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Eugster Pediatrics 2007;120;e304-e307 DOI: 10.1542/peds.2006-2993
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/120/2/e304
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Four patients (1 boy. MD. Eugster.2% vs 2%– 4%).org/cgi/doi/10. None of the patients developed any impairment in renal function. The objective of this study was to determine the incidence. Of these. METHODS. 2007 Address correspondence to Zeina M. Riley Hospital for Children. Room 5960. EUGSTER Downloaded from www. Provided by Indonesia:AAP Sponsored on October 22. 1098-4275). ureteral reimplantation Abbreviations CAH— congenital adrenal hyperplasia UTI— urinary tract infection VCUG—voiding cystourethrogram VUR—vesicoureteral reﬂux Accepted for publication Jan 26. 2009 . and duplicated collecting system (1). vesicoureteral reﬂux. Indianapolis. IN 46202. This association represents a potentially signiﬁcant medical issue because some patients may require surgical intervention and antibiotic prophylaxis to prevent urinary tract infections and impairment in renal function. MD Section of Pediatric Endocrinology/Diabetology. Copyright © 2007 by the American Academy of Pediatrics hyperplasia between 1985 and 2005 were reviewed. Indianapolis. The incidence of upper-tract genitourinary anomalies in girls with congenital adrenal hyperplasia is much higher in our cohort than in the general population (21. and the other had a left malrotated kidney with hydronephrosis.1542/peds. The anomalies consisted of vesicoureteral reﬂux grades 1 to 3 (9). Nabhan. 0031-4005. RESULTS. e304 NABHAN. Department of Pediatric Endocrinology/ Diabetology. speciﬁc ab- normalities. genitourinary malformations. MD. and clinical signiﬁcance of upper-tract genitourinary malformations in girls with congenital adrenal hyperplasia.edu PEDIATRICS (ISSN Numbers: Print. E-mail: email@example.com doi:10. 14 were found to have upper-tract genitourinary abnormalities. Indiana The authors have indicated they have no ﬁnancial relationships relevant to this article to disclose. Of 107 patients with congenital adrenal hyperplasia. ABSTRACT OBJECTIVE. 3 girls) underwent surgery that consisted of ureteral reimplantation (2) and ureteral stent placement (2).org.2006-2993 Key Words congenital adrenal hyperplasia. Medical charts of children who received a diagnosis of congenital adrenal www. The reﬂux eventually resolved in 3 patients and worsened in 1. Two boys with congenital adrenal hyperplasia and known upper-tract genitourinary anomalies were also identiﬁed. Hydronephrosis improved in 1 patient. Indiana University School of Medicine.ARTICLE Upper-Tract Genitourinary Malformations in Girls With Congenital Adrenal Hyperplasia Zeina M. Online.pediatrics. Nabhan. CONCLUSION. 66 girls were identi- ﬁed. Department of Pediatrics. hydronephrosis (4). Erica A.1542/ peds. One had ureteropelvic junction obstruction. 702 Barnhill Dr. James Whitcomb Riley Hospital for Children.pediatrics.
Four patients (3 girls.2 Affected individuals have defects in cortisol biosynthesis.1. and clinical signiﬁcance of upper-tract genitourinary anomalies detected during baseline imaