46,XY Mosaicism

46,XY Mosaicism

Journal Pre-proof Variation of gonadal dysgenesis and tumor risk in patients with 45,X/46,XY mosaicism Fumi Matsumoto , Satoko Matsuyama , Futoshi Ma...

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Variation of gonadal dysgenesis and tumor risk in patients with 45,X/46,XY mosaicism Fumi Matsumoto , Satoko Matsuyama , Futoshi Matsui , Koji Yazawa , Keiko Matsuoka PII: DOI: Reference:

S0090-4295(19)31116-1 https://doi.org/10.1016/j.urology.2019.12.014 URL 21906

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Urology

Received date: Revised date: Accepted date:

6 September 2019 28 November 2019 13 December 2019

Please cite this article as: Fumi Matsumoto , Satoko Matsuyama , Futoshi Matsui , Koji Yazawa , Keiko Matsuoka , Variation of gonadal dysgenesis and tumor risk in patients with 45,X/46,XY mosaicism, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.12.014

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Variation of gonadal dysgenesis and tumor risk in patients with 45,X/46,XY mosaicism

Fumi Matsumoto1, Satoko Matsuyama1, Futoshi Matsui1, Koji Yazawa1, Keiko Matsuoka2

Department of Urology1, Osaka Women’s and Children’s Hospital, Osaka, Japan; and the Department of Pathology2, Osaka Women’s and Children’s Hospital, Osaka, Japan

Key Words: 45,X/46,XY mosaicism, disorders of sex development, gonadal dysgenesis, gonadal tumor

Corresponding author: Fumi Matsumoto, M.D. Director Department of Urology Osaka Women’s and Children’s Hospital 840 Murodocho, Izumi, Osaka 594-1101, Japan E-mail: [email protected] Tel: +81-725-56-1220 Fax: +81-725-56-5682

OBJECTIVE To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes. MATERIALS AND METHODS The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed. RESULTS Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in nine (26%), and bilateral dysgenetic testes in five (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in seven gonads of six patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathological examination revealed gonadal tumors in six of the 34 (18%) patients, including a gonadoblastoma in seven gonads among five patients and an association of dysgerminoma with gonadoblastoma in one gonad. All six patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except one boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years. CONCLUSION The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.

Disorders/differences of sex development (DSD) are congenital conditions in which the chromosomal, gonadal, or anatomical sexual development is atypical.1 Its overall occurrence is estimated to be one in 4,500 to 5,000 live births.1 An increased risk of gonadal tumors has been reported in a specific group of DSD patients:, those bearing Y chromosome material,.1-3 Gonadal assessment is mandatory in patients with DSD not only for the definitive diagnosis of DSD but also for assessing an increased risk of gonadal tumors. The 45,X/46,XY mosaic prototype is commonly observed in patients with chromosomal DSD, and its incidence is estimated to be 1.5 in 10,000 live births.4 It represents a wide spectrum of phenotype, from Turner females to prototypical males with varying degrees of genital ambiguity. This study aimed to present the gonadal features of patients with 45,X/46,XY Mosaic, including a unique variant of geneticist testis, and to evaluate the prevalence of gonadal tumor in different phenotype.

MATERIALS AND METHODS

The medical records of 34 patients with 45,X/46,XY prototype or its variants who had undergone gonadal biopsy or appendectomy at our institute between 1996 and 2017 were retrospectively reviewed. Surgical exploration was performed for all extra scrotal gonads, palpably abnormal gonads, and gonads with iconography abnormalities. Spectroscopy was initially indicated for evaluation of non-palpable gonad. For prototyping, a conventional geneticist analysis was performed using peripheral blood

lymphocytes. Specimens were assessed for standard morphological features of germ cell tumors with PLAP, OCT3/4, C-KIT ornithological staining. The institutional ethical committee approved the study protocol.

