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Urological Manifestations of Down Syndrome
0022-5347/04/1713-1250/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 1250 –1253, March 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000112915.69436.91
Review Article UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME ERICA SCHALOW MERCER, BRUCE BROECKER,* EDWIN A. SMITH, ANDREW J. KIRSCH, HAL C. SCHERZ AND CHARLOTTE A. MASSAD From Pediatric Urology P. S. C. and the Department of Urology, Emory University School of Medicine, Atlanta, Georgia
ABSTRACT
Purpose: We identified the urological anomalies seen in patients with Down syndrome. Materials and Methods: We reviewed the literature on Down syndrome and its associated genitourinary pathology. Results: Associated defects have been reported throughout the genitourinary tract. The most common renal anomalies seen are renal hypoplasia, obstructive uropathy and glomerular microcysts. Decreased creatinine clearance has also been noted. Developmental anomalies, such as megaureter and vesicoureteral reflux, have been reported. Dysfunctional voiding and urinary retention have been found in these patients. Posterior urethral valves and hypospadias have also been seen. The testicular abnormalities most frequently reported are cryptorchidism, testicular cancer and infertility. Conclusions: Improved understanding and identification of the various urological anomalies associated with Down syndrome will aid in the care of these patients. In addition, an awareness of perioperative issues will further facilitate a smooth clinical course. KEY WORDS: kidney, ureter, testis, abnormalities, Down syndrome
In 1866 the British physician Dr. John Langdon H. Down first described Down syndrome.1 He grouped these patients due to their characteristic facies and invariable mental retardation, and proposed that this condition was caused by tuberculosis in the parents. He termed them Mongols based on the flat, broad face and slanted, narrow palpebral fissures. When it was realized that these patients were not true Mongols, the name mongolism was changed to Down syndrome.2 In 1959 Lejeune reported that the etiology is actually an extra copy of chromosome 21.3 In more than 95% of patients with Down syndrome the condition is due to nonfamilial trisomy 21 or nondisjunction,4 while in 3% to 4% the extra chromosome material is the result of an unbalanced translocation.5 The remaining 1% to 2% of patients have mosaicism, possessing normal and abnormal cell types with resultant wide phenotypic variability.2 The syndrome has been reported to occur in about 1/1,000 live births in the United States6 and life tables have demonstrated that more than 50% of these patients live more than 50 years.7 The syndrome has multiple well-known associated congenital abnormalities, particularly cardiac defects in 26% to 50% of cases, eye disease in 60%, hearing loss in 75%, obstructive sleep apnea in 50% to 75%, gastrointestinal atresia in 12% and thyroid disease in 15%.5, 8 With such a significant portion of the population affected by the disease it is important to identify the urological anomalies seen in patients with Down syndrome. MATERIALS AND METHODS
A bibliographic PubMed and MEDLINE search was performed for 1966 to the present. We reviewed all English literature on Down syndrome and its associated genitouri-
nary pathology. Applicable secondary references found through these articles were also reviewed. RESULTS
Associated defects are reported throughout the genitourinary tract. Upper urinary tract. Kidney: In 1960 Berg et al first noted the coincidence of renal anomalies and Down syndrome.9 They reported that 5 of 141 Down syndrome autopsy cases (3.5%) had renal malformations. Four of these patients had renal agenesis or hypoplasia and 1 had a horseshoe kidney. In a more current autopsy/necropsy study Ariel et al examined 124 cases of Down syndrome for urinary system abnormalities.10 Multiple renal anomalies were noted, particularly in patients 1 day and older. Renal hypoplasia, defined as less than two-thirds of expected renal weight in an otherwise normal-appearing kidney, was found in 18 of 84 evaluable cases (21.4%). Glomerular microcysts were found in 23 of 97 patients (23.7%) older than 1 day and younger than 25 years. Rare glomerular microcysts believed to be within the range of normal were found in an additional 17 cases. Only 1 patient with glomerular microcysts was noted to have urinary tract obstruction. Obstructive uropathy was seen in 8 of the 124 cases (6.45%). Two of these 8 cases were fetuses at 16 to 22 weeks of gestation (2 of 18 in this age group or 11.1%), 2 were fetuses or newborns (2 of 9 or 22.2%), and 4 were older than 1 day (4 of 97 or 4.1%). Cystic dysplasia was noted in 4 of the 124 cases (3.23%) as well as obstructive lesions of the urinary tract. Lastly, simple renal cysts were found in 7 of the 124 cases (5.6%), much higher than the reported pediatric incidence of 0.1%.11 To our knowledge the clinical significance of the glomerular microcysts and renal cysts is unknown. Another autopsy study was performed by Lo et al.12 In this study the focus was on glomerular alterations in patients
* Correspondence: Department of Urology, Emory University School of Medicine, 1901 Century Blvd., Suite 14, Atlanta, Georgia 30345 (telephone: 404-320-9179; FAX: 404-320-1912; e-mail: [email protected]). 1250
UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME
with Down syndrome compared to a control group. The only morphological finding more common in the Down syndrome group was glomerular microcysts. They additionally found several cases of acquired glomerular disease in Down cases, including membranous nephropathy, nephrotic syndrome and minimal change disease, glomerulonephritis and focal segmental glomerulosclerosis with hyalinosis. Multiple cases of glomerulonephritis have been reported in patients with Down syndrome. Gupta et al described 4 patients with mesangiocapillary glomerulonephritis.13 There have also been single case reports of chronic glomerulonephritis,14 immunotactoid glomerulopathy15 and antineutrophil cytoplasmic antibody associated glomerulonephritis.16 Little has been published on renal function and renal replacement therapy in Down syndrome. In these patients there is a decrease in the clearance of uric acid and creatinine.17 One report details 2 patients without preexisting renal disease who had acute renal failure and died following angiotensin-converting enzyme inhibitor therapy for heart failure.18 Renal replacement therapy in patients with Down syndrome is only briefly addressed in the literature but it is believed to be a viable option for any cooperative patient with Down syndrome and end stage renal disease.19, 20 Renal transplantation has been performed in Down syndrome cases. The North American Pediatric Renal Transplant Cooperative Study identified 14 such patients who received renal transplants between January 1987 and November 1995.21 The primary diagnoses were known in 10 of the 14 patients, including obstructive uropathy in 4, hypoplastic/dysplastic renal disease in 2, focal segmental glomerulosclerosis in 2 and chronic glomerulonephritis in 2. Eight of these 14 patients underwent cadaveric transplants, while 6 received a living related transplant from a parent or sibling. Initial findings imply no difference in rejection rates between these patients and all pediatric transplant patients, although due to the sample size, it is a limited conclusion. Five grafts failed, including 2 due to rejection and 3 due to patient death (cardiopulmonary complications in 2 and viral infection in 1). The study concludes that renal transplantation is a reasonable option for patients with Down syndrome and end stage renal disease. Ureter: The autopsy study of Ariel et al also revealed ureteral abnormalities.10 Obstructive megaureters were seen in 2 patients and ureteral atresia was seen in 1. Vesicoureteral reflux has been reported in Down syndrome cases, although to our knowledge no study has been done to determine its incidence. Importantly reflux has been reported to have a poor prognosis in these cases. Ahmed detailed 4 cases of Down syndrome associated with reflux.22 Two of the 4 children required nephrectomy for advanced reflux nephropathy. The other 2 children underwent ureteral reimplantation but surgery was unsuccessful. It was postulated that the failure of open surgery might have been the result of abnormal bladder function. Lower urinary tract. Bladder: As Ahmed noted, these patients may have voiding dysfunction.22 Handel et al reviewed trisomy 21 cases referred to their tertiary care center in a 10-year period.23 Of the 26 patients identified, who were all incidentally male, 4 (15%) were found to have voiding dysfunction as well as severe constipation. These 4 patients underwent negative evaluation for Hirschsprung’s disease, posterior urethral valves and spinal cord defects. Despite no evidence of neurological defects they appeared to have nonneurogenic neurogenic bladder. Unfortunately, 3 of these 4 patients had some degree of renal insufficiency, raising concern that delay in diagnosis may lead to irreversible renal injury by the time of presentation. Urethra: Kupferman et al reported on 3 patients with Down syndrome and posterior urethral valves.24 This study was followed by that of Bielek et al, who reviewed experience at their institution.25 They found that between 1973 and
1251
1995, 48 cases of posterior urethral valves were diagnosed. Two of these patients (4.17%) had trisomy 21. These reports suggest an increased incidence of posterior urethral valves in Down syndrome cases. Hypospadias has a higher incidence in patients with Down syndrome than in the general population. The overall incidence of hypospadias has been reported as approximately 1/250.26 Lang et al evaluated the incidence of hypospadias in Down syndrome.27 Nine of 91 patients (9.89%) with the condition who were examined were found to have distal hypospadias. Genitalia. Testis: Cryptorchidism has been reported to occur in 14% to 27% of males with Down syndrome.28 It is likely linked to the high rate of hypogonadism in these patients.29 In addition, cryptorchidism and hypogonadism can explain the association of Down syndrome and testicular cancer.30 Two studies indicated the incidence of Down syndrome in patients with testicular cancer. Of patients with testicular cancer 0.5% were found to have Down syndrome in 1 study31 and 0.9% were found to have Down syndrome in another study.32 There also seems to be a preponderance of seminoma reported in the literature.33–35 Gonadal function and reproduction. As noted, there is a high incidence of hypogonadism in Down cases. Hasen et al evaluated 39 patients (27 males and 12 females) with trisomy 21.29 Follicle stimulating hormone (FSH) was elevated in 33% of patients and luteinizing hormone (LH) was elevated in 22%. Plasma testosterone was normal in all except 2 male patients and estradiol was normal in all female patients. Another study of 17 males with Down syndrome also found significantly higher FSH and LH levels in these patients.36 Adolescent development seemed relatively normal in 1 large study. Pueschel et al examined 46 male adolescents and young adults with Down syndrome.37 They found that the development of secondary sex characteristics appeared normal. They compared mean penile length, circumference and testicular volume of the patients with Down syndrome to those of normal adolescents. The Down population had decreased penile length, and slightly increased penile circumference and testicular volume, although these differences were not statistically different. In addition, FSH, LH and testosterone were similar to those of normal adolescents. Fetal oogenesis appears to be normal.38 In accordance with these findings females with Down syndrome are capable of reproduction. Of these patients 24 gave birth to 15 chromosomally normal and 10 trisomy 21 offspring.39 Two chromosomally normal offspring were mentally retarded and 3 were stillborn. On the other hand, spermatogenesis seems to be impaired. Testicular histology has revealed spermatogenic arrest and oligospermia.40 There are no reported cases of a male with Down syndrome fathering a child.40 UROLOGICAL SCREENING RECOMMENDATIONS
In reviews of health maintenance and screening in the Down syndrome population there are no standard recommendations for urological screening.5, 41 It is reasonable to circumcise boys with congenital heart defects to prevent bacteremia from urinary tract infection, provided that it is done in a setting where the cardiologist is comfortable with it and the hospital has a cardiac anesthesia staff that is experienced with caring for pediatric heart patients. Boys with Down syndrome should be monitored for cryptorchidism due to the elevated incidence in this population. We also believe that screening renal/bladder ultrasound is justified even in an asymptomatic patient. Autopsy studies have shown that renal anomalies such as hypoplasia, dysplasia or obstruction can be present in 3% to 21% of patients.9, 10 With this noninvasive study the kidneys can be evaluated for size, parenchyma and hydronephrosis. If performed after the patient
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UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME
voids, it is also useful to assess bladder emptying. Further studies would then be prompted by abnormalities on this baseline ultrasound. In the symptomatic patient with infection or retention other studies such as a voiding cystogram would be indicated. PERIOPERATIVE MANAGEMENT
If a patient with Down syndrome requires surgery, several perioperative issues must be addressed. Patients with known cardiac disease should undergo preoperative cardiology evaluation for surgery clearance and perioperative recommendations. However, it has been suggested that even patients without known cardiovascular disease should be considered for referral for echocardiographic evaluation.42 Geggel et al performed echocardiographic studies in 35 asymptomatic adolescents and young adults with Down syndrome.43 Of their patients 18 (51%) had abnormal studies. Mitral valve prolapse was found in 16 patients (46%), of whom 2 also had tricuspid valve prolapse, and aortic regurgitation was found in 2 (6%). They concluded that adolescents and young adults with the syndrome should undergo echocardiographic evaluation prior to surgical procedures. Another consideration is atlanto-axial instability, which is seen in almost 17% of patients.44 The preoperative evaluation of a patient should assess atlanto-axial instability with a thorough history and physical examination. Any history or physical finding of pain on flexion or extension, or a limited range of cervical motion warrants a flexion-extension radiology study. Patients found to have subluxation require careful intubation, while keeping the head in a neutral or limited extended position, often using a laryngeal mask airway or fiberoptic wand intubation.45 An intraoperative issue is the high incidence of infraglottic stenosis in this patient group.46 Miller et al found that age appropriate endotracheal tubes are too large for the patient with Down syndrome and they result in mucosal trauma.46 They recommended using an endotracheal tube 0.5 mm smaller than the age appropriate diameter. Another potential intubation issue is the large tongue invariably seen in Down cases.47 A curved MacIntosh blade has been recommended to hold the tongue out of the way for intubation.45 A postoperative consideration is post-intubation croup. The incidence of this complication has been lowered by the use of noncuffed endotracheal tubes in patients younger than 5 years as well as by using heated, humidified gases intraoperatively. However, despite these measures children with Down syndrome seem prone to this problem.48 CONCLUSIONS
Improved understanding and identification of the various urological anomalies associated with Down syndrome will aid in the care of these patients. In addition, an awareness of perioperative issues will further facilitate a smooth clinical course. REFERENCES
1. Down, J. L. H.: Observations on an ethnic classification of idiots. Clin Lect Rep, 3: 259, 1866 2. Mange, A. P. and Mange, E. J.: Nondisjunction of human autosomes: sporadic Down syndrome. In: Genetics: Human Aspects. Sunderland: Sinauer Associates, Inc., 1990 3. Lejeune, J.: Le Mongolism. Premier exemple d’aberration autosomique humaine. Ann Genet, 1: 41, 1959 4. Hassold, T. and Sherman, S.: Down syndrome: genetic recombination and the origin of the extra chromosome 21. Clin Genet, 57: 95, 2000 5. American Academy of Pediatrics Committee on Genetics: American Academy of Pediatrics: health supervision for children with Down syndrome. Pediatrics, 107: 442, 2001 6. Down syndrome prevalence at birth—United States, 1983–1990. MMWR Morb Mortal Wkly Rep, 43: 617, 1994
