Scholarly article on topic 'Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome'

Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome Academic research paper on "Clinical medicine"

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{"Turner syndrome" / "Y chromosome" / Gonadoblastoma / Prevalence / "Polymerase chain reaction" / "Gonadal dysgenesis" / "Síndrome de Turner" / "Cromossomo Y" / Gonadoblastoma / Prevalência / "Reação em cadeia da polimerase" / "Disgenesia gonadal"}

Abstract of research paper on Clinical medicine, author of scientific article — Alessandra Bernadete Trovó de Marqui, Roseane Lopes da Silva-Grecco, Marly Aparecida Spadotto Balarin

Abstract Objective To assess the prevalence of Y-chromosome sequences and gonadoblastoma in patients with Turner syndrome (TS) using molecular techniques. Data source A literature search was performed in Pubmed, limiting the period of time to the years 2005–2014 and using the descriptors: TS and Y sequences (n=26), and TS and Y-chromosome material (n=27). The inclusion criteria were: articles directly related to the subject and published in English or Portuguese. Articles which did not meet these criteria and review articles were excluded. After applying these criteria, 14 papers were left. Data synthesis The main results regarding the prevalence of Y-chromosome sequences in TS were: (1) about 60% of the studies were conducted by Brazilian researchers; (2) the prevalence varied from 4.6 to 60%; (3) the most frequently investigated genes were SRY, DYZ3 and TSPY; (4) seven studies used only polymerase chain reaction, while in the remaining seven it was associated with FISH. Nine of the 14 studies reported gonadectomy and gonadoblastoma. The highest prevalence of gonadoblastoma (33%) was found in two studies. In five out of the nine papers evaluated the prevalence of gonadoblastoma was 10–25%; in two of them it was zero. Conclusions According to these data, molecular analysis to detect Y-chromosome sequences in TS patients is indicated, regardless of their karyotype. In patients who test positive for these sequences, gonadoblastoma needs to be investigated.

Academic research paper on topic "Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome"

Rev Paul Pediatr. 2015;xxx(xx):xxx-xxx



Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome

Q1 Alessandra Bernadete Trovó de Marqui *, Roseane Lopes da Silva-Grecco, Marly Aparecida Spadotto Balarin

7 Universidade Federal do Triangulo Mineiro (UFTM), Uberaba, MG, Brazil

8 Received 5 March 2015; accepted 4 June 2015

10 11 12

20 21 22


Turner syndrome; Y chromosome; Gonadoblastoma; Prevalence; Polymerase chain reaction;

Gonadal dysgenesis


Objective: To assess the prevalence of Y-chromosome sequences and gonadoblastoma in patients with Turner syndrome (TS) using molecular techniques.

Data source: A literature search was performed in Pubmed, limiting the period of time to the years 2005-2014 and using the descriptors: TS and Y sequences (n=26), and TS and Y-chromosome material (n=27). The inclusion criteria were: articles directly related to the subject and published in English or Portuguese. Articles which did not meet these criteria and review articles were excluded. After applying these criteria, 14 papers were left. Data synthesis: The main results regarding the prevalence of Y-chromosome sequences in TS were: (1) about 60% of the studies were conducted by Brazilian researchers; (2) the prevalence varied from 4.6 to 60%; (3) the most frequently investigated genes were SRY, DYZ3 and TSPY; (4) seven studies used only polymerase chain reaction, while in the remaining seven it was associated with FISH. Nine of the 14 studies reported gonadectomy and gonadoblastoma. The highest prevalence of gonadoblastoma (33%) was found in two studies. In five out of the nine papers evaluated the prevalence of gonadoblastoma was 10-25%; in two of them it was zero. Conclusions: According to these data, molecular analysis to detect Y-chromosome sequences in TS patients is indicated, regardless of their karyotype. In patients who test positive for these sequences, gonadoblastoma needs to be investigated.

© 2015 Sociedade de Pediatria de Sao Paulo. Published by Elsevier Editora Ltda. All rights reserved.

DOI of original article: http://dx.doi.Org/10.1016/j.rpped.2015.06.007

* Corresponding author. E-mail: (A.B.T. de Marqui).

