Available online at www.annclinlabsci.
org
Annals of Clinical & Laboratory Science, vol. 47, no. 6, 2017 761
A Novel Sex Chromosome Mosaicism
45,X/45,Y/46,XY/46,YY/47,XYY Causing Ambiguous
Genitalia
Muhammad Riaz Khan1,*, Ihtisham Bukhari1,3,*, Tang Junxiang2, Liu Hui2, Niaz Muhammad5, Cui Fan4,
Jiangsheng Zhu2, and Mian Wu1
1Translational Research Institute, School of Medicine, Henan Provincial People’s Hospital, Henan University, Zheng-
zhou, China, 2Maternity and Child Health Hospital of Anhui Province, The Maternal and Child Health Clinical Col-
lege, Anhui Medical University, Hefei, China, 3Department of Biochemistry, College of Science, King Saud University,
Riyadh, Saudi Arabia, 4The First People's Hospital of Wuhu, Wuhu, Anhui, China, and 5Department of Biochemistry,
College of Life Sciences, Shaanxi Normal University, Xian, China
Abstract. Sex chromosomal mosaicism has been considered as a major cause of human sexual differentiation
disorders, like partial virilization and ambiguous genitalia. 45,X/ 46,XX, 45,X/46,XY and 46,XY/47,XXY
are three most common sex chromosome mosaics associated with human ambiguous genitalia. Here, we
report the case of a 3-year-old boy with ambiguous genitalia, bilateral cryptorchidism, and with an inguinal
hernia. G banded cytological karyotyping and FISH analyses revealed that the patient has extremely rare
and novel sex chromosome mosaic 45,X/45,Y/46,XY/46,YY/47,XYY karyotype. These cells exist in differ-
ent percentages, important for phenotypic appearance of the patient. This is a first report of an unusual
mosaic karyotype causing ambiguous genitalia.
Key words: Sex Chromosome Mosaicism, Ambiguous Genitalia, 45,X/45,Y/46,XY/46,YY/47,XYY.
Introduction Materials and Methods
Ambiguous genitalia, the condition commonly found A three years old apparently male child was referred
in disorders of sex development (DSDs) characterized to Anhui Provincial hospital with a complaint of un-
by imperfect differentiation of external genitalia be- differentiated external genitalia. The clinical and
tween male and female [1]. Sex Chromosome mosa- physical assessment of the patient were performed
by experienced surgeons and clinicians. Accordingly,
icisms like 45,X/46,XY or 45,X/47,XYY have been
radiographic examination of the groin region showed
considered as major causes of ambiguous genitalia bilateral undescended testes. Furthermore, to iden-
[2]. The clinical phenotype of the patients with tify the cause of the phenotype observed in the pa-
45,X/46,XY mosaicism is broad, ranging from wom- tient, cytogenetic analyses were performed [4].
en, with or without Turner syndrome, to apparently Analysis of sex chromosomes was performed on
normal males, with intervening variable ambiguous metaphase preparation by FISH using classical chro-
phenotypes [3]. Several other rare mosaic karyotypes mosome enumeration probes (CEP) for the X and Y
have also been reported in a different set of pheno- chromosomes, CEP-X and CEP-Y respectively, as
typic features including genital ambiguity. Here, we described previously [5]. Informed written consents
present a case with very rare and novel mosaic were taken from the parents of a patient for using
biological samples of patient for current research.
karyotype 45,X/45,Y/46,XY/ 46,YY/47, XYY from
The Ethical Review Committee of the Maternal and
Anhui province of China. Child Health Clinical College, Anhui Medical
*These authors have contributed equally to this work. Address University, Anhui, PR China, has approved the cur-
correspondence to Prof. Main Wu, PhD; Translational Research Institute, rent study. All the sampling and experimental proce-
School of Medicine, Henan Provincial People’s Hospital, Henan University,
Zhengzhou, China; e mail: [email protected], or Dr. Jiangsheng Zhu, dures were performed in accordance with ethical
Maternity and Child Health Hospital of Anhui Province, The Maternal standards of the Helsinki declaration, 1964 and its
and Child Health Clinical College, Anhui Medical University, Hefei,
China; e mail: [email protected] amendments.
0091-7370/17/0600-761. © 2017 by the Association of Clinical Scientists, Inc.
