Background: It has been described that the incidence of testicular microlithiasis is high in several congenital disorders which may be associated with testicular impairment and infertility. Several reports have shown that a prepubertal or pubertal hormonal abnormality in the pituitary-gonadal axis was identified in some patients with hypospadias that is one of the most common disorders of sex development. However, exact prevalence or risk factors of testicular microlithiasis in patients with hypospadias have not reported so far. In the present study, to clarify the prevalence and risk factors of testicular microlithiasis in patients with hypospadias, a retrospective chart review was performed. Methods: Children with hypospadias who underwent testicular ultrasonography between January 2010 and April 2016 were enrolled in the present study. Severity of hypospadias was divided into mild and severe. The prevalence and risk factors of testicular microlithiasis or classic testicular microlithiasis were examined. Results: Of 121 children, mild and severe hypospadias were identified in 66 and 55, respectively. Sixteen children had undescended testis. Median age at ultrasonography evaluation was 1.7 years old. Testicular microlithiasis and classic testicular microlithiasis were documented in 17 children (14.0%) and 8 (6.6%), respectively. Logistic regression analysis revealed that presence of undescended testis was only a significant factor for testicular microlithiasis and classic testicular microlithiasis. The prevalence of testicular microlithiasis or classic testicular microlithiasis was significantly higher in children with undescended testis compared to those without undescended testis (testicular microlithiasis; 43.8% versus 9.5% (p = 0.002), classic testicular microlithiasis; 37.5% versus 1.9% (p < 0.001). Conclusions: The current study demonstrated that the presence of undescended testis was only a significant risk factor for testicular microlithiasis or classic testicular microlithiasis in patients with hypospadias. As co-existing undescended testis has been reported as a risk factor for testicular dysfunction among patients with hypospadias, the current findings suggest that testicular microlithiasis in children with hypospadias may be associated with impaired testicular function. Conversely, patients with isolated HS seem to have lower risks for testicular impairment. Further investigation with longer follow-up will be needed to clarify these findings. Keywords: Testicular microlithiasis, Hypospadias, Undescended testis, Ultrasonography * Correspondence: firstname.lastname@example.org Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-Ku, Sapporo 060-8638, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nakamura et al. BMC Pediatrics (2018) 18:179 Page 2 of 6 Background demonstrated that patients with associated genital anomaly, Hypospadias (HS) is one of the most common disorders including UDT, were at higher risk for impaired testicular of sex development, occurring in 0.52 to 8.2 of every 1000 function [6, 9, 21], we speculated that TM may be identified live male births [1, 2]. Although the exact etiology of HS is at a higher rate in such patients. However, the exact preva- unknown in the majority of patients, a multifactorial eti- lence of and TM in patients with HS has not been reported ology including genetic, endocrine and environmental fac- so far. tors is considered to be involved in the genesis of this In the present study, we retrospectively examined the disorder . HS is also considered as one of the symptoms prevalence and the risk factors of TM among children of testicular dysgenesis syndrome (TDS), which was pro- with HS. posed in 2001 . It has been speculated that impaired de- velopment of fetal testes could lead to increased risk of Methods undescended testis (UDT), HS, decreased spermatogenesis Medical charts of children who visited our hospital for and testicular cancer . Several reports have shown that the management or follow-up of HS between January a prepubertal or pubertal hormonal abnormality in the 2010 and April 2016 were retrospectively reviewed. pituitary-gonadal axis was identified in some patients with Among them, patients who were born between HS from endocrinological point of view [6–10], which is December 1999 and August 2015, and who underwent compatible with the concept of TDS. on testicular US were included in the present study. Testicular microlithiasis (TM) is characterized by mul- Patients with obvious disorders of sex development or tiple, small, uniform-appearing echogenic foci of less with chromosomal abnormalities were excluded. To than 3 mm without acoustic shadowing in the seminifer- evaluate and define risk factors of TM in children