2359-3482/© 2015 Sociedade de Pediatria de Sao Paulo. Published by Elsevier Editora Ltda. All rights reserved.

de Marqui ABT et al.

Prevalência de sequências do Y e de gonadoblastoma em síndrome de Turner Resumo

Objetivo: Apresentar a prevalência de sequências do cromossomo Y por técnicas moleculares e de gonadoblastoma em pacientes com síndrome de Turner.

Fontes de dados: Foi feita uma pesquisa bibliográfica no Pubmed, com limite de período entre 2005 e 2014, com os descritores Turner syndrome and Y sequences (n=26) e Turner syndrome and Y chromosome material (n=27). Os critérios de inclusâo foram artigos que tivessem relaçao direta com o tema e publicados no idioma inglês ou portugués. Foram excluidos aqueles que nao cumpriram esses critérios e eram do tipo revisao. Após aplicacao desses critérios, 14 foram selecionados.

Síntese dos dados: Os principais resultados quanto à prevalência de sequências do cromossomo Y em síndrome de Turner foram: 1 - cerca de 60% dos estudos foram feitos por pesquisadores brasileiros; 2 - a frequência variou de 4,6 a 60%; 3 - os genes SRY, DYZ3 e TSPY foram os mais investigados; 4 - a técnica de PCR foi empregada exclusivamente em sete estudos e nos sete restantes, associada à FISH. Nove dos 14 estudos apresentaram informacoes sobre gonadecto -mia e gonadoblastoma. Dois estudos relataram a maior prevalência para gonadoblastoma (33%). Cinco dos nove estudos referiram prevalência de 10 a 25% e em dois esse valor foi nulo. Conclusôes: De acordo com os dados apresentados, é indicada a pesquisa molecular para sequências do cromossomo Y em pacientes com ST, independentemente do cariótipo. Naquelas com positividade para essas sequências, é necessária a investigacao de gonadoblastoma. © 2015 Sociedade de Pediatria de Sao Paulo. Publicado por Elsevier Editora Ltda. Todos os direitos reservados.


Síndrome de Turner; Cromossomo Y; Gonadoblastoma; Prevalência; Reaçâo em cadeia da polimerase; Disgenesia gonadal


Turner syndrome (TS) is a chromosomal disorder with an incidence of 1:2500 girls; its etiology is associated with total or partial X-chromosome monosomy and the diagnosis is made by karyotype testing.12 A retrospective study of 260 patients with TS showed that the improvement in chromosomal analysis provided a change in the proportion of observed karyotype types.3

Patients with TS exhibit have short stature and gonadal dysgenesis as main clinical signs. They also may have low hairline at the nape of the neck, strabismus, ptosis, high-arched palate, micrognathia, short and/or webbed neck, lymphedema of hands and/or feet, metacarpal and/or metatarsal shortening, Madelung deformity, cubitus valgus, genu valgum, scoliosis and multiple pigmented nevi, cardiovascular and renal disorders, thyroid disorders, hearing impairment, hypertension, osteoporosis, and obesity.1,2 However, this syndrome is characterized by wide pheno-typic variability, from patients with the classic phenotype to those almost indistinguishable from the general population.

Women with TS who have Y chromosome material are at increased risk of developing gonadal tumors, such as gonadoblastoma and dysgerminoma. Gonadoblastoma is a benign gonadal tumor with a high potential for malignancy; it can differentiate into invasive dysgerminoma in 60% of cases and also in other forms of malignant tumors. About 90% of patients with gonadoblastoma have Y-chromosome material in their genetic makeup. Therefore, sequence detection of Y-chromosome by cytogenetic and/or molecular techniques in patients with TS is critical. In positive cases, prophylactic removal of gonads has been indicated.4 Two

recently published retrospective studies showed Y chromosome material frequencies in TS by classical cytogenetics of 6.6% (4/61)5 and 7.6% (12/158).6 In one such study, 33% of patients (4/12) had gonadoblastoma and in two patients it progressed to disgerminona or teratoma.6 In another study with 11 patients with sexual differentiation disorders, 7 had Turner phenotype and mosaic karyotype Y in peripheral blood.7 All patients with TS underwent gonadectomy, and histopathological findings revealed that four of them (57.1%) had gonadoblastoma, and in two cases it was associated with dysgerminoma.7 Regarding the classical cytogenetic analysis by GTG banding, peripheral blood lymphocytes are the material of choice because it is easy to harvest this tissue, and the analysis is usually performed in 30 metaphases, which allows detection of 10% of mosaicism.8 The advantage of molecular methods is that it require no cell culture and only a small sample for analysis and are more sensitive to detect low mosacismo, frequent in TS.8