7. Baird, P. A. and Sadovnick, A. D.: Life tables for Down syndrome. Hum Genet, 82: 291, 1989 8. Kallen, B., Mastroiacovo, P. and Robert, E.: Major congenital malformations in Down syndrome. Am J Med Genet, 65: 160, 1996 9. Berg, J. M., Crome, L. and France, N. E.: Congenital cardiac malformations in mongolism. Br Heart J, 22: 331, 1960 10. Ariel, I., Wells, T. R., Landing, B. H. and Singer, D. B.: The urinary system in Down syndrome: a study of 124 autopsy cases. Pediatr Pathol, 11: 879, 1991 11. Mir, S., Rapola, J. and Koskimies, O.: Renal cysts in pediatric autopsy material. Nephron, 33: 189, 1983 12. Lo, A., Brown, H. G., Fivush, B. A., Neu, A. M. and Racusen, L. C.: Renal disease in Down syndrome: autopsy study with emphasis on glomerular lesions. Am J Kidney Dis, 31: 329, 1998 13. Gupta, S. K., Venkataseshan, V. S. and Churg, J.: Mesangiocapillary glomerulonephritis in Down’s syndrome. Am J Nephrol, 11: 112, 1991 14. Robson, W. L. and Leung, A. K.: Down’s syndrome and renal abnormalities. Pediatr Nephrol, 7: 775, 1993 15. Takemura, T., Yoshioka, K., Akano, N., Michihata, I., Okada, M., Maki, S. et al: Immunotactoid glomerulopathy in a child with Down syndrome. Pediatr Nephrol, 7: 86, 1993 16. Robson, W. L., Leung, A. K., Woodman, R. C. and Trevenen, C. L.: Anti-neutrophil cytoplasmic antibody associated glomerulonephritis in a patient with Down’s syndrome. Pediatr Nephrol, 9: 204, 1995 17. Coburn, S. P., Seidenberg, M. and Mertz, E. T.: Clearance of uric acid, urea, and creatinine in Down’s syndrome. J Appl Physiol, 23: 579, 1967 18. Subrahmanyam, A. B. and Mehta, A. V.: Renal anomalies in Down syndrome. Pediatr Nephrol, 9: 253, 1995 19. Ehrich, J. H.: What is known about renal replacement therapy in a child with Down’s syndrome? Pediatr Nephrol, 7: 248, 1993 20. Webb, N., Hebert, D. and Arbus, G.: Renal replacement therapy in Down’s syndrome. Pediatr Nephrol, 7: 771, 1993 21. Baqi, N., Tejani, A. and Sullivan, E. K.: Renal transplantation in Down syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant, 2: 211, 1998 22. Ahmed, S.: Vesico-ureteric reflux in Down’s syndrome: poor prognosis. Aust N Z J Surg, 60: 113, 1990 23. Handel, L. N., Barqawi, A., Checa, G., Furness, P. D., III and Koyle, M. A.: Males with Down’s syndrome and nonneurogenic neurogenic bladder. J Urol, 169: 646, 2003 24. Kupferman, J. C., Stewart, C. L., Kaskel, F. J. and Fine, R. N.: Posterior urethral valves in patients with Down syndrome. Pediatr Nephrol, 10: 143, 1996 25. Bielek, J., Carvajal-Busslinger, M. I. and Bianchetti, M. G.: Posterior urethral valves in trisomy 21. Pediatr Nephrol, 10: 678, 1996 26. Paulozzi, L. J., Erickson, J. D. and Jackson, R. J.: Hypospadias trends in two US surveillance systems. Pediatrics, 100: 831, 1997 27. Lang, D. J., Van Dyke, D. C., Heide, F. and Lowe, P. L.: Hypospadias and urethral abnormalities in Down syndrome. Clin Pediatr, 26: 40, 1987 28. Wilson, G. N. and Cooley, W. C.: Down syndrome. In: Preventive Management of Children With Congenital Anomalies and Syndromes. Cambridge: Cambridge University Press, 2000 29. Hasen, J., Boyar, R. M. and Shapiro, L. R.: Gonadal function in trisomy 21. Hormone Res, 12: 345, 1980 30. Dieckmann, K.-P., Ru¨ be, C. and Henke, R. P.: Association of Down’s syndrome and testicular cancer. J Urol, 157: 1701, 1997 31. Dexeus, F. H., Logothetis, C. J., Chong, C., Sella, A. and Ogden, S.: Genetic abnormalities in men with germ cell tumors. J Urol, 140: 80, 1988 32. Thornhill, J. A., Conroy, R. M., Kelly, D. G., Walsh, A., Fennelly, J. J. and Fitzpatrick, J. M.: An evaluation of predisposing factors for testis cancer in Ireland. Eur Urol, 14: 429, 1988 33. Kamidono, S., Takada, K., Ishigami, J., Furumoto, M. and Urano, Y.: Giant seminoma of undescended testis in Down syndrome. Urology, 25: 637, 1985 34. Ichiyanagi, O., Sasagawa, I., Kubota, Y., Yaguchi, H., Suzuki, Y. and Nakada, T.: Down’s syndrome associated with seminoma in an undescended testis. Scand J Urol Nephrol, 32: 365, 1998
UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME 35. Roberge, D., Souhami, L. and Laplante, M.: Testicular seminoma and Down’s syndrome. Can J Urol, 8: 1203, 2001 36. Campbell, W. A., Lowther, J., McKenzie, I. and Price, W. H.: Serum gonadotrophins in Down’s syndrome. J Med Genet, 19: 98, 1982 37. Pueschel, S. M., Orson, J. M., Boylan, J. M. and Pezzullo, J. C.: Adolescent development in males with Down syndrome. Am J Dis Child, 139: 236, 1985 38. Luciani, J. M., Devictor, M., Morazzani, M. R. and Stahl, A.: Meiosis of trisomy 21 in the human pachytene oocyte. Behaviour of the supernumerary chromosome, identification of chromomere sequence and numerous sub-bands. Chromosoma, 57: 155, 1976 39. Jagiello, G.: Reproduction in Down syndrome. In: Trisomy 21 (Down Syndrome): Research Perspectives. Edited by F. F. de la Cruz and P. S. Gerald. Baltimore: University Park Press, 1981 40. Johannisson, R., Gropp, A., Winking, H., Coerdt, W., Rehder, H. and Schwinger, E.: Down’s syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet, 63: 132, 1983 41. Smith, D. S.: Health care management of adults with Down syndrome. Am Fam Physician, 64: 1031, 2001
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42. White, J. and Christmann, L.: Screening for retinopathy of prematurity. Pediatrics, 108: 1385, 2001 43. Geggel, R. L., O’Brien, J. E. and Feingold, M.: Development of valve dysfunction in adolescents and young adults with Down syndrome and no known congenital heart disease. J Pediatr, 122: 821, 1993 44. Pueschel, S. M., Herndon, J. H., Gelch, M. M., Senft, K. E., Scola, F. H. and Goldberg, M. J.: Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop, 4: 682, 1984 45. Infosino, A.: Pediatric upper airway and congenital abnormalities. Anesthesiol Clin North Am, 20: 747, 2002 46. Miller, R., Gray, S. D., Cotton, R. T., Myer, C. M., 3rd and Netterville, J.: Subglottic stenosis and Down syndrome. Am J Otolaryngol, 11: 274, 1990 47. Kanamori, G., Witter, M., Brown, J. and Williams-Smith, L.: Otolaryngologic manifestations of Down syndrome. Otolaryngol Clin North Am, 33: 1285, 2000 48. Maxwell, L. G. and Yaster, M.: Perioperative management issues in pediatric patients. Anesthesiol Clin North Am, 18: 601, 2000
