A Case Report of a Child with a Marker Chromosome Presenting As Isodicentric Yp and Literature Review

Available online at www.annclinlabsci.org 352 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015 A Case Report of a Child with a Marker Chromosome Presenting as Isodicentric Yp and Literature Review

Chi Hyun Cho1, Baik-Lin Eun2, Seon Hee Kwon1, Myung Hyun Nam1, Chae Seung Lim1, Chang Kyu Lee1, Yunjung Cho1, Young Kee Kim1, and Soo Young Yoon1

1Department of Laboratory Medicine, College of Medicine, Korea University and 2Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea

Introduction skills equivalent to those of a normal 2.5 and 2 year old, respectively. His gross and fine motor development has Abnormal Y chromosome includes Yq– of various been normal. Examination demonstrated head circum- th th extents (excluding normal Yq variation), Yp–, r(Y), ference 52.5 cm (75 –90 centile). He had a non-dys- and isochromosomes or isodicentric chromosomes, morphic facial appearance and his eyes and ears were normally set. His external genitalia were normally written variously as i(Yp), idic(Yp), i(Yq), and developed. idic(Yq) [1]. The least rare of these rare conditions is the Y isochromosome, or isodicentric chromo- Chromosome analysis with peripheral blood was per- some, usually seen as 46,X,i(Y)(p10) or 46,X,i(Y) formed as part of the investigation of his speech delay. (q11), in which the essential imbalance is a double The karyotype was interpreted as 46,X,+mar (Figure 1). dose of Yp material, and absence (or nearly so) of Marker chromosome was identified as an isochromo- Yq [1]. There have only been a few definite reports some of the Y chromosome short arm by three kinds of of nonmosaic isodicentric Yp [2-4]. We describe a fluorescence in situ hybridization (FISH) studies using case with non-mosaic isochromosome of the short the following probes: (1) Probes for the X centromere arm of Y in which the phenotype includes mild de- (CEP X, alpha satellite, and DXZ1) and the SRY gene on Yp11.3 (2) Probes for the X centromere (CEP X, al- velopmental delay, heart defects, normal genitalia, pha satellite, and DXZ1) and the Y heterochromatin on and normal stature. In addition, we review the lit- Yq12 (CEP Y, satellite III, and DYZ1) (3) Probes for the erature associated with non-mosaic isochromosome X centromere (CEP X, alpha satellite, and DXZ1) and of the short arm of Y. the Y centromere (CEP Y, alpha satellite, and DYZ3). The Y isochromosome shown to be dicentric, included Case Report the Y chromosome short arms and proximal Y long arm material between the two centromeres with the break at The proband is a 5-year-old boy who is the second child Yq11.2. The patient’s karyotype was interpreted as to non-consanguineous Korean parents. The cousin of 46,X,?i(Y)(p10).ish idic(Y)(q11.2)(DXZ1+, SRY++, the proband had a history of developmental delay; he DYZ3++, DYZ1-) (Figure 2). G-banding and FISH started talking at the age of 6 years. He was born at term studies on 50 cells showed no evidence of mosaicism. following ceasarean section due to no progress in in- Parental chromosomes have been normal. duced labor, with birth weight of 3.3 kg. At birth, he had an atrial septal defect (ASD) and a ventricular septal Discussion defect (VSD). He was regularly checked up for heart defects in the pediatric department, and he had the ASD Y isochromosome may be seen in both non-mosaic and VSD closed at the age of one and four years, respec- and (typically more) mosaic form [1]. However, al- tively. In addition, he had a protruding umbilicus with most all cases to date have been mosaic cases, with discharge, for which he was checked up in the department of colorectal surgery. Additionally, concerns about the second cell line typically being 45, X [1,2]. To his language development arose from the age of 2 years. our knowledge, there were five cytogenetic studies At 4 years, he had receptive and expressive language worldwide in which non-mosaic isochromosome of the short arm of Y was identified definitely [2-5].