Thus, the aim of this review is to present the prevalence of Y chromosome sequences by molecular techniques and gonadoblastoma in patients with TS.


A literature search was performed on Pubmed, on 10/24/2014, with time limit between 2005 and 2014. Fig. 1 shows the flowchart of this electronic search.


Table 1 shows the frequency of Y chromosome sequences, identified by molecular techniques, of the 14 selected

Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome

Figure 1 Representation of the method and electronic search results.

studies. Table 2 shows the karyotype of these patients. The in 9 of 14 studies. The results of five studies3-14'15-17-21 are not

frequency of gonadoblastoma in TS patients with positive included in Table 3 for the following reasons: (1) two stud-

amplification for Y-chromosome is summarized in Table 3, ies had no information on gonadectomy and gonadoblastoma

with information on gonadectomy and gonadoblastoma in TS in the text3-21; (2) in two studies patients were scheduled

Table 1 Frequency of Y-chromosome sequences identified by molecular techniques in patients with Turner syndrome.

Reference Method(s) and Y-chromosome sequence(s) and/or probe used n/origin PY Frequency

Bianco et al.9 PCR: SRY/DYZ3 20/Brazil 7 35.0%

Bianco et al.10 PCR: SRY/DYZ3 5/Brazil 3 60.0%

Bianco et al.11 PCR: SRY/DYZ3/TSPY 87/Brazil 16 18.5%

Bianco et al.12 PCR: SRY/TSPY 104/Brazil 17 16.3%

Barros et al.3 PCR and PCR nested: SRY/TSPY/DYZ3 96/Brazil 10 10.4%

Barros et al.13 PCR and PCR nested: SRY/TSPY/DYZ3; FISH: DXZ1/DYZ3 101/Brazil 16 15.8%

Araujo et al.14 PCR: SRY/ZFY/DYZ1/PABY/DYS1/DYZ3 42/Brazil 2 4.8%

Bispo et al.15 FISH: CEP X/CEP Y; PCR multiplex: SRY/TSPY/AMGY/DAZ 74/Brazil 5 6.8%

Mazzanti et al.16 PCR: SRY/DYZ3; FISH: CEP 18 SA/X SG/Y SO 171/Itly 14 8.2%

Semerci et al.17 PCR: PABY/SRY/DYS14/AMGY/DYZ3/DYS273/ DYS280/DYS218/DYS224/DYS209/DYS231/ DYS1/YRRM/DYZ1 40/Turkey 2 5.0%

Sallai et al.18 RT-PCR: SRY/DDX3Y/HSFY1/TSPY; FISH: 130/Hungary 9 (RT-PCR) 6.9%

whole chromosome painting Y/wcp 6 (FISH) 4.6%

Cortes-Gutierrez et al.19 PCR: SRY; FISH: CEP-Y 32/Mexico 3 9.4%

Freriks et al.20 FISH: CEP X/CEP Y/SRY; PCR: Yp (SRY) and Yq (sY84/sY86/sY127/sY134/sY254/sY255); RT-PCR: SRY/DSY14 63/Holland 5 7.9%

Knauer-Fischer et al.21 FISH: Ycen-1089/1090; PCR Multiplex: Yp11 (GBY: TSPY/SRY), Yq11 (AZFa/AZFb/AZFc) 60/Germany 7 11.7%

PY, patients with Y sequence; PCR, polymerase chain reaction; SRY, sex-determining region on the Y chromosome or sex related region Y; FISH, fluorescence in situ hybridization; RT-PCR real-time PCR; DDX3Y, DEAD/H box polypeptide, Y-chromosome; HSFY1, heat-shock transcription factor, Y-linked; AZF, azoospermia factor; CEP X, X-specific centromeric probe; CEP Y, Y-specific centromeric probe; GBY, gonadoblastoma Y gene; TSPY, testis-specific protein Y-encoded or testis specific protein Y.


de Marqui ABT et al.