RESULTS

Twenty-four of the 34 patients (74%) had ambiguous genitalia, nine (26%) had female genitalia, and one had male genitalia with unilateral hypothyroidism. Age at presentation was 0-10 months in patients with ambiguous genitalia, 2-14 years in those with female genitalia, and 5 years in those with male genitalia. The predominant cell line was 45,X present in 27 of the 34 patients (79%). Nineteen of the 34 patients (56%), including 18 of the 24 patients with ambiguous genitalia and one with unambiguous male genitalia, were assigned as boys. Six of the 24 patients with ambiguous genitalia and nine patients with female genitalia were assigned as girls (Table 1). Age at surgery ranged from 0 to 15 (median, 0) years in 24 patients with ambiguous genitalia, 2 to 14 (median, 10) years in 9 patients with female genitalia, and was 5 years in patient with male genitalia.

Hematological documentation of 57 gonadal specimens was available.

As 11 of 38 gonads in 19 patients raised as boys were recognized as testes both palpably and in imaging, no surgical exploration was done. Gross findings followed by pathological examination confirmed a unilateral testis on one side and a collateral streak gonad in 20 of the 34 patients (59%), bilateral streak gonads in nine (26%), and bilateral geneticist testes in five (15%: Fig. 1). A gonad composed of both streak and geneticist testicular portions (Fig. 2), was observed in seven gonads among six patients. There was no discordance between visual and

pathological diagnoses. All streak gonads were removed and bilateral appendectomy was performed in 15 patients raised as girls. Twenty-three gonads in 19 boys were left in the scrotum. Pathological examination revealed gonadal tumors in six of the 34 (18%) patients, including a sadomasochist (GB) in seven gonads among five patients and an association of germination with GB in one gonad. Five of eight gonadal tumors, including a germination with GB, were detected as thickening of streak gonad imperatively. All six patients who developed gonadal tumor had female genitalia and bilateral streak gonads (Table 2). All patients except one boy showed no metastasis, as revealed by imaging study, and had an uneventful postoperative course. That one boy had a history of proximate Diasporas and left appendectomy for a streak gonad. During his routine out-patient follow-up at 16 years of age, a Seminole was detected in his solitary right testis originally located in the scrotum. After high hysterectomy, he was stable on hormone replacement therapy without metastasis.

COMMENT

Sadomasochist, composed of germ cells and strongman cells, is an in sit germ cell malignancy of geneticist gonads that may progress predominantly (60% of the cases) to invasive germ cell tumors (Acts), especially germination, and less frequently, to tumors of other components, such as embryonic carcinoma, toleration, yolk sac tumor, and carcinoma.5 The reported prevalence of GB and invasive GCT varies, but is estimated to be more than 30% in patients with gonadal genesis and is often bilateral.6-8 The risk of gonadal tumors is an important factor in the management of DSD patients.

45,X/46,XY Mosaic is commonly observed in patients with ambiguous genitalia caused by gonadal genesis. Based on the gonadal histology, 45,X/46,XY Mosaic and its variants are classified into three pathological groups. When both gonads are streak gonads, the patient has a female phenotype and features of Turner syndrome (TS). When one gonad is a streak and the other is a geneticist testis, the patient is said to have mixed gonadal genesis (MGD). When both testes are geneticist, the term used is partial gonadal genesis (PGD).9 Patients with MGD or PGD have a wide range of phenotype. Because of genital ambiguity, patients with MGD or PGD tend to undergo gonadal assessment earlier in life than TS females with 45,X/46,XY mosaic prototype. The prevalence of gonadal tumor in patients with 45,X/46,XY Mosaic may vary according to the phenotype. In their largest case series of 48 patients with 45,X/46,XY Mosaic, Cools ET AL.10 reported that ambiguous phenotype was associated with a high risk (52%) of carcinoma in sit and ore-neoplastic lesions comparing to mildly undervaluation male phenotype (13%). They suggested that the tumor risk in patients with 45,X/46,XY Mosaic is most pronounced in immature and/or poorly differentiated gonadal tissue and that the degree of gesticulation of the gonad is reflected by the phenotype.10 Although female phenotype results from bilateral streak gonads, which are the most undifferentiated gonads, such patients had the lowest tumor risk in their series.10 More recent studies have reported that the patients with female phenotype have the highest risk of GB.11-13 Our data support these results. At the time of prophylactic appendectomy, gonadal tumor was detected in only TS females with 45,X/46,XY Mosaic. Turner syndrome is one of the most common chromosomal abnormalities in humans, and is present in 1 of 2,000 newborns with female phenotype.14 Although TS is