Address correspondence to Soo Young Yoon, Department of The phenotype in those cases has ranged from de- Laboratory Medicine, Guro Hospital, Korea University College of velopmentally delayed but otherwise normal male Medicine, Guro 2 Dong, Guro Gu, Seoul 152-703, Republic of Korea; phone: +82 2 2636 3246; fax: +82 2 2626 1465; e mail: labmd@ to actual genital ambiguity (Table 1). While the korea.ac.kr; case no. 2, 3, and 5 had developmental delay as a

Table 1. Cytogenetic and clinical findings of the reported cases with non mosaic isochromosome of the Short Arm of Y.

Author No. Age and sex Karyotype in PB FISH Clinical findings

Genuardi 1 16 year 46,X,idic(Y)(q11.2) Nil Primary amenorrhoea, et al. (1995) old/female hypotrophic female ex ternal genitalia, 2 cm blind-ended vagina, inguinally situated tes tes but no female inter nal genitalia, normal stature, no develop mental delay Neas 2 4 year 46,X,?i(Y)(p10) Ish idic(Y)(q11.2) Mild developmental et al. (2005) old/male (DYZ3++,SRY++) delay,normal genitalia, and normal stature Bruyere 3 Prenataly 46,X,idic(Y)(q11.2) [FU] ish idic(Y) Normal male genitalia et al. (2006) dignosed case/male (SRY++) at birth and at 8 months, Height at 95th centile DesGroseilliers 4 4 year 46,X,idic(Y)(q11.2) Ish idic(Y)(q11.2) Dysmorphic features, et al. (2006) old/male (SRY++,DYZ3++, high growth DYZ1-) parameters, global de velopmental delay, dyspraxia DesGroseilliers 5 2 year 46,X,idic(Y)(q11.2) Ish idic(Y)(q11.2) Mild language delay et al. (2006) old/male (91H4.5++, DYZ3++,DYZ1-) Mild developmental This case 6 5 year 46,X,?i(Y)(p10) Ish idic(Y)(q11.2) delay, heart defects, old/male (DXZ1+, SRY++, normal genitalia, and DYZ3++, DYZ1-) normal stature

Abbreviations: FU, follow up; Nil, no study or no information; No., number; PB, peripheral blood.

main clinical feature, case no. 4 and our case had dyspraxia and heart defects as an addi- tional clinical feature, respectively. The existence of a low level of mosaicism for an un- identified second cell line could have resulted in the var- iegated phenotypes of the reported cases shown in table 1 [2,6].

Notably, five cases among six cases had a developmental delay (Table 1). Each sex chromosome has two pseudoauto- somal regions (PAR1 and PAR2). The genes identified in PAR2 have no known role Figure 1. G-banded Karyotype demonstrating an isodicentric Yp. 354 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015 (associated with normal X chromosome and two Yp) could have caused developmental delay, although further genetic tests were not per- formed due to non-approval by the parents.

Given that absence of SRY present in Yp leads to female development [1], in all cases except case No. 1, the probands were males with normal genitalia (Table 1). However, case No. 1 was a 16-year-old female with primary amenorrhoea and normal stature in spite of the pres- ence of Yp. She had hypotrophic female external genitalia, a 2 cm blind-ended vagina, and inguinally situated testes but no female internal genitalia [5]. In Figure 2. Interphase (A) and metaphase (B) fluorescence in situ hybridization (FISH) results, showing the probe DXZ1 (green) and duplication of the probe SRY (red). Interphase (C) and that case, there metaphase (D) FISH results, showing the probe DXZ1 (red) and absence of the probe DYZ1 for might be a muta- Y heterochromatin (green). Interphase (E) and metaphase (F) FISH results, showing the probe tion in SRY or DXZ1 (green) and duplication of the probe DYZ3 (red). other genes controlling a later in neurodevelopment [7]. Whereas, PAR1 at the tip event in the testicular developmental pathway [9]. of the short arm (Xp-Yp PAR) is thought to play a Those genes include WT1, SF1, WNT4, RSPO1, role in the neuropsychiatric features. Neas et al. re- SOX9, FGF9, MAP3K1, CBX2, DHH, DAX1, ported a case of non-mosaic isodicentric Yp with DMRT1, SOX3, and TSPYL1 [9]. mild developmental delay, normal genitalia, and normal stature [7,8]. They suggested that the pa- The genes controlling spermatogenesis are located tient was trisomic for PAR1, and had mild develop- in Yq11.2 [10]. It has been postulated that Yq11 mental delay not unlike that seen in some girls with encompasses three nonoverlapping regions, AZFa, 47,XXX [2]. Similarly, three PAR1 in our case AZFb, and AZFc, which could be responsible for Spinal stenosis with paraparesis in AHO boy: a novel GNAS mutation 355