Table 2 Karyotypes determined by conventional cytogenetics (GTG) in patients with Y-chromosome sequences identified by molecular techniques.

Reference Karyotypes

Bianco et al.9 45,X: n=7

Bianco et al.10 45,X/46,X,+mar: n=2; 45,X/45,X,add(15)(p11): n=1

Bianco et al.11 45,X: n=12; 45,X/46,X,+mar: n=2; 45,X/45,X,add(15)(p11): n=1; 45,X/46,X,r(?): n=1

Bianco et al.12 45,X: n=12; 45,X/46,X,+mar: n=2; 45,X/45,X,add(15)(p11): n=1; 45,X/46,X,r(?): n=1;

45,X/47,XXX: n=1

Barros et al.3 45,X/46,X,+mar: n=5; 45,X: n=3; 45,X/46,X,r(?): n=2

Barros et al.13 45,X: n=3; 45,X/46,XY: n=5; 45,X/46,X,+mar: n=5; 45,X/46,X,r(?): n=2; 45,X/47,XYY: n=1

Araujo et al.14 45,X: n=2

Bispo et al.15 45,X/46,XY: n=2; 45,X: n=1; 45,X/46,XY: n=1; 46,X,i(Xq): n=1

Mazzanti et al.16 45,X/46,XY: n=6; 45,X: n=2; 45,X/46,X,idic(Y): n=3; 45,X/46,X,+mar: n=2;

45,X/46,XY/46,X,idic(Y): n=1

Semerci et al.17 45,X: n=2

Sallai et al.18 45,X: n=3; 45,X/46,XY: n=3; 45,X/46,X,+mar: n=2; 45,X/46,X,del(Xq): n=1

Cortes-Gutierrez et al.19 45,X/46,X,+mar: n=1; 45,X/46,XY: n=1; 45,X: n=1

Freriks et al.20 45,X: n=5

Knauer-Fischer et al.21 45,X: n=2; 45,X/46,X,idicY(q11.2): n=2; 46,X,i(X)(q10): n=1; 46,X,del(X)(q12 ou q13.1): n=1;

46,X,der(X)t(X;Y)(p22.3;q11.21): n=1

121 122

for clinical follow-up17 or monitoring by a multidisciplinary team of biologist, psychologist, geneticist, endocrinologist, and gynecologist14; and (3) in one study prophylactic gonadectomy was offered to all patients with Y sequences, however, the same patients opted for regular monitoring by ultrasound and CT.15


The present literature review study showed the prevalence of Y-chromosome sequences and the risk of developing gonadoblastoma in TS patients.

Y-chromosome sequences 131

Of the 14 studies included in this review, 60% were per- 132

formed by Brazilian investigators.3,9"15 Four have been 133

published by the same group and the two studies repor- 134

ting a higher prevalence of Y-chromosome sequences9"12 135

analyzed samples from different tissues (peripheral blood, 136

oral mucosa cells, and hair root).9,10 One study evaluated 137

20 patients with TS and karyotype 45,X9 and the other 5 138

patients with chromosomal abnormalities, such as chromo- 139

some marker, additional material, or ring chromosome.10 140

Three studies9"11 showed that all investigated patients had 141

Table 3 Frequency of gonadoblastoma in patients with Turner syndrome and Y-chromosome sequences.