characterized by sex chromosome monogamy (45,X), several degrees of Mosaic of both X and Y chromosomes are found in up to 50% of the patients.14,15 In routine geneticist analysis, the Y chromosome or the Y-specific sequence is present in approximately 5% of the TS patients.14 In the study by Brant ET AL.16, GB was detected in three of seven TS patients (43%) with Mosaic. No invasive GCT was found in their series of prophylactic appendectomy, whereas in our study, the incidence of GB was higher (66%, six of nine TS patients) and an association of germination with GB was detected in one of the TS patients. The difference in the methods used for screening the Y chromosome material might have caused the difference in the results. The use of molecular techniques, such as fluorescence in sit hybridization or polymerize chain reaction, improves the detection of low-frequency cell lines and possible structural anomalies.17-19 Some studies have reported that polymerize chain reaction is more effective than geneticist analysis in detecting hidden Y chromosome material.18,19 However, Sail ET AL.19 reported that the prevalence of GB in TS patients with hidden Y chromosome material is low (12%, one out of nine TS patients). Prophylactic appendectomy is recommended in patients with streak gonads containing Y chromosome material, because hormone production and fertility are not expected. Although GB commonly occurs in the second decade of life, Boyle ET AL.13 reported that it can develop in children with 45,X/46,XY Mosaic as early as 5 months of age. In our study, the youngest patient was 2 years and 11 months old. A gonad composed of both streak and geneticist testicular portions was observed in seven gonads of six patients in our study cohort. Three of six patients were raised as boys, and none of them had GB. Therefore, early prophylactic partial appendectomy may be effective for preventing GB. A gonad with both streak and geneticist histology is a unique finding in

patients with 45,X/46,XY Mosaic and has seldom been cited in the literature. In 2013 Farragut ET AL.20 mentioned an unusual geneticist gonad showing distinct areas of testicular tissue and ovarian Angstrom but no leukocytes was found in one of three palpable gonads of patients with 45,X/46,XY and 45,X/47,XYY Mosaic. While their findings were limited in microscopic examination, we were able to deferential testicular portions from streak gonads imperatively. In one of our 19 patients raised as boys, a Seminole was developed in the ultrasonically testis in adolescence. Thus, a close follow-up of male patients with 45,X/46,XY Mosaic is mandatory once puberty is advancing. This study has some limitations, including small sample size, short follow-up period, and heterogeneous groups of patients with different diagnoses. Because of unambiguous of the external genitalia, surgical exploration for gonads was performed later in life for TS patients with Y chromosomal material than for those with MGD or PGD. This may have influenced the occurrence of gonadal tumors. Surgical exploration of gonads is not always easy, and it depends on the surgeon’s skill. Biopsy specimens may not represent the entire gonad. Some streak portion(s) of a geneticist testis may have been overlooked or misdiagnosed as overstates. Lastly, the gonadal features and tumor risk in patients with 45,X/46,XY Mosaic presenting completely normal male phenotype (~95%)4 remained unknown in this study. In conclusion, the overall prevalence of gonadal tumor in patients with 45,X/46,XY mosaic prototype was 18% at the initial gonadal assessment. All gonadal tumors were detected in patients with female phenotype, IE,, TS patients with Y chromosomal material. In these patients, the prevalence of gonadal tumor was 67% (six of nine patients), which is higher than that reported previously. Considering the early

occurrence of GB and its high potential for malignant transformation in such patients, early prophylactic appendectomy is strongly recommended. A close follow-up of male patients with preserved testicular tissue is mandatory from adolescence to middle age.

