Testicular microlithiasis and testicular volume in boys with Down syndrome

Transcription

1 Chapter 2.5 Testicular microlithiasis and testicular volume in boys with Down syndrome J Goede ME Weijerman CJM Broers JP de winter LM van der Voort-Doedens WWM Hack J Urol, in press 81

2 Chapter 2.5 Abstract Purpose Studies have suggested that testicular microlithiasis and Down syndrome are linked, yet the clear correlation remains unclear. Our purpose was to investigate the prevalence of testicular microlithiasis in Down syndrome patients. We hypothesize that testicular microlithiasis is present at a higher rate in Down syndrome patients. We further hypothesize that Down syndrome patients have lower testicular volumes than normal age matched boys. We will test our hypothesis by ultrasound investigation in Down syndrome boys aged 0-18 years. Materials and Methods Testicular ultrasound was performed in 79 boys with Down syndrome (mean age 8.8 years, range years). Testicular microlithiasis was assessed and testicular volume was measured according to the formula: π/6 x length x width x height. Results Testicular microlithiasis was present in 18 of the 79 boys (22.8%). It was diagnosed in 6 of the 28 boys < 7 years (21.4%), in 6 of the 28 boys between 7 and 12 years (21.4%), and in 6 of the 23 boys 12 years (26.1%). No significant difference was found in the prevalence of testicular microlithiasis between these three groups. The mean volumes of patients with Down syndrome (2.19 ml) were significantly smaller than the normative values. Conclusions This study reveals a 22.8% prevalence of testicular microlithiasis in boys with Down syndrome, which is at a significant higher rate as compared to normative values. In addition, testis volume is significantly smaller in boys with Down syndrome than the normative values. 82

3 Testicular microlithiasis and testicular volume in boys with Down syndrome Introduction Down syndrome (DS) is one of the most common chromosomal disorders, occurring once in every 1,000 live births. 1 Patients with DS have an increased risk of childhood leukaemia, gastrointestinal cancer and testicular germ cell tumours (TGCT). 2-5 Testicular microlithiasis (TM) is a condition in which multiple small calcifications are present in the seminiferous tubules, which may be indicative of a degeneration of the testis parenchyma. 6-8 The prevalence of TM in DS patients has only been documented in one study, which reported a rate of 29%. 9 However, this study included paediatric as well as adult patients. Recently, a prevalence rate of 4.2% of TM has been determined in non- DS boys. 10 We hypothesize that TM is present at a higher rate in DS boys. We further hypothesize that DS boys have lower testicular volumes than normal age matched boys. 11 We will test our hypothesis by ultrasound investigation in DS boys aged 0-18 years. Materials and methods Study Design Boys were recruited from the records and via the magazine of the Dutch Down Syndrome Association (Stichting Downsyndroom) and the records of the paediatric departments of the 3 different hospitals. A total of 94 patients responded, of whom 81 enrolled in this study. Inclusion and exclusion criteria Included were boys with DS confirmed by chromosomal analysis, aged 0 18 years. It proved not possible to measure testicular volume by US three times in all boys. The boys whose testicular volume was measured less than three times were excluded from the determination of testicular volume, but not from the determination of TM. Definitions Descent was defined as a spontaneous stable position of the testis at the bottom of the scrotum. Undescended testis (UDT) was defined as a testis that could not be manipulated into a stable scrotal position and where further tension on cord structures caused discomfort. UDT was classified as high scrotal, inguinal or non-palpable. 83

4 Chapter 2.5 TM was defined as classical TM (CTM) if five or more foci measuring 1 3 mm in diameter were seen on US plane in one or both testes. 12 Patients who had at least one microlith but who did not meet the criteria for CTM were considered to have limited TM (LTM). TM was differentiated as diffusely scattered throughout the parenchyma or as segmented. Study protocol Questionnaire At the paediatric outpatient clinic, a questionnaire was used which included the following items: diagnosis DS confirmed by karyotype, age of diagnosis, medical problems, major surgery, prior groin surgery, medication use, diet, gestational age, birth weight, ethnicity and school level. Ethnical background was divided into Caucasian, Turkish, North African, Asian or African American. Physical examination The physical examination and measurement of height and weight of each boy was performed by the same physician (JG). A full physical examination was not routinely performed. With the boy in supine and crossed-legged position, testicular examination of the left testis was carried out first, followed by the right testis. Testis position was classified as low scrotal, high scrotal, inguinal or absent, and the testis was diagnosed as descended or undescended. Testicular ultrasonography After the physical examination, US was performed of both testis to assess the presence or absence of TM. All US were performed with the same equipment (Falco Auto Image, Falco Software Co, Tomsk, Russia), using a 12 MHz linear array transducer. After that, testicular volume of the left testis was measured, followed by the right testis. To measure testicular volume, the scanner was placed on the testis with only light pressure to avoid distorting the testicular shape. If the testis could be brought into a scrotal position, volume measurement was performed on the scrotum. However, if the testis was positioned in the groin region, the US was performed there. Three separate transverse and longitudinal images of each testis were recorded. The epididymis was not included. When maximum length, width and height had been obtained in the ultrasonogram, these were measured and the volume was calculated with the formula for an ellipsoid = π/6 x length x width x height. The highest value of the three testicular volumes was taken as the volume measurement. Parenchymal disturbances were not studied and Doppler flow studies to assess testicular blood flow were not performed. 84