Reference PY/P total PG/PY PG operated % With gonadoblastoma PG age (years)

Bianco et al.9 7/20 4/7 (57.1) 1 25.0 16

Bianco et al.10 3/5 3/3 (100) 0 0 -

Bianco et al.11 16/87 11/16 (68.7) 2 18.2 16 and 19a

Bianco et al.12 17/104 12/17 (70.6) 2 16.7 16 and 19a

Barros et al.13 16/101 16/16 (100) 3 18.8 15.9b (OCT4+: GL); 18.2b (OCT4+: GR); 17.7b (OCT4+: GR and GL)

Mazzanti et al.16 14/171 12/14 (85.7) 4 33.3 7.64 and 2.8: GBBb 15.9 and 11.6: GBMb

Sallai et al.18 9/130 9/9 (100) 1 11.1 5.5b

Cortés-Gutiérrez et al.19 3/32 3/3 (100) 1 33.3 10

Freriks et al.20 5/63 4/5 (80) 0 0 -

PY/P total, patients with Y sequence in relation to the total number of patients; PG/PY, gonadoblastoma patients compared to patients with Y sequence; PG operated, gonadoblastoma patients undergoing surgery; OCT4, octamer-binding transcription factor 4; G, gonad; R, right; E, left; GBB, bilateral gonadoblastoma; GBM, gonadoblastoma monolateral. a Age at diagnosis. b Age at gonadectomy.

Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome 5

142 amplification for SRY gene and only a few for DYZ3 and gonadal tissue showed that Y-chromosome was present in 57, 204

143 TSPY. This data shows that the SRY gene should be especially 46 and 26% of cells, respectively. Investigation by PCR/SRY 205

144 investigated in patients with TS.9"11 In a study published in in lymphocytes and gonads was positive in all three cases. 206

145 2010, Bianco et al.12 also evaluated gene expression (SRY, The case considered Y-negative in lymphocytes by GTG and 207

146 TSPY, SF1, WT1, DAX1, OCT4, GATA4, FOG2, STRA8) in right FISH (45,X) was positive for SRY by PCR/lymphocytes. There- 208

147 and left gonads of six patients undergoing gonadectomy fore, the authors suggested: (1) the use of PCR, in addition 209

148 and found no difference in the expression of these genes to conventional cytogenetic analysis, to rule out the pos- 210

149 in this tissue both in patients and controls, except in one sibility of hidden Y-chromosome mosaicism; and (2) the 211

150 case with high expression of genes SRY, TSPY, and OCT4 use of FISH technique only after a positive result for PCR 212

151 in both gonads [karyotype:45,X/45,X,add(15)(p11)]. These because it is expensive and laborious.19 In addition to FISH, 213

152 nine investigated genes are involved in sex determination, real-time PCR (RT-PCR) was also used.18,20 The first study18 214

153 differentiation, and gonadal tumorigenesis.12 In this study,12 identified Y-chromosome mosaicism by conventional cyto- 215

154 all patients showed SRY gene amplification, which highlight genetic analysis in three of the 130 patients investigated 216

155 the findings previously publicados.9"11 The studies pre- (karyotypes: 45,X/46,XY n=3). Two patients have mosaicism 217

156 sented above used exclusively the polymerase chain reaction around the Y-chromosome, while the other patient had only 218

157 (PCR) technique for the investigation of Y-chromosome part of the Y-chromosome. By RT-PCR, nine patients were 219

158 sequences in TS9"12 and reported frequencies ranging from positive for Y. Of the four Y-chromosome specific probes 220

159 16.3 to 60%. used in the RT-PCR technique, two (SRY and TSPY1) are 221

160 Two studies performed by another group of investiga- on the Y-chromosome short arm (Yp) and two (DDX3Y and 222

161 tors also used PCR and PCR in it.3,13 One of them assessed HSFY1) on the long arm (Yq). Six patients had amplifica- 223

162 Y-chromosome sequences in 96 TS patients a total of tion to the four sequences, three to two (SRY and TSPY1) 224

163 260.3 This research was indicated only in cases of: (a) or three (SRY, TSPY1, and DDX3Y) sequences; that is, three 225

164 45,X karyotype and negative X-chromatin; (b) presence patients had no complications of HSFY1 gene and one had 226

165 of marker chromosomes in karyotype, i.e., chromosome loss of DDX3Y region, which suggests Yq deletion. FISH 227

166 fragments of unknown origin; and (c) impossibility of cyto- analysis confirmed positive for Y in six cases. Thus, the 228

167 genetic identification of ring chromosome origin. Thus, 96 frequency of Y-chromosome sequences was 2.3, 4.6, and 229