disruption of spermatogenesis [10]. Accordingly, 2. Neas KR, Yip MY, James C, Kirk EP. Patient with a non-mosaic isodicentric Yp and mild developmental delay. Am J Med intactness of Yp with loss of Yq loci, and in particu- Genet A 2005;137:223-224. lar the azoospermia factor regions (AZF) spermato- 3. Bruyere H, Speevak MD, Winsor EJ, de Freminville B, Farrell genesis loci, is associated with male infertility [1]. SA, McGowan-JordanJ, McGillivray B, Chitayat D, McFadden D, Adouard V, Terespolsky D, Prieur F, Pantzar T, Hrynchak Therefore, the four cases in Table 1 (No. 2,3,4,5) M. Isodicentric Yp: prenatal diagnosis and outcome in 12 cases. and our case could have had infertility but were not Prenat Diagn 2006;26:324-329. tested for infertility. 4. DesGroseilliers M, Beaulieu Bergeron M, Brochu P, Lemyre E, Lemieux N. Phenotypic variability in isodicentric Y patients: study of nine cases. Clin Genet 2006;70:145-150. In conclusion, we have presented the cytogenetic 5. Genuardi M, Bardoni B, Floridia G, Chiurazzi P, Scarano G, Zollino M, Garcea N, Martini-Neri ME, Neri G. Dicentric analysis of a case with non-mosaic isodicentric Yp, chromosome Y associated with Leydig cell agenesis and sex re- reviewing the previously reported five cases. versal. Clin Genet 1995;47:38-41. Nevertheless, further cases need to be reported to 6. Codina-Pascual M, Oliver-Bonet M, Navarro J, Starke H, Liehr T, Gutierrez-Mateo C, Sanchez-Garcia JF, Arango O, elucidate clearly the correlation between the pheno- Egozcue J, Benet J. FISH characterization of a dicentric Yq type and the karyotype. (p11.32) isochromosome in an azoospermic male. Am J Med Genet A 2004;127A:302-306. Acknowledgment 7. Charchar FJ, Svartman M, El-Mogharbel N, Ventura M, Kirby P, Matarazzo MR, Ciccodicola A, Rocchi M, D'Esposito M, This research was supported by Basic Science Research Program Graves JA. Complex events in the evolution of the human pseu- through the National Research Foundation of Korea (NRF) doautosomal region 2 (PAR2). Genome Res 2003;13:281-286. funded by the Ministry of Science, ICT & Future Planning 8. Bender BG, Linden MG, Harmon RJ. Neuropsychological and (No. 2008-0061891). The authors would like to thank the as- functional cognitive skills of 35 unselected adults with sex sistance of Myung Soon Cho and Jung Hee Kim, Medical chromosome abnormalities. Am J Med Genet Technicians of the Korea University Guro Hospital. 2001;102:309-313. 9. Gardner RJM. Chapter 20. Chromosomal Disorders of Sex References Development. In: Chromosomal Abnormalities and Genetic Counseling, 4th ed (Gardner RJM, Sutherland GR, Shaffer 1. Gardner RJM. Chapter 27. Chromosome Abnormalities LG, Eds), Oxford University Press, 198 Madison Avenue, New Detected at Prenatal Diagnosis. In: Chromosomal York, New York 10016, USA, 2012; pp 333-340. Abnormalities and Genetic Counseling, 4th ed (Gardner RJM, 10. Lin YH, Chuang L, Lin YM, Lin YH, Teng YN, Kuo PL. Sutherland GR, Shaffer LG, Eds), Oxford University Press, 198 Isochromosome of Yp in a man with Sertoli-cell-only syn- Madison Avenue, New York, New York 10016, USA, 2012; pp drome. Fertil Steril 2005;83:764-766. 439-488.