with ous tubules, which may be indicative of degeneration of HS, the following parameters were assessed with respect the testicular parenchyma [11, 12]. Several theories to their relation to the prevalence of TM: birth weight, about the origin or causes of TM have been reported, presence of UDT, severity of HS, testosterone adminis- however, the exact etiology of TM still remains unclear tration before HS surgery, and age at US. Severity of HS . Previous studies have reported an association was divided into mild and severe based on the necessity between TM and testicular germ cell tumors and/or car- of transecting urethral plate for correction of chordee cinoma in situ [14, 15]. In addition, an association be- deformity according to Koyanagi et al. . tween TM and infertility has been reported . TM was defined as 1 or more foci measuring 1 to 3 mm Although real impact of TM in children is still a matter in diameter on testicular US. TM was classified as limited of debate, it has been described in previous reports that TM (LTM, echogenic foci < 5 /field) or classic TM (CTM, the incidence of TM is high in some congenital disor- echogenic foci ≥ 5 /field) as reported by Goede et al.  ders, such as UDT, Down’s syndrome, Klinefelter syn- (Fig. 1). Among patients with TM, children with CTM in drome, McCune-Albright syndrome and Peuzt-Jeghers at least one testis were diagnosed with CTM, whereas syndrome, which may be associated with testicular im- others were classified as having LTM. pairment and infertility [16–20]. All US evaluation was performed without sedation by Based on these previous reports, TM may be a sign of a sonographers. US evaluations were performed using a future endocrinological abnormality in the pituitary-gonadal PLT-1204BT, a linear probe, 7.2–18 MHz equipped with axis [6–10] or testicular malignancy among patients with Aplio™ XG/500 (Toshiba Medical Systems Corp., Tochigi, HS as a phenotype of TDS. Therefore, we performed tes- Japan), a EUP-65, a linear probe 6–14 MHz equipped with ticular ultrasonography (US) for the screening of testicular HI VISION Avius (Hitachi- Medical, Tokyo, Japan), and a abnormalities in patients with HS. Because several reports ML6–15, a linear probe 6–15 MHz equipped with Logiq a b Fig. 1 Representative pictures of LTM and CTM. a Limited testicular microlithiasis (arrows) in an 11-year-old boy with hypospadias and undescended testis. Ultrasonography of right testis showed 2 small, uniform-appearing echogenic foci without acoustic shadowing. His left testis also displayed 4 echogenic foci per field. b Classic testicular microlithiasis in a 1-year-old boy with hypospadias. Ultrasonography of left testis demonstrated more than 5 echogenic foci per field. Right testis also displayed more than 5 echogenic foci per field Nakamura et al. BMC Pediatrics (2018) 18:179 Page 3 of 6 E9 (GE Healthcare, Amersham, UK). If multiple examina- factor for TM (p =0.006) (Table 2). Regarding CTM, pres- tions were performed during follow-up, the final assess- ence of UDT was only a risk factor on univariate analysis ment findings were evaluated for prevalence and risk (p <0.001) (Table 3). The incidence of TM or CTM was factors of TM. significantly higher in children with UDT compared with JMP®pro version 12 was used for all statistical analyses. those without UDT (TM; 43.8% versus 9.5% (p = 0.002), Statistical analyses were performed using logistic regres- CTM; 37.5% versus 1.9% (p < 0.001)) (Table 4). sion analysis and Fisher’s exact test. P < 0.05 was consid- ered significant. Side of TM and UDT (Table 5) In 11 children with bilateral UDT, unilateral and bilat- Results eral TM were observed in 1 and 4, respectively. Among Among 219 children who visited during the study period, them, CTM in at least one side was identified in 4. Of 5 121 children (55.3%) were included in the current study. with unilateral UDT, TM was identified in 2 (both with Patient characteristics are shown in Table 1. Median birth bilateral CTM). Among 105 children without UDT, uni- weight was 2456 g, and the number of children with low lateral and bilateral TM were observed in 6 and 4, re- birth weight (less than 2500 g) was 62. Mild and severe HS spectively. Of those, CTM in at least one side was were identified in 66 and 55 children, respectively. UDT observed only in 2. was observed in 16 patients (bilateral in 11, unilateral in 5). Of those, 4 had mild HS, and 12 had severe HS. Regarding Discussion co-existing congenital anomaly, inguinal hernia and heart To our knowledge, the current study represented the anomaly were observed in 13 and 8, respectively. Testos- first report on the prevalence of TM in children with terone administration before HS surgery was performed in HS. TM and CTM