168 patients met these criteria and of these 10 showed posi- 6.9% by GTG bands, RT-PCR, and FISH techniques, respec- 230

169 tive amplification for the investigated genes. In this same tively. In the 2013 study,20 with 162 TS patients, 75 had 231

170 study, six cases of intact Y-chromosome had previously a 45,X karyotype and of these 63 have agreed to undergo 232

171 been identified by classical cytogenetics (45,X/46,XY: n=5 additional molecular investigations. Y sequences were iden- 233

172 and 45,X/47,XYY: n=1). In a subsequent study, these same tified by FISH in five patients on oral cell samples but 234

173 authors evaluated 101 of 260 TS patients by PCR and, not in peripheral blood lymphocytes by PCR. RT-PCR anal- 235

174 when positive, they used the fluorescence in situ hybridiza- ysis revealed the presence of SRY and DYS14 in two of 236

175 tion (FISH) technique.13 The 101 cases analyzed by PCR for them.20 In another study, the combined use of PCR and 237

176 Y-chromosome sequences showed 45, X karyotype and nega- FISH allowed the identification of a frequency of approxi- 238

177 tive Barr corpuscle (n=73), marker chromosome (n=25), and mately 12% of Y-chromosome sequences in TS. Of the seven 239

178 ring chromosome (n=3). patients with Y-sequences,21 four did not show it in the kary- 240

179 Two other studies reported the lower Y-chromosome fre- otype. 241

180 quency values among studies performed in Brazil.14,15 In four In short, in the present study the frequency of Y- 242

181 TS patients, the detection of Y-chromosome sequences was chromosome sequences in TS patients ranged from 4.6 to 243

182 identified only by PCR [karyotypes: 45,Xand 46,X,i(Xq)].1415 60%. According to the literature, the prevalence is 0-61%.19 244

183 Thus, the inclusion of PCR technique in TS routine investiga- This difference may be due to the following factors: 245

184 tion would be indicated.14 It is noteworthy that six Brazilian selection criteria of patients, sample size, methodology, 246

185 studies have used only the PCR technique for the inves- and Y-chromosome markers used. When the analyzed tissue 247

186 tigation of Y-chromosome sequences. Advantages of this was peripheral blood alone, the prevalence of Y sequences 248

187 technique include: (1) quick execution; (2) low cost; (3) ranged from 4.6 to 18.5%.11,21 However, in studies where Q2 249

188 simultaneous processing of multiple samples; (4) applicabil- more than one tissue evaluated, the prevalence was 250

189 ity in screening of a large number of patients; and (5) high greater.9,10 SRY, DYZ3, and TSPY genes were the most 251

190 sensitivity for detection of mosaicism. The use of PCR to widely investigated. SRY gene is located in the short arm 252

191 investigate 14 Y-chromosome sequences identified a preva- of Y-chromosome (Yp11.3) and DYZ3 gene in the pericen- 253

192 lence of 5%,17 value similar to that reported by a study tromeric region at Yp12. Both genes play a role in sex 254

193 analyzing only six sequences.14 determination and chromosomal stability, respectively.22 255

194 FISH and PCR techniques were concurrently used in TSPY (testis-specific protein Y encoded), located in the 256

195 several studies.15,16,18"21 One study published in 2005 iden- gonadoblastoma region of the Y-chromosome (GBY) at 257

196 tified a frequency of about 6% by classical cytogenetics Yp11.2, is involved in the development of gonadoblastoma 258

197 (10/171) and 8% by molecular analysis (14/171).16 In another and its expression was detected in this tissue and testis.23"25 259

198 study,19 GTG banding revealed three positive cases: kary- Regarding technique, seven studies3,9"14,17 used PCR alone 260

199 otypes 45,X/46,X,mar; 45,X/46,XY, and 45,X. FISH analysis to investigate Y-chromosome sequences in TS and in the 261

200 of lymphocytes revealed: (1) that the marker chromo- remaining seven studies FISH was also used.13,15,16,18"21 An 262

201 some was Y; (2) confirmed the Y-chromosome previously intriguing finding was reported by one of these studies, 263

202 identified by classical cytogenetics; and (3) did not iden- which found Y-negative sequences in all 56 cases, including 264

203 tify Y-chromosome material, respectively. FISH analysis of the five positive cases by FISH/buccal cells.20 This result 265

6 de Marqui ABT et al.