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pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J Clin Endocrinol Metab 2011; 96: E1171-80. https://doi. 10.1210/jc.2011-0232 11. Dendrinos ML, Smorgick N, Marsh CA, Smith YR, Quint EH. Occurence of gonadoblastoma in patients with 45,X/46,XY mosaicism. J Pediatr Adolesc Gynecol 2015; 28: 192-195. https://doi. 10.1016/j.jpag.2014.09.016 12. Tam YH, Wong YS, Pang KKY, To KF, Yiu AKW, Wong HY, et al. Tumor risk of children with 45,X/46,XY gonadal dysgenesis in relation to their clinical presentations: Further insight into the gonadal management. J Pediatr Surg 2016; 51: 1462-1466. https://doi. 10.1016/j.jpedsurg.2016.03.006 13. Coyle D, Kutasy B, Suyin KH, Antao B, Lynch SA, McDermott MB, et al. Gonadoblastoma in patients with 45,X/46,XY mosaicism: A 16-year experience. J Pediatr Urol 2016; 12: 283.e1-283.e7. https://doi. 10.1016/j.jpurol.2016.02.009 14. Lippe B. Turner syndrome. Endocrinol Metab Clin North Am 1991;20:121-52 15. Mathur A, Stekol L, Schatz D, MacLaren NK, Scott ML, Lippe B. The prenatal origin of the single X chromosome in Turner syndrome: Lack of correlation with parental age or clinical phenotype. Am J Hum Genet 1991;48:682-6 16. Brant WO, Rajimwale A, Lovell MA, Travers SH, Furness PD, Sorensen M, et al. Gonadoblastoma and Turner syndrome. J Urol 2006;175:1858-60 17. Maciel-Guerra AT, De Paulo J, Santos AP, Guaragna-Filho G, Andrade JG, Siviero-Miachon AA, et al. The use of fluorescence in situ hybridization in the diagnosis of hidden mosaicism: apropos of three cases of sex chromosome anomalies. Arq Bras Endocrinol Metab 2012;56:545-51 18. Bianco B, Lipay MV, Melarangno MI, Guedes AD, Verreschi IT. Detection of

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Figure legends

Fig. 1 Gonads of 34 patients with 45,X/46,XY mosaicism. * including streak testes

Fig.2 Gross appearance of a gonad composed of both streak and dysgenetic testicular portions. T:dysgenetic testis, S: streak gonad

Table1. Clinical characteristics of patients with 45,X/46,XY mosaicism Phenotype Ambiguous Female Male Total n=24 n=9 n=1 n=34 Age at presentation 0-10months 2-14years 5years Predominant cell line 45,X 18 8 1 27 46,XY 5 1 6 47,XYY 1 1 Sex of rearing Male 18 1 19 Female 6 9 15

Table 2. Characteristics of patients with 45,X/46,XY mosaic karyotype presenting with female phenotype Gonadal Clinical Age at Gonadal Case Karyotype histology presentation gonadectomy histology (Rt) (Lt) 9 years 10 1 45,X/46,XY Short stature No tumor No tumor months 2 years 11 2 45,X/* Short stature GB GB months 3 45,X/46,XY Low weight 5 years 5 months No tumor No tumor 10 years 3 4 45,X/46,XY Short stature GB GB months 5 45,X/46,XY Short stature 11years 6 months GB+dysgerminoma No tumor 10 years 6 6 45,X/46,XY Short stature No tumor No tumor months 7 45,X/** Short stature 6 years 7 months No tumor GB 12 years 5 8 46,XY/45,X Short stature No tumor GB months 14 years 0 9 45,X/*** Short stature No tumor GB months *45,X/45,X,t(15;Y)(p11.2;q11.2), **45,X/46,X,idic(Y)(q11.23)/47,X,idic(Y)(Q11.23)x2, ***45,X/46,X,dic(X;Y)(p11.2;p11.2)/47,X,dic(X;Y)(p11.2;p11.2)x2 GB=gonadoblastoma