762 Annals of Clinical & Laboratory Science, vol. 47, no. 6, 2017
undescended testes (left
testis=0.9cm×0.7cm, and right
testis=1.2cm×0.9cm) in inguinal region
and epididymis was seen in the shallow
space of bilateral inguinal canal.
Intestines were seen just above the tes-
tes, some fluid and shady spaces were
also seen around the testes. CDFI
showed a few color bloodstream signals
in the bilateral testes which means bilat-
eral cryptorchidism coupled with an in-
guinal hernia (Figure 1 C&D).
G-banding cytological karyotyping was
performed to find any of associated
chromosomal abnormalities with ob-
served phenotype, and we found an un-
known karyotype and 45,X (Figure
1E). Furthermore, to clarify it, we per-
formed FISH to study sex chromosomes
in the patient’s lymphocytes. FISH
analysis revealed an exciting pattern of
karyotypic variations among the cells.
25% of the examined cells contain
46,XY, 20% 45,X and 47.5% of 47,
XYY karyotype. In addition, we also ob-
served a small percentage of other geno-
types including 5% with 45,Y and 2.5%
with 46,YY. Overall, the patient was
found to have mosaic
45,X/45,Y/46,XY/46,YY/47,XYY
karyotype (Figure 2). Thus, we believe
that the observed novel mosaic karyo-
type in the patient is the cause of am-
biguous genitalia and bilateral
cryptorchidism.
Discussion
Figure 1. The phenotypic features of the patient. (A&B) Three years old boy
with undifferentiated genitalia. (C&D) The ultrasonic images of patient bilat- Genital ambiguity is one of the rare dis-
eral cryptorchid testes in inguinal canal. (E) G banding karyotyping showing orders of gonadal differentiation, and
45,XO karyotype. sex chromosome mosaicisms have been
considered as a major cause of it [6,7].
Minor or major phenotypic differences
Results do exist among patients containing
same mosaic karyotype [8], some male
A three years old apparent male child was referred to Anhui patients showed normally differentiated
Provincial Hospital with a complaint of undifferentiated external penis or significantly smaller in size and
genitalia (Figure 1 A&B). The ultra-sonographic examination of some patients have normal genitalia but
the lower abdominal and groin region revealed bilateral presence of fertility problems [9,10]. Mosaics with
A novel Mosaic Karyotype and Ambiguous Genitalia 763
Figure 2. Fluorescence in-situ hybrid-
ization of interphase nuclei. (A) 45,X
(B) 45, Y (C) 46, XY (D) 46, YY (E)
47, XYY; Red fluorescence indicates an
Y chromosome, and green fluorescence
indicates a X chromosome.
45,X/47,XYY karyotype are relatively common current patient bears undescended testes and am-
[11,12]. Recently, an infertile male was identified biguous genitalia which may be the cumulative ef-
with 45,X/46,XY/47,XYY and Yq microdeletion fect of current mosaic karyotype.
which are supposed to be the cause of infertility in
same patient [13]. An apparent female with gonad- Acknowledgements
oblastoma was also reported with same mosaic We are thankful to the parents of the patient for their
45,X/46,XY/47,XYY karyotype [14]. In addition, cooperation in current research. We also highly acknowl-
45,X/46,XY/47,XXY was reported to cause hyper- edge the work of physicians, surgeons and paramedic
staff of the Maternity and Child Health Hospital of
gonadotropic hypogonadism in a 62 years old man Anhui Province, Hefei, China. Current research was
[15]. The underlying mechanism behind physical funded by National Key R&D Program of China
appearance of mosaic patients is still not well un- (2016YFC1302302) and National Natural Science
Foundation of the China (81430065 and 31371388).
derstood, we believe that it may depend upon the
percentage of particular types of the cells. Most of References
the sex chromosome mosaic patients have male
1. Blackless M, Charuvastra A, Derryck A, Fausto-Sterling A,
phenotype, while ratio of mosaic females is com- Lauzanne K, Lee E. How sexually dimorphic are we? Review
paratively low. A current case of ambiguous genita- and synthesis. Am J Hum Biol 2000; 12:151-166.