266 contradicts those published in the literature that recom- the frequency of gonadoblastoma is variable and may reflect 325

267 mend the use of PCR in the investigation of Y-chromosome an early investigation. 326

268 sequences in TS. The authors attribute this low sensitivity In studies performed by Bianco etal.,9-12 results obtained 327

269 to the difficulty in detecting mosaicism below 10%.20 were: (1) one 45,X patient with bilateral gonadoblas- 328

270 Chromosomal mosaicism is defined as the presence of toma positive SRY gene amplification for the three tissues 329

271 two or more distinct cell lines within the same individual analyzed9; (2) two patients with bilateral gonadoblas- 330

272 resulting from post-zygotic nondisjunction. When it occurs toma [45,X: SRY+ and 45,X/46,X,r(?): SRY+DYZ3+]11; (3) two 331

273 in already differentiated cells, mosaicism may be confined patients with bilateral gonadoblastoma [45,X: SRY+ and 332

274 to one or a few tissues.26 In this context, investigation of 45,X/46,X,r(?): SRY+].12 Although there was no patient iden- 333

275 Y-chromosome sequences in tissues of different embryonic tified with gonadoblastoma, histopathological study of the 334

276 origins is advised, such as cells of the oral mucosa, which gonads of one patient revealed stromal cell hyperplasia and 335

277 can easily be harvested by non-invasive procedures. luteoma.10 Subsequent studies also showed patients with 336

278 To our knowledge, there is only one systematic review these histopathological findings.11,12 337

279 focusing on clinical and genetic characteristics of TS, Another gene associated with gonadoblastoma is OCT4 338

280 mosaicism, Y-chromosome, and risk of gonadal tumor.8 Data (octamer-binding transcription factor 4),12,13 also known as 339

281 presented in this study show: (1) that the detection of Y- OCT3 or POU5FI. This gene is considered to be a tumor 340

282 chromosome sequences in TS, regardless of the karyotype, marker of germ cells, such as gonadoblastoma, dysger- 341

283 is necessary to prevent the development of gonadoblastoma; minoma, seminoma, and others, and its expression was 342

284 and (2) PCR technique should be employed due to its high detected by immunohistochemistry in 100% of cases of 343

285 sensitivity, low cost, and easy to perform. gonadoblastoma.32 The study published in 2010 showed 344

286 After TS confirmation by cytogenetics, the inclusion of high expression of the SRY, TSPY, and OCT4 genes in both 345

287 the PCR technique is suggested as a complement for detec- gonads of a patient with positive PCR (SRY+ and TSPY+).12 346

288 tion of Y-chromosome sequences in these patients. This Another study showed that immunohistochemical analy- 347

289 molecular technique is more sensitive and can detect the sis for OCT4 was positive in three cases (karyotypes: 45, 348

290 presence of Y-chromosome material. X/46,XY: n=2 and 45,X/46,X,+mar: n=1), a suggesting result 349

of germ cell tumor (gonadoblastoma or carcinoma in situ).13 350

In this study, the 16 cases of Y sequences underwent bilat- 351

291 Gonadoblastoma eral gonadectomy, and the left and right gonads were 352

assessed by conventional staining with hematoxylin and 353

292 Gonadoblastoma, often observed in the second decade of eosin (H&E) and immunohistochemical staining for OCT4. 354

293 life, is a benign gonadal tumor with a high potential for Gonadal neoplasia was not detected in any of 32 gonads 355

294 malignant transformation.4 It has a good prognosis and evaluated by H&E; however, four gonads (12%) of three 356

295 may differentiate into a germ cell tumor, such as dysger- patients (19%) were positive for OCT4, suggesting the exis- 357

296 minomas, and less frequently into teratomas, embryonal tence of germ cell tumors.13 For this reason, the authors 358