5 Testicular microlithiasis and testicular volume in boys with Down syndrome Data recording and statistical methods The statistical package SPSS for Windows, version 14.0, was used for all calculations and statistical analyses. Differences in age between boys with and without TM was tested with the Mann-Whitney test. The Chi-square test was used to determine whether there was a relation between the ages of the boys and whether they had TM or not. It was also used to test whether there was a relationship between TM boys and boys who had any co-morbidity. Finally, the Mann-Whitney test was used to compare the testicular volumes of DS boys with normative values. Ethical approval The study was approved by the Ethical Committee of the hospital (reference no. M08-001). Results Numbers of patients and ultrasounds A total of 81 patients with DS enrolled in this study. Mean age was 8.8 years (range ). Of these boys, 79 (97.5%, age range years, mean age 8.4 years) were included in this study. Two patients were excluded as they were above 18 years old. General characteristics Of the 79 boys included in the study, all diagnoses were confirmed by karyotype and all were diagnosed before the age of 3 months. One boy (age 6.2 years) had mosaic trisomy 21; the other 78 had karyotype 47 XY +21. Fifteen boys (19.0%) had had a birth weight < 2,500 grams and 13 (16.5%) had been born prematurely. Of the 79 patients, 74 (93.7%) were Caucasian, 3 (3.8%) were North African and 2 (2.5%) were Turkish. All patients with TM were Caucasian. Of the 79 boys, 14 (17.7%) were educated at a normal primary or high school, whereas 42 (53.2%) were educated at a special needs school (23 boys were under the age of 4 years and therefore not yet attending school). The history of relevant pathology of the included boys is summarised in Table 1. Height and weight were compared with the reference data for boys with DS 13 ; this comparison yielded no significant differences. 85

6 Chapter 2.5 Table 1 History of relevant pathology of the included boys with Down syndrome (n = 79). Age at examination n % minimum maximum mean No substantional history of pathology 14 17,7 0,6 18,3 7,3 Congenital heart defect 38 48,1 0,4 18,0 8,7 Visual disturbances 32 40,5 1,9 18,0 10,1 Hypothyroidism 13 16,5 1,9 17,9 9,5 Undescended testis 12 15,2 0,7 15,7 6,2 Hearing disabilities 11 13,9 3,4 18,0 11,4 Groin surgery 7 8,9 2,8 17,9 10,4 Leukemia 4 5,1 1,2 14,5 7,9 Pancreas annulare 2 2,5 1,1 4,5 2,8 Celiac disease 2 2,5 8,7 11,1 9,9 Abnormal cervical vertebrae 1 1,3 12,9 Other diseases 12 15,2 0,8 17,9 8,8 Table 2 Characteristics of boys with Down syndrome (n = 79) with and without testicular microlithiasis (TM) on ultrasound. Boys with TM (n =18) Boys without TM (n = 61) (age 1,7-18,0) (age ) n % n % p* Birthweight <2500 gr 2 11, ,4 0,293 Prematurity 1 5, ,7 0,156 Groin surgery 6 33,3 1 1,6 < 0,001 Undescended testis 5 27,8 7 11,5 0,090 Other diagnosis ** 14 77, ,6 0,569 * chi-square ** as mentioned in Table 1 86

7 Testicular microlithiasis and testicular volume in boys with Down syndrome Testicular microlithiasis TM was present in 18 boys (22.8%, mean age 9.2 years, range years), with CTM manifesting in 11 of these 18 boys (61.1%) and LTM in 7 of these 18 boys (38.9%). No relation was found between the ages of the boys and whether they had TM or not (p = 0.860). TM was diagnosed in 6 of the 28 boys < 7 years (21.4%), in 6 of the 28 boys between 7 and 12 years (21.4%) and in 6 of the 23 boys 12 years (26.1%). There was no relation between the three groups in the prevalence of TM (p = 0.904). TM was diffusely scattered throughout the parenchyma in 15 of the 18 boys with TM (83.3%) and segmented in the other 3 boys (16.7%). TM was found bilateral in 13 (72.2%) and unilateral in 5 patients (27.8%). No testicular tumour was detected in any of the patients. As shown in Table 2, 14 of the 18 boys with TM (77.8%) and 51 of the 61 boys without TM (83.6%) were diagnosed with any of the mentioned diagnosis in the table. Testicular volume Ultrasound Of the 79 patients included in the study, volume measurement by US could be performed three times in 62 patients (78.5%); not more than twice in 8 patients (10.1%) and only once in 5 patients (6.3%). In 4 patients (5.1%) only the presence of TM could be determined and no volume measurement was possible. One patient had only one testis and therefore TM and volume measurement could only be obtained for this (left) testis. All 62 boys for whom volume measurement could be performed three times were included for volume measurement by US, except 10 boys (16.1%) with a history of UDT or groin surgery because since it might negatively influence the testicular volume. Mean testicular volumes (n = 52) ranged from 0.13 to 8.98 ml (mean 2.19 ml). There was no significant difference between left and right testicular volumes (p = 0.975; paired t-test). Figure 1 presents the mean testicular volumes related to normative values and Figure 2 shows the mean testicular volumes of DS boys with and without TM. Table 3 shows the testicular volumes for the three age groups related to normative values. The mean testicular volumes of DS boys were significantly smaller than the normative values for all boys and for boys < 7 years and 12 years (p < 0.05). 87

8 Chapter 2.5 Table 3 Testicular volume (ml) as measured by ultrasound in boys with Down syndrome (n = 52) related to normative values in three different age groups. Testicular volume (ml) Down syndrome Testicular volume (ml) normative values** Age group N Min Max Mean N Min Max Mean p-value* Total 52 0,13 8,98 2, ,018 < 7 years 21 0,13 0,63 0, ,23 1,36 0,53 <0, years 16 0,27 4,84 1, ,30 9,13 1,11 0, years 15 1,97 8,98 5, ,68 20,23 8,90 0,002 *Mann-Whitney test ** Earlier published data (8) Figure 1 Mean testicular volumes (ml) per age for boys with Down syndrome (n = 52) as measured by ultrasound related to reference values. testis volume (ml) P 90 P P 10 Down Syndrome age (yrs) 88

9 Testicular microlithiasis and testicular volume in boys with Down syndrome Discussion The prevalence of TM in boys with DS aged 0 18 years is 22.8%, compared to a prevalence rate of 4.2% in non-ds boys. Moreover, testicular volume in boys with DS is significantly smaller than the normative values. The lifetime risk of TGCT in the general population is approximately %, whereas in individuals with DS this risk is 6 50 times higher. 14,15 Although TM is generally considered to be an additional predisposing factor for testicular malignancy, the development of TGCT following the diagnosis of TM is reported anecdotic. TM has only been described once in an adult patient with DS and a TGCT and only one case has been reported of a tumour developing in a DS patient with pre-existing TM. 16,17 The high prevalence of TM in boys with DS may be related to the potential higher risk to develop TGCT. Segmented TM may be more prevalent in patients with TGCT; therefore, it must be differentiated from diffuse TM. 12 In this series, we found segmented TM in only 1 of the 18 boys with TM. The TM rate in healthy boys is 4.2% 10, compared to 2.0% in symptomatic boys. 18 In symptomatic adults the rate varies from 0.6% to 9%, while two studies in healthy populations reported rates of %. 19,20 The TM rate of 22.8% in DS boys found in this study is in accordance with the TM rate of 29% reported in a recent study in 92 Latino DS patients aged 0 30 years. In our study we found more TM in boys with a UDT (5 of 10 boys, 50%) than in boys with descended testes (12 of 74 boys, 16.2%). This may be the result of the higher UDT rate in DS boys. The high prevalence of TM in boys with DS may be associated with the known infertility in these patients. This infertility is caused by the existence of the extra chromosome in the meiotic prophase, which leads to an inability to produce sufficient gametes and consequently to decreased spermatogenesis. 21,22 The formation of microliths is thought to be the result of a degeneration of cells in the seminiferous tubules. 23 We found significantly smaller testis volumes in DS boys, which supports the association between TM and the degeneration of the testis parenchyma, since a major part of the testis parenchyma consists of seminiferous tubules. In addition, significantly more boys with TM had a history of groin surgery; this also supports this association, since an operative procedure could damage the surrounding tissue, and this damage may result in degeneration of the testis parenchyma. However, the disappearance of TM during followup, which has been described earlier 24, contradicts the theory of degeneration of the 89

