Genet 36:365. Gardiner A, Brown MM, Gray J E (1978): Unusual chromosome variant in Klinefelter’s syndrome. Br Med J 21123. Geneix A, Janny L, Perissel B, Hermabassiere J, Loubier R, Malet P (1983): 47,X,iso(Xq),Y karyotype. A new case. Pathologica 75425428.
Weight (kg) 84 ? 53
Karyotype Xi(Xq)Y Xi(Xq)Y Xi(Xa)Y
57 60 89 57 59 75
Xi(Xq)Y Xi(Xq)Y XXY/XXi(Xa)Y Xi(Xq)Y Xidic(Xq)Y
Kalousek D, Cushman Biddle CJ, Rudner M, Arronet GH, Fraser FC (1978): 47,X,i(Xq),Y karyotype in Klinefelter’s syndrome. Hum Genet 43:107-110. Kleczkowska A, Fryns JP, Van den Berghe H (1988): X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet 80:16-22 Patil SR, Bartley JA, Hanson W (1981): Association of the X chromosomal region qll-22 and Klinefelter syndrome. Clin Genet 19:342-346. Ponzio G, De Marchi M, Gallone G, Fonzo D, Carbonara A 0 (1980): A case of Klinefelter’s syndrome with 47,XXXq)Y karyotype. J Med Genet 17:152-155. Richer CL, Bleau G, Chapdelaine A, Murer-Orlando M, Lemieux N, Cadotte M (1989): A man with isochromosome Xq Klinefelter syndrome with lack of height increase and normal androgenization. Am J Med Genet 3242-44. Trunca C, Roginsky M, Ugrinsky C, Milson J (1979): 47,X,i(Xq),Y:An unusual chromosome complement associated with the Klinefelter syndrome. Am J Hum Genet 31:113A (abstract). Zang KD, Singer H, Loeffler L, Souvatzoglou A., Halbfass J, Mehnert H (1969): Klinefelter-Syndrom mit dem Chromosomensatz 47,XXpiY [sic]. Eine neue genetische Variante des Syndroms. Klin Wochenschr 47:237-244.
LeoDoldo Zelante Savino Calvano Servizio di Genetica Medica Ospedale CCS San Giovanni Rotondo, Italy Bruno Dallapiccola Cattedra di Genetica Umana I1 Universita di Roma, Italy