297 carcinoma, yolk sac tumor, and choriocarcinoma.13 This recommend a specific histopathological study in gonads, 359

298 tumor is present mainly in women with gonadal dysgenesis, such as OCT4 immunohistochemistry, to assess the real risk 360

299 and approximately 95% of them have Y-chromosome mate- of gonadal tumors in patients with TS and Y-chromosome 361

300 rial in their genomes. Therefore, the detection of these sequences.12,13 362

301 sequences by cytogenetic and/or molecular techniques has Regarding the studies that reported a higher prevalence 363

302 been encouraged to guide the prophylactic indication for of gonadoblastoma, one of them reported two patients 364

303 surgical removal of gonads in this group of patients, as gen- with monolateral gonadoblastoma (karyotype: 45,X and 365

304 erally they are not metastatic tumors, and there is the 45,X/46,X,+mar) and two with bilateral gonadoblastoma 366

305 possibility of cure with their removal.4 Women with TS (karyotype: 45,X/46,XY)16 and the other reported a patient 367

306 have gonadal dysgenesis and therefore the detection of the 45,X/46,XY with gonadoblastoma.19 In the study published 368

307 Y-chromosome sequences in these patients is of extreme in 2010, prophylactic surgery was performed in all nine 369

308 clinical importance. patients with Y-chromosome material before age of 20 and 370

309 The highest prevalence for gonadoblastoma in this review one of them, a girl of 5-year old, the youngest patient 371

310 was 33%16,19 and is in line with other studies.6,27 This percent- in the study, had bilateral gonadoblastoma without clini- 372

311 age was identified in a recent survey, and four patients with cal signs.18 This patient had a 45,X/46,XY karyotype (GTG), 373

312 ST had the karyotype 45,X/46,XY.6 Two of them had a dys- wcpY+93 (FISH), and was positive for all Y-specific sequences 374

313 germinoma (age at surgery: 11.25 years) and a teratoma (15 (SRY, TSPY1, DDX3Y, and HSFY1). Ovarian tissue histology 375

314 years). In the two patients with gonadoblastoma alone, age revealed no gonadoblastoma in four of the patients under- 376

315 at surgery was 1.5 and 11.7 years.6 Another study published going gonadectomy.20 377

316 recently reported 35.3% incidence of gonadoblastoma.28 A recent histopathological study reported gonadal tumors 378

317 Twenty patients with TS had Y-chromosome sequences from in 6 out of 11 patients (56%), including 4 out of 7 (57%) 379

318 a total of 217 and 17 of them underwent gonadectomy.28 An with TS.7 Two patients with TS had gonadoblastoma in 380

319 even higher frequency was reported by Alvarez-Nava etal.29 the right and left gonads [karyotypes and age at gonadec- 381

320 who investigated 52 patients and detected four with Y- tomy, respectively: 45,X/45,X,t (15; Y)(p11.2; q11.2) and 382

321 chromosome sequences (7.7%), all underwent gonadectomy 2 years and 11 months; 45,X/46,XY and 10 years and 3 383

322 and two had gonadoblastoma (50%). Five studies reported months]. Gonadoblastoma associated with dysgerminoma 384

323 incidence of 10-25%.9,11-13,18 Previous studies have reported was seen in only one gonad (right, in a patient; and left, in 385

324 frequencies of 7-10%30 and 16.7%.31 These findings show that other) and in two other patients (karyotype 45,X/46,XY and 386

Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome

46,X,+der(15)/46,XY and ages: 11 years and 6 months and 15 years and 4 months, respectively). The youngest patient with TS submitted to gonadectomy was 2 years old.7

According to data presented, it can be concluded that molecular investigation is indicated for Y-chromosome sequences in TS patients, regardless of the karyotype, as a complement to the cytogenetic diagnosis. PCR is the technique suggested because it is inexpensive, sensitive, rapid, and enable the tracking of various sequences of Y-chromosome simultaneously. It would also be appropriate for analysis of a second tissue, in addition to peripheral blood. In those patients with Y-positive sequences, gonadoblastoma investigation is required.


The study received no funding. Conflicts of interest

The authors have no conflicts of interest to declare. References

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