were identified in 14.0 and 6.6%, re- 94 children. Median age at testicular US was 1.7 years old. spectively, of children with HS. Presence of UDT was only a risk factor for TM and CTM. Prevalence of TM and CTM Previous studies have shown that TM is associated TM and CTM were documented in 17 children (14.0%) with several conditions, including impaired spermato- and in 8 children (6.6%), respectively. TM was identified genesis, testicular cancer and carcinoma in situ [14, 15]. unilaterally in 7, and bilaterally in 10. Among 8 children In asymptomatic adults, the rate of CTM varies from 0.6 with CTM, bilateral CTM was identified in 5. In the to 9% [24, 25]. Recent studies revealed that the preva- remaining 3 children, unilateral CTM alone was detected in lence of TM and CTM in asymptomatic boys was 4.2 1, and CTM on one side and LTM on the other side in 2. and 2.4% respectively, and increased with age . The No testicular tumors were detected on US in any children. prevalence of TM (14.0%) and CTM (6.6%) in children with HS in the current study seems to be relatively Risk factors of TM and CTM higher compared with that in asymptomatic boys in the Univariate analysis demonstrated that the severe type of previous reports. Although the etiology of HS is consid- HS and presence of UDT were risk factors for TM. On ered to be multifactorial, the concept of TDS, which multivariate analyses, presence of UDT was only a risk suggests that impaired development of fetal testes could lead to increased risk of HS, has been proposed as one Table 1 Patient characteristics of the causes of HS. Drut et al. proposed that TM may be related with Sertoli cell dysfunction and abnormal n = 121 range embryogenesis during the early stages of testicular devel- Birth weight 2456 ± 834 (unknown 1) (472–4048) (g, median ± SD) opment . Wohlfahrt-Veje et al. reported that dysge- netic testes often have an irregular US pattern in which Low birth weight 62 (< 2500 g) (pts) TM may also be visible . The reason for the relatively Type of HS (pts) mild: 66 / severe: 55 high prevalence of TM may be due to that children who have such embryological causes of testis anomaly could UDT (pts) 16 (unilateral: 5 / bilateral: 11) have been included in the present study. Testosterone yes: 94, no: 20 (unknown 7) We demonstrated that the presence of UDT was only a administration before surgery (pts) risk factor for TM and CTM. There are several reports of topical: 67 / systemic: prepubertal or pubertal hormonal abnormalities of the 10 / topical+systemic: 17 pituitary-gonadal axis in some patients with HS [6–10]. In Age at USG 1.7 ± 4.0 (0.5–18.2) addition, there are several reports on patients with both (yrs, median ± SD) HS and UDT, which is a risk factor of TM and CTM as TM (pts) 17 demonstrated in our study, who were at a higher risk for (LTM / CTM) (9 / 8) decreased testicular function or impaired spermatogenesis Nakamura et al. BMC Pediatrics (2018) 18:179 Page 4 of 6 Table 2 Risk factors for TM Univariate analysis Multivariate analysis Odds ratio (95% confidence interval) p value Odds ratio (95% confidence interval) p-value Birth weight (g, median ± SD) 0.44 (0.04–4.09) n.s. Low birth weight (< 2500 g) 0.84 (0.68–4.09) n.s. Severe type of HS 3.40 (1.17–11.35) 0.024 2.48 (0.79–8.65) n.s. * * UDT 7.39 (2.23–24.55) 0.001 5.8 (1.68–19.95) 0.006 Testosterone administration 1.57 (0.39–10.59) n.s. Age at USG 0.28 (0.04–2.52) n.s. p < 0.05 [6, 21]. A number of reports have demonstrated the TM in the asymptomatic population ranged from 2.4 to relationship between TM and impaired spermatogenesis 5.6% [24, 25], which is much higher than the prevalence [26–28], although this issue is still controversial . of the lifetime risk of testicular cancer in the general Accordingly, TM in children with HS may be associated population. Nowadays, it is recognized that TM in adults with decreased testicular function and/or impaired sperm- without known risk factors, such as previous testicular atogenesis. To determine the relationship between TM cancer, a history of UDT or testicular atrophy, seems to and testicular function/spermatogenesis in patients with be a benign condition [19, 24, 25, 30]. Regarding TM de- HS, further follow-up with endocrinological evaluations tected in childhood, Suominen et al. found 15 patients until puberty is necessary. with neoplasms among 421 pediatric patients (3.6%) by While the prevalence of TM in patients with HS and systematic review . They described that TM should without UDT (9.5%) in the current study was slightly be considered a benign condition even in the pediatric higher compared to that in asymptomatic boys (4.2%) age group, but the fact that TM is associated with tes- reported in the previous literature , the