10 Chapter 2.5 Figure 2 Mean testicular volumes (ml) per age for boys with Down syndrome (n = 52) with and without testicular microlithiasis as measured by ultrasound. testis volume (ml) Testicular Microlithiasis no yes age (yrs) testis parenchyma. Further research on the TM prevalence in DS adults should give more information about whether TM resolves in DS patients during live. In the age group 7 12 years, we found testicular volumes which were comparable with normative values. A comparison of the pubertal stages in DS boys and in healthy boys led us to conclude that this finding could not be explained by an earlier pubertal development in DS boys. We found significantly smaller testicular volumes in the age group 12 years. The difference in testicular size in this age group may be more manifest since pubertal development had been occurred from this age on. Therefore, testicular volumes are generally higher and good to compare in these boys. There is some controversy regarding the type and duration of follow-up in patients with TM. Even so, some degree of follow-up seems to be indicated. 25 The 22.8 % prevalence of TM and the much lower incidence of testicular cancer in DS patients (approximately 200 per 100,000 person-years 26 ) disproves any epidemiological association with testicular malignancies. However, there may be a genetic susceptibility to TM that also predisposes to TGCT. 27 In non-ds boys with TM, we advise testicular self-examination every 3 months beginning at age 15, since testicular malignancies are known to occur from this age onward. We believe that routine US should only be considered for patients with 90

11 Testicular microlithiasis and testicular volume in boys with Down syndrome other potentially premalignant features such as UDT. However, in DS boys regular selfexamination may be more difficult to perform and less reliable as a result of the mild to moderate mental impairment which is usually present. 28 Therefore, we advise routine US every 12 months in DS boys from the age of 15. This is especially important in boys with other potentially premalignant features such as UDT. Figure 3 shows a flow-chart of the follow-up of boys with TM. In addition, we believe that testicular US should be included in DS screening programmes. 28,29 The limitations of this study need to be addressed. To promote participation in our study, we invited DS boys from the Dutch Down Syndrome Association and three different hospitals. Only a proportion of these boys agreed to participate. The reasons for not participating were not analysed, which may have introduced a selection bias. The prevalence of TM was assessed in DS boys from birth to adolescence, which may be a second limitation. The age of presentation of TM is largely unknown, but may occur somewhere later in childhood. 10 Therefore, the true prevalence of TM in DS patients may be higher than the reported 22.8%. Furthermore, we analysed testicular volumes in three different age groups and found no difference in boys between 7 and 12 years compared to normative values. However, there is a possibility that this finding is caused by the Figure 3 Flow chart of follow up of boys with testicular microlithiasis. Testicular microlithiasis <15 years No follow up necessary 15 years Risk factor: Testicular pain History of Testicular Germ Cell Tumor Undescended testis No risk factor Down syndrome No Down syndrome Annual ultrasound Self examination every 3 months 91

12 Chapter 2.5 relatively small number of boys in this age group included in this study. Finally, of the 19 boys with TM, 5 were known with UDT and another 6 had a history of groin surgery. These co-morbidity might be a contributing factor leading to TM and might therefore led to a higher prevalence. If we exclude patients with UDT and a history of groin surgery, the prevalence of TM should be 11.7% which is still significant higher than the prevalence of 4.2% in non-ds boys. Conclusions This study reveals a 22.8% prevalence of TM in DS boys, which is significantly higher than in non-ds patients. TM prevalence was higher in DS boys with UDT than in DS boys with normally descended testes. Furthermore, the testis volumes in DS boys were significantly smaller than the normative values. Acknowledgments We would like to thank the Dutch Down Syndrome Association Stichting Downsyndroom for their assistance in the recruitment of the participants. 92