Vol. 171, 1250 –1253, March 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000112915.69436.91
Review Article UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME ERICA SCHALOW MERCER, BRUCE BROECKER,* EDWIN A. SMITH, ANDREW J. KIRSCH, HAL C. SCHERZ AND CHARLOTTE A. MASSAD From Pediatric Urology P. S. C. and the Department of Urology, Emory University School of Medicine, Atlanta, Georgia
ABSTRACT
Purpose: We identified the urological anomalies seen in patients with Down syndrome. Materials and Methods: We reviewed the literature on Down syndrome and its associated genitourinary pathology. Results: Associated defects have been reported throughout the genitourinary tract. The most common renal anomalies seen are renal hypoplasia, obstructive uropathy and glomerular microcysts. Decreased creatinine clearance has also been noted. Developmental anomalies, such as megaureter and vesicoureteral reflux, have been reported. Dysfunctional voiding and urinary retention have been found in these patients. Posterior urethral valves and hypospadias have also been seen. The testicular abnormalities most frequently reported are cryptorchidism, testicular cancer and infertility. Conclusions: Improved understanding and identification of the various urological anomalies associated with Down syndrome will aid in the care of these patients. In addition, an awareness of perioperative issues will further facilitate a smooth clinical course. KEY WORDS: kidney, ureter, testis, abnormalities, Down syndrome
In 1866 the British physician Dr. John Langdon H. Down first described Down syndrome.1 He grouped these patients due to their characteristic facies and invariable mental retardation, and proposed that this condition was caused by tuberculosis in the parents. He termed them Mongols based on the flat, broad face and slanted, narrow palpebral fissures. When it was realized that these patients were not true Mongols, the name mongolism was changed to Down syndrome.2 In 1959 Lejeune reported that the etiology is actually an extra copy of chromosome 21.3 In more than 95% of patients with Down syndrome the condition is due to nonfamilial trisomy 21 or nondisjunction,4 while in 3% to 4% the extra chromosome material is the result of an unbalanced translocation.5 The remaining 1% to 2% of patients have mosaicism, possessing normal and abnormal cell types with resultant wide phenotypic variability.2 The syndrome has been reported to occur in about 1/1,000 live births in the United States6 and life tables have demonstrated that more than 50% of these patients live more than 50 years.7 The syndrome has multiple well-known associated congenital abnormalities, particularly cardiac defects in 26% to 50% of cases, eye disease in 60%, hearing loss in 75%, obstructive sleep apnea in 50% to 75%, gastrointestinal atresia in 12% and thyroid disease in 15%.5, 8 With such a significant portion of the population affected by the disease it is important to identify the urological anomalies seen in patients with Down syndrome. MATERIALS AND METHODS
A bibliographic PubMed and MEDLINE search was performed for 1966 to the present. We reviewed all English literature on Down syndrome and its associated genitouri-
nary pathology. Applicable secondary references found through these articles were also reviewed. RESULTS
Associated defects are reported throughout the genitourinary tract. Upper urinary tract. Kidney: In 1960 Berg et al first noted the coincidence of renal anomalies and Down syndrome.9 They reported that 5 of 141 Down syndrome autopsy cases (3.5%) had renal malformations. Four of these patients had renal agenesis or hypoplasia and 1 had a horseshoe kidney. In a more current autopsy/necropsy study Ariel et al examined 124 cases of Down syndrome for urinary system abnormalities.10 Multiple renal anomalies were noted, particularly in patients 1 day and older. Renal hypoplasia, defined as less than two-thirds of expected renal weight in an otherwise normal-appearing kidney, was found in 18 of 84 evaluable cases (21.4%). Glomerular microcysts were found in 23 of 97 patients (23.7%) older than 1 day and younger than 25 years. Rare glomerular microcysts believed to be within the range of normal were found in an additional 17 cases. Only 1 patient with glomerular microcysts was noted to have urinary tract obstruction. Obstructive uropathy was seen in 8 of the 124 cases (6.45%). Two of these 8 cases were fetuses at 16 to 22 weeks of gestation (2 of 18 in this age group or 11.1%), 2 were fetuses or newborns (2 of 9 or 22.2%), and 4 were older than 1 day (4 of 97 or 4.1%). Cystic dysplasia was noted in 4 of the 124 cases (3.23%) as well as obstructive lesions of the urinary tract. Lastly, simple renal cysts were found in 7 of the 124 cases (5.6%), much higher than the reported pediatric incidence of 0.1%.11 To our knowledge the clinical significance of the glomerular microcysts and renal cysts is unknown. Another autopsy study was performed by Lo et al.12 In this study the focus was on glomerular alterations in patients
* Correspondence: Department of Urology, Emory University School of Medicine, 1901 Century Blvd., Suite 14, Atlanta, Georgia 30345 (telephone: 404-320-9179; FAX: 404-320-1912; e-mail: [email protected]). 1250
UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME
with Down syndrome compared to a control group. The only morphological finding more common in the Down syndrome group was glomerular microcysts. They additionally found several cases of acquired glomerular disease in Down cases, including membranous nephropathy, nephrotic syndrome and minimal change disease, glomerulonephritis and focal segmental glomerulosclerosis with hyalinosis. Multiple cases of glomerulonephritis have been reported in patients with Down syndrome. Gupta et al described 4 patients with mesangiocapillary glomerulonephritis.13 There have also been single case reports of chronic glomerulonephritis,14 immunotactoid glomerulopathy15 and antineutrophil cytoplasmic antibody associated glomerulonephritis.16 Little has been published on renal function and renal replacement therapy in Down syndrome. In these patients there is a decrease in the clearance of uric acid and creatinine.17 One report details 2 patients without preexisting renal disease who had acute renal failure and died following angiotensin-converting enzyme inhibitor therapy for heart failure.18 Renal replacement therapy in patients with Down syndrome is only briefly addressed in the literature but it is believed to be a viable option for any cooperative patient with Down syndrome and end stage renal disease.19, 20 Renal transplantation has been performed in Down syndrome cases. The North American Pediatric Renal Transplant Cooperative Study identified 14 such patients who received renal transplants between January 1987 and November 1995.21 The primary diagnoses were known in 10 of the 14 patients, including obstructive uropathy in 4, hypoplastic/dysplastic renal disease in 2, focal segmental glomerulosclerosis in 2 and chronic glomerulonephritis in 2. Eight of these 14 patients underwent cadaveric transplants, while 6 received a living related transplant from a parent or sibling. Initial findings imply no difference in rejection rates between these patients and all pediatric transplant patients, although due to the sample size, it is a limited conclusion. Five grafts failed, including 2 due to rejection and 3 due to patient death (cardiopulmonary complications in 2 and viral infection in 1). The study concludes that renal transplantation is a reasonable option for patients with Down syndrome and end stage renal disease. Ureter: The autopsy study of Ariel et al also revealed ureteral abnormalities.10 Obstructive megaureters were seen in 2 patients and ureteral atresia was seen in 1. Vesicoureteral reflux has been reported in Down syndrome cases, although to our knowledge no study has been done to determine its incidence. Importantly reflux has been reported to have a poor prognosis in these cases. Ahmed detailed 4 cases of Down syndrome associated with reflux.22 Two of the 4 children required nephrectomy for advanced reflux nephropathy. The other 2 children underwent ureteral reimplantation but surgery was unsuccessful. It was postulated that the failure of open surgery might have been the result of abnormal bladder function. Lower urinary tract. Bladder: As Ahmed noted, these patients may have voiding dysfunction.22 Handel et al reviewed trisomy 21 cases referred to their tertiary care center in a 10-year period.23 Of the 26 patients identified, who were all incidentally male, 4 (15%) were found to have voiding dysfunction as well as severe constipation. These 4 patients underwent negative evaluation for Hirschsprung’s disease, posterior urethral valves and spinal cord defects. Despite no evidence of neurological defects they appeared to have nonneurogenic neurogenic bladder. Unfortunately, 3 of these 4 patients had some degree of renal insufficiency, raising concern that delay in diagnosis may lead to irreversible renal injury by the time of presentation. Urethra: Kupferman et al reported on 3 patients with Down syndrome and posterior urethral valves.24 This study was followed by that of Bielek et al, who reviewed experience at their institution.25 They found that between 1973 and
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1995, 48 cases of posterior urethral valves were diagnosed. Two of these patients (4.17%) had trisomy 21. These reports suggest an increased incidence of posterior urethral valves in Down syndrome cases. Hypospadias has a higher incidence in patients with Down syndrome than in the general population. The overall incidence of hypospadias has been reported as approximately 1/250.26 Lang et al evaluated the incidence of hypospadias in Down syndrome.27 Nine of 91 patients (9.89%) with the condition who were examined were found to have distal hypospadias. Genitalia. Testis: Cryptorchidism has been reported to occur in 14% to 27% of males with Down syndrome.28 It is likely linked to the high rate of hypogonadism in these patients.29 In addition, cryptorchidism and hypogonadism can explain the association of Down syndrome and testicular cancer.30 Two studies indicated the incidence of Down syndrome in patients with testicular cancer. Of patients with testicular cancer 0.5% were found to have Down syndrome in 1 study31 and 0.9% were found to have Down syndrome in another study.32 There also seems to be a preponderance of seminoma reported in the literature.33–35 Gonadal function and reproduction. As noted, there is a high incidence of hypogonadism in Down cases. Hasen et al evaluated 39 patients (27 males and 12 females) with trisomy 21.29 Follicle stimulating hormone (FSH) was elevated in 33% of patients and luteinizing hormone (LH) was elevated in 22%. Plasma testosterone was normal in all except 2 male patients and estradiol was normal in all female patients. Another study of 17 males with Down syndrome also found significantly higher FSH and LH levels in these patients.36 Adolescent development seemed relatively normal in 1 large study. Pueschel et al examined 46 male adolescents and young adults with Down syndrome.37 They found that the development of secondary sex characteristics appeared normal. They compared mean penile length, circumference and testicular volume of the patients with Down syndrome to those of normal adolescents. The Down population had decreased penile length, and slightly increased penile circumference and testicular volume, although these differences were not statistically different. In addition, FSH, LH and testosterone were similar to those of normal adolescents. Fetal oogenesis appears to be normal.38 In accordance with these findings females with Down syndrome are capable of reproduction. Of these patients 24 gave birth to 15 chromosomally normal and 10 trisomy 21 offspring.39 Two chromosomally normal offspring were mentally retarded and 3 were stillborn. On the other hand, spermatogenesis seems to be impaired. Testicular histology has revealed spermatogenic arrest and oligospermia.40 There are no reported cases of a male with Down syndrome fathering a child.40 UROLOGICAL SCREENING RECOMMENDATIONS