prevalence ticular malignancy (< 5%) cannot be ignored. Although of CTM (1.9%) was almost similar to that in asymptom- the concept of TDS included symptoms of HS, UDT and atic boys (2.4%). Accordingly, patients with isolated HS testicular cancer , as far as we know, there is no re- seem to have lower risks for testicular impairment. On port demonstrating that the prevalence of testicular tu- the contrary, although the presence of UDT in patients mors is higher in patients with HS. Although UDT is with HS was demonstrated as a risk factor for TM in the well-known as a risk factor for testicular malignancy , current study or impaired semen quality in the previous it is obscure whether UDT is also a risk factor for testicu- report , there has been no comparative study focus- lar malignancy among patients with HS. Longer follow-up ing on risk of TM or testicular dysfunction between pa- will clarify the exact associations among testicular malig- tients with isolated UDT and those with HS and UDT. nancy, TM and/or UDT in children with HS. To clarify the impact of HS in patients with UDT in There is some controversy regarding the method and terms of the risk of TM or testicular dysfunction, duration of follow-up in patients with TM. In the guide- additional studies are necessary. lines produced by the European Society of Urogenital Previous studies reported that the prevalence of pri- Radiology, the consensus opinion is that the presence of mary testicular tumors in patients with TM ranged from TM alone in the absence of other risk factors is not an 15 to 45% [15, 29]. Thus, there was some concern that indication for regular follow-up in adults . However, TM may lead to testicular cancer at the end of the this guideline did not mentioned children with HS. At 1990’s. However, two studies revealed that the rate of this time, we believe that the follow-up protocol for pa- tients with HS and TM should be determined based on the presence or absence of UDT because the exact risk Table 3 Risk factors for CTM for testicular malignancy in patients with HS alone re- Univariate analysis mains obscure. Odds ratio p-value Several limitations of the present study should be ad- (95% confidence interval) dressed. First, this study was conducted in a retrospective Birth weight (g, median ± SD) 4.26 (0.20–85.70) n.s. Low birth weight (< 2500 g) 1.61 (0.38–8.14) n.s. Table 4 Prevalence of TM and CTM Severe type of HS 3.92 (0.86–27.53) n.s. UDT (+) UDT (−) p-value UDT 30.90 (6.23–231.37) < 0.001 Prevalence of TM 43.8% (7/16) 9.5% (10/105) 0.002 Age at USG 0.19 (0.01–3.62) n.s. Prevalence of CTM 37.5% (6/16) 1.9% (2/105) < 0.001 p < 0.05 Nakamura et al. BMC Pediatrics (2018) 18:179 Page 5 of 6 Table 5 Sides of testicular microlithiasis and undescended testis Ethics approval and consent to participate The present study was approved by the Institutional Review Board of Hokkaido Bilateral UDT Unilateral UDT Without UDT University Hospital and the necessity to obtain written consent was waived n =11 n =5 n = 105 because of its retrospective nature. Administrative permissions were received from the Institutional Review Board of Hokkaido University Hospital for Unilateral TM 1 0 6 accessing medical records in this study. (Approval number: 016–0095). CTM 1 0 0 Competing interests LTM 0 0 6 The authors declare that they have no competing interests. Bilateral TM 4 2 4 Bilateral CTM: 2 2 1 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in CTM and LTM 1 0 1 published maps and institutional affiliations. Bilateral LTM 1 0 2 Author details Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-Ku, Sapporo 060-8638, nature and relatively small number of children. Second, 2 Japan. Diagnostic Center for Sonography, Hokkaido University Hospital, there was no control group such as Japanese boys who Sapporo, Japan. Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan. had no genital disease or isolated UDT. Third, evaluation of chromosomal abnormalities was not performed in all Received: 10 September 2017 Accepted: 18 May 2018 children. Fourth, as children included in the current study were relatively young and because TM sometimes appears References later in childhood , the true prevalence of TM in pa- 1. Levitt SB, Reda EF. Hypospadias. Pediatr Ann. 1988;17(1):48–9. 53-44, 57 tients with HS may be higher than the prevalence in this 2. Springer A, van den Heijkant M, Baumann S. Worldwide prevalence of hypospadias. J Pediatr Urol. 2016;12(3):152.e151–7. study. Fifth, as endocrinological examination or semen 3. Marrocco G, Grammatico P, Vallasciani S, Gulia C, Zangari A, Marrocco F, analysis was not performed in the current study, testicular Bateni ZH, Porrello A, Piergentili R. 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