13 Testicular microlithiasis and testicular volume in boys with Down syndrome References 1. Roizen, N. J. and Patterson, D.: Down s syndrome. Lancet, 361: 1281, Villanueva, M. J., Navarro, F., Sanchez, A. et al.: Testicular germ cell tumor and Down syndrome. Tumori, 86: 431, Aguilar-Ponce, J. L., Vidal-Millan, S., Molina-Calzada, C. et al.: Treatment experiences of testicular cancer in Hispanic patients with Down s syndrome at the National Cancer Institute of Mexico. Clin Transl Oncol, 10: 768, Patja, K., Pukkala, E., Sund, R. et al.: Cancer incidence of persons with Down syndrome in Finland: a population-based study. Int J Cancer, 118: 1769, Kuroda, N., Amano, S., Shiotsu, T. et al.: Mixed testicular germ cell tumor in an adult with cryptorchidism and Down s syndrome. APMIS, 115: 1292, Aizenstein, R. I., DiDomenico, D., Wilbur, A. C. et al.: Testicular microlithiasis: association with male infertility. J Clin Ultrasound, 26: 195, Pierik, F. H., Dohle, G. R., van Muiswinkel, J. M. et al.: Is routine scrotal ultrasound advantageous in infertile men? J Urol, 162: 1618, Thomas, K., Wood, S. J., Thompson, A. J. et al.: The incidence and significance of testicular microlithiasis in a subfertile population. Br J Radiol, 73: 494, Vachon, L., Fareau, G. E., Wilson, M. G. et al.: Testicular microlithiasis in patients with Down syndrome. J Pediatr, 149: 233, Goede, J., Hack, W. W., van der Voort-Doedens LM et al.: Prevalence of testicular microlithiasis in asymptomatic males 0 to 19 years old. J Urol, 182: 1516, Goede, J., Hack, W. W., Sijstermans, K. et al.: Normative Values for Testicular Volume Measured by Ultrasonography in a Normal Population from Infancy to Adolescence. Horm Res Paediatr, Backus, M. L., Mack, L. A., Middleton, W. D. et al.: Testicular microlithiasis: imaging appearances and pathologic correlation. Radiology, 192: 781, Myrelid, A., Gustafsson, J., Ollars, B. et al.: Growth charts for Down s syndrome from birth to 18 years of age. Arch Dis Child, 87: 97, Satge, D., Sasco, A. J., Cure, H. et al.: An excess of testicular germ cell tumors in Down s syndrome: three case reports and a review of the literature. Cancer, 80: 929, Dexeus, F. H., Logothetis, C. J., Chong, C. et al.: Genetic abnormalities in men with germ cell tumors. J Urol, 140: 80, Vachon, L., Fareau, G. E., Wilson, M. G. et al.: Testicular microlithiasis in patients with Down syndrome. J Pediatr, 149: 233,

14 Chapter Miller, R. L., Wissman, R., White, S. et al.: Testicular microlithiasis: a benign condition with a malignant association. J Clin Ultrasound, 24: 197, Miller, F. N., Rosairo, S., Clarke, J. L. et al.: Testicular calcification and microlithiasis: association with primary intra-testicular malignancy in 3,477 patients. Eur Radiol, 17: 363, Peterson, A. C., Bauman, J. M., Light, D. E. et al.: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol, 166: 2061, Serter, S., Gumus, B., Unlu, M. et al.: Prevalence of testicular microlithiasis in an asymptomatic population. Scand J Urol Nephrol, 40: 212, Johannisson, R., Gropp, A., Winking, H. et al.: Down s syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet, 63: 132, Pradhan, M., Dalal, A., Khan, F. et al.: Fertility in men with Down syndrome: a case report. Fertil Steril, 86: 1765, Vegni-Talluri, M., Bigliardi, E., Vanni, M. G. et al.: Testicular microliths: their origin and structure. J Urol, 124: 105, Coley, B. D.: Resolving testicular microlithiasis in a 12-year-old boy. J Ultrasound Med, 24: 1445, Tan, M. H. and Eng, C.: Testicular microlithiasis: recent advances in understanding and management. Nat Rev Urol, 8: 153, Satge, D., Jacobsen, G. K., Cessot, F. et al.: A fetus with Down syndrome and intratubular germ cell neoplasia. Pediatr Pathol Lab Med, 16: 107, Coffey, J., Huddart, R. A., Elliott, F. et al.: Testicular microlithiasis as a familial risk factor for testicular germ cell tumour. Br J Cancer, 97: 1701, Weijerman, M. E. and de Winter, J. P.: Clinical practice. The care of children with Down syndrome. Eur J Pediatr, 169: 1445, Roizen, N. J.: Medical care and monitoring for the adolescent with Down syndrome. Adolesc Med, 13: 345,

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