In reviews of health maintenance and screening in the Down syndrome population there are no standard recommendations for urological screening.5, 41 It is reasonable to circumcise boys with congenital heart defects to prevent bacteremia from urinary tract infection, provided that it is done in a setting where the cardiologist is comfortable with it and the hospital has a cardiac anesthesia staff that is experienced with caring for pediatric heart patients. Boys with Down syndrome should be monitored for cryptorchidism due to the elevated incidence in this population. We also believe that screening renal/bladder ultrasound is justified even in an asymptomatic patient. Autopsy studies have shown that renal anomalies such as hypoplasia, dysplasia or obstruction can be present in 3% to 21% of patients.9, 10 With this noninvasive study the kidneys can be evaluated for size, parenchyma and hydronephrosis. If performed after the patient
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voids, it is also useful to assess bladder emptying. Further studies would then be prompted by abnormalities on this baseline ultrasound. In the symptomatic patient with infection or retention other studies such as a voiding cystogram would be indicated. PERIOPERATIVE MANAGEMENT
If a patient with Down syndrome requires surgery, several perioperative issues must be addressed. Patients with known cardiac disease should undergo preoperative cardiology evaluation for surgery clearance and perioperative recommendations. However, it has been suggested that even patients without known cardiovascular disease should be considered for referral for echocardiographic evaluation.42 Geggel et al performed echocardiographic studies in 35 asymptomatic adolescents and young adults with Down syndrome.43 Of their patients 18 (51%) had abnormal studies. Mitral valve prolapse was found in 16 patients (46%), of whom 2 also had tricuspid valve prolapse, and aortic regurgitation was found in 2 (6%). They concluded that adolescents and young adults with the syndrome should undergo echocardiographic evaluation prior to surgical procedures. Another consideration is atlanto-axial instability, which is seen in almost 17% of patients.44 The preoperative evaluation of a patient should assess atlanto-axial instability with a thorough history and physical examination. Any history or physical finding of pain on flexion or extension, or a limited range of cervical motion warrants a flexion-extension radiology study. Patients found to have subluxation require careful intubation, while keeping the head in a neutral or limited extended position, often using a laryngeal mask airway or fiberoptic wand intubation.45 An intraoperative issue is the high incidence of infraglottic stenosis in this patient group.46 Miller et al found that age appropriate endotracheal tubes are too large for the patient with Down syndrome and they result in mucosal trauma.46 They recommended using an endotracheal tube 0.5 mm smaller than the age appropriate diameter. Another potential intubation issue is the large tongue invariably seen in Down cases.47 A curved MacIntosh blade has been recommended to hold the tongue out of the way for intubation.45 A postoperative consideration is post-intubation croup. The incidence of this complication has been lowered by the use of noncuffed endotracheal tubes in patients younger than 5 years as well as by using heated, humidified gases intraoperatively. However, despite these measures children with Down syndrome seem prone to this problem.48 CONCLUSIONS
Improved understanding and identification of the various urological anomalies associated with Down syndrome will aid in the care of these patients. In addition, an awareness of perioperative issues will further facilitate a smooth clinical course. REFERENCES
1. Down, J. L. H.: Observations on an ethnic classification of idiots. Clin Lect Rep, 3: 259, 1866 2. Mange, A. P. and Mange, E. J.: Nondisjunction of human autosomes: sporadic Down syndrome. In: Genetics: Human Aspects. Sunderland: Sinauer Associates, Inc., 1990 3. Lejeune, J.: Le Mongolism. Premier exemple d’aberration autosomique humaine. Ann Genet, 1: 41, 1959 4. Hassold, T. and Sherman, S.: Down syndrome: genetic recombination and the origin of the extra chromosome 21. Clin Genet, 57: 95, 2000 5. American Academy of Pediatrics Committee on Genetics: American Academy of Pediatrics: health supervision for children with Down syndrome. Pediatrics, 107: 442, 2001 6. Down syndrome prevalence at birth—United States, 1983–1990. MMWR Morb Mortal Wkly Rep, 43: 617, 1994