2. Farrugia MK, Sebire NJ, Achermann JC, Eisawi A, Duffy PG,
lia contains a very rare and novel sex chromosome Mushtaq I. Clinical and gonadal features and early surgical
mosaicism 45,X/45,Y/46,XY/46,YY/47,XYY. management of 45,X/46,XY and 45,X/47,XYY chromosomal
However, relatively low percentages of the cells de- mosaicism presenting with genital anomalies. J Pediatr Urol
2013; 9:139-144.
tected with 45,Y and 46,YY karyotypes which is 3. El Moussaif N, Haddad NE, Iraqi N, Gaouzi A. 45,X/46,XY
indeed a novel presentation of the study. Moreover, mosaicisme: report of five cases and clinical review. Ann
previous cases containing 45,X/46,XY/47,XYY Endocrinol (Paris) 2011; 72:239-243.
4. Zhu J, Liu H, Tang J, Riaz Khan M, Wang B, Bukhari I.
were phenotypically female with gonadoblastoma Identification of minor chromosomal defects causing abnormal
or males with normal external genitalia while the foetus and spontaneous abortions. Br J Biomed Sci 2016;
73:67-73.
764 Annals of Clinical & Laboratory Science, vol. 47, no. 6, 2017
5. Fernandez-Garcia R, Garcia-Doval S, Costoya S, Pasaro E. 10. Layman LC, Tho SP, Clark AD, Kulharya A, McDonough PG.
Analysis of sex chromosome aneuploidy in 41 patients with Phenotypic spectrum of 45,X/46,XY males with a ring Y chro-
Turner syndrome: a study of 'hidden' mosaicism. Clin Genet mosome and bilaterally descended testes. Fertil Steril 2009;
2000; 58:201-208. 91:791-797.
6. Sangeetha R, Balachandar V, Devi SM, Velmurugan P, Kumar 11. Pettenati MJ, Wheeler M, Bartlett DJ, Subrt I, Rao N,
BL, Manikantan P, Arun M, Kumar AK, Ahamed SM, Kroovand RL, Burton BK, Kahler S, Park HK, Cosper P et al.
Balamuralikrishnan B, Sasikala K. Cytogenetic Study on 45,X/47,Xyy Mosaicism - Clinical Discrepancy between
Sexual Ambiguity in Humans. Int J Hum Genet 2010; Prenatally and Postnatally Diagnosed Cases. American Journal
10:81-86. of Medical Genetics 1991; 39:42-47.
7. Hsu LY, Yu MT, Richkind KE, Van Dyke DL, Crandall BF, 12. Imai A, Horibe S, Fuseya T, Takagi H, Takagi A, Tamaya T.
Saxe DF, Khodr GS, Mennuti M, Stetten G, Miller WA, Priest Detection of SRY in 45,X/47,XYY mosaicism leading to phe-
JH. Incidence and significance of chromosome mosaicism in- notypic female. Clin Genet 1997; 51:124-126.
volving an autosomal structural abnormality diagnosed prena- 13. Bulakbasi T, Sahin FI, Yil MZ, Zeyneloglu HB. A
tally through amniocentesis: a collaborative study. Prenat 45,X/47,Xyy/46,Xy Karyotype and Y Chromosome
Diagn 1996; 16:1-28. Microdeletion in an Infertile Male. Balk J Med Gen 2008;
8. Telvi L, Lebbar A, Del Pino O, Barbet JP, Chaussain JL. 11:51-53.
45,X/46,XY mosaicism: report of 27 cases. Pediatrics 1999; 14. Osztovics M, Ivady G, Ruzicska P, Buhler EM, Kiraly L.
104:304-308. 45,X-46,Xy-47,Xyy Mosaicism in a Phenotypic Female with
9. Kilic S, Yukse B, Tasdemir N, Dogan M, Ozdemir E, Yesilyurt Gonadoblastoma. Acta Paediatr Hung 1974; 15:295-299.
A, Keskin I. Assisted reproductive treatment applications in 15. Kreft B, Greiwe M, Schwinger E, Peters A. [45,X/46,XY/47,XXY
men with normal phenotype but 45,X/46,XY mosaic karyo- chromosome mosaicism as a cause of hypergonadotropic hypo-
type: clinical and genetic perspectives. Taiwan J Obstet gonadism diagnosed in late middle age]. Dtsch Med
Gynecol 2010; 49:199-202. Wochenschr 1995; 120:1114-1117.