7. Baird, P. A. and Sadovnick, A. D.: Life tables for Down syndrome. Hum Genet, 82: 291, 1989 8. Kallen, B., Mastroiacovo, P. and Robert, E.: Major congenital malformations in Down syndrome. Am J Med Genet, 65: 160, 1996 9. Berg, J. M., Crome, L. and France, N. E.: Congenital cardiac malformations in mongolism. Br Heart J, 22: 331, 1960 10. Ariel, I., Wells, T. R., Landing, B. H. and Singer, D. B.: The urinary system in Down syndrome: a study of 124 autopsy cases. Pediatr Pathol, 11: 879, 1991 11. Mir, S., Rapola, J. and Koskimies, O.: Renal cysts in pediatric autopsy material. Nephron, 33: 189, 1983 12. Lo, A., Brown, H. G., Fivush, B. A., Neu, A. M. and Racusen, L. C.: Renal disease in Down syndrome: autopsy study with emphasis on glomerular lesions. Am J Kidney Dis, 31: 329, 1998 13. Gupta, S. K., Venkataseshan, V. S. and Churg, J.: Mesangiocapillary glomerulonephritis in Down’s syndrome. Am J Nephrol, 11: 112, 1991 14. Robson, W. L. and Leung, A. K.: Down’s syndrome and renal abnormalities. Pediatr Nephrol, 7: 775, 1993 15. Takemura, T., Yoshioka, K., Akano, N., Michihata, I., Okada, M., Maki, S. et al: Immunotactoid glomerulopathy in a child with Down syndrome. Pediatr Nephrol, 7: 86, 1993 16. Robson, W. L., Leung, A. K., Woodman, R. C. and Trevenen, C. L.: Anti-neutrophil cytoplasmic antibody associated glomerulonephritis in a patient with Down’s syndrome. Pediatr Nephrol, 9: 204, 1995 17. Coburn, S. P., Seidenberg, M. and Mertz, E. T.: Clearance of uric acid, urea, and creatinine in Down’s syndrome. J Appl Physiol, 23: 579, 1967 18. Subrahmanyam, A. B. and Mehta, A. V.: Renal anomalies in Down syndrome. Pediatr Nephrol, 9: 253, 1995 19. Ehrich, J. H.: What is known about renal replacement therapy in a child with Down’s syndrome? Pediatr Nephrol, 7: 248, 1993 20. Webb, N., Hebert, D. and Arbus, G.: Renal replacement therapy in Down’s syndrome. Pediatr Nephrol, 7: 771, 1993 21. Baqi, N., Tejani, A. and Sullivan, E. K.: Renal transplantation in Down syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant, 2: 211, 1998 22. Ahmed, S.: Vesico-ureteric reflux in Down’s syndrome: poor prognosis. Aust N Z J Surg, 60: 113, 1990 23. Handel, L. N., Barqawi, A., Checa, G., Furness, P. D., III and Koyle, M. A.: Males with Down’s syndrome and nonneurogenic neurogenic bladder. J Urol, 169: 646, 2003 24. Kupferman, J. C., Stewart, C. L., Kaskel, F. J. and Fine, R. N.: Posterior urethral valves in patients with Down syndrome. Pediatr Nephrol, 10: 143, 1996 25. Bielek, J., Carvajal-Busslinger, M. I. and Bianchetti, M. G.: Posterior urethral valves in trisomy 21. Pediatr Nephrol, 10: 678, 1996 26. Paulozzi, L. J., Erickson, J. D. and Jackson, R. J.: Hypospadias trends in two US surveillance systems. Pediatrics, 100: 831, 1997 27. Lang, D. J., Van Dyke, D. C., Heide, F. and Lowe, P. L.: Hypospadias and urethral abnormalities in Down syndrome. Clin Pediatr, 26: 40, 1987 28. Wilson, G. N. and Cooley, W. C.: Down syndrome. In: Preventive Management of Children With Congenital Anomalies and Syndromes. Cambridge: Cambridge University Press, 2000 29. Hasen, J., Boyar, R. M. and Shapiro, L. R.: Gonadal function in trisomy 21. Hormone Res, 12: 345, 1980 30. Dieckmann, K.-P., Ru¨ be, C. and Henke, R. P.: Association of Down’s syndrome and testicular cancer. J Urol, 157: 1701, 1997 31. Dexeus, F. H., Logothetis, C. J., Chong, C., Sella, A. and Ogden, S.: Genetic abnormalities in men with germ cell tumors. J Urol, 140: 80, 1988 32. Thornhill, J. A., Conroy, R. M., Kelly, D. G., Walsh, A., Fennelly, J. J. and Fitzpatrick, J. M.: An evaluation of predisposing factors for testis cancer in Ireland. Eur Urol, 14: 429, 1988 33. Kamidono, S., Takada, K., Ishigami, J., Furumoto, M. and Urano, Y.: Giant seminoma of undescended testis in Down syndrome. Urology, 25: 637, 1985 34. Ichiyanagi, O., Sasagawa, I., Kubota, Y., Yaguchi, H., Suzuki, Y. and Nakada, T.: Down’s syndrome associated with seminoma in an undescended testis. Scand J Urol Nephrol, 32: 365, 1998
UROLOGICAL MANIFESTATIONS OF DOWN SYNDROME 35. Roberge, D., Souhami, L. and Laplante, M.: Testicular seminoma and Down’s syndrome. Can J Urol, 8: 1203, 2001 36. Campbell, W. A., Lowther, J., McKenzie, I. and Price, W. H.: Serum gonadotrophins in Down’s syndrome. J Med Genet, 19: 98, 1982 37. Pueschel, S. M., Orson, J. M., Boylan, J. M. and Pezzullo, J. C.: Adolescent development in males with Down syndrome. Am J Dis Child, 139: 236, 1985 38. Luciani, J. M., Devictor, M., Morazzani, M. R. and Stahl, A.: Meiosis of trisomy 21 in the human pachytene oocyte. Behaviour of the supernumerary chromosome, identification of chromomere sequence and numerous sub-bands. Chromosoma, 57: 155, 1976 39. Jagiello, G.: Reproduction in Down syndrome. In: Trisomy 21 (Down Syndrome): Research Perspectives. Edited by F. F. de la Cruz and P. S. Gerald. Baltimore: University Park Press, 1981 40. Johannisson, R., Gropp, A., Winking, H., Coerdt, W., Rehder, H. and Schwinger, E.: Down’s syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet, 63: 132, 1983 41. Smith, D. S.: Health care management of adults with Down syndrome. Am Fam Physician, 64: 1031, 2001
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42. White, J. and Christmann, L.: Screening for retinopathy of prematurity. Pediatrics, 108: 1385, 2001 43. Geggel, R. L., O’Brien, J. E. and Feingold, M.: Development of valve dysfunction in adolescents and young adults with Down syndrome and no known congenital heart disease. J Pediatr, 122: 821, 1993 44. Pueschel, S. M., Herndon, J. H., Gelch, M. M., Senft, K. E., Scola, F. H. and Goldberg, M. J.: Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop, 4: 682, 1984 45. Infosino, A.: Pediatric upper airway and congenital abnormalities. Anesthesiol Clin North Am, 20: 747, 2002 46. Miller, R., Gray, S. D., Cotton, R. T., Myer, C. M., 3rd and Netterville, J.: Subglottic stenosis and Down syndrome. Am J Otolaryngol, 11: 274, 1990 47. Kanamori, G., Witter, M., Brown, J. and Williams-Smith, L.: Otolaryngologic manifestations of Down syndrome. Otolaryngol Clin North Am, 33: 1285, 2000 48. Maxwell, L. G. and Yaster, M.: Perioperative management issues in pediatric patients. Anesthesiol Clin North Am, 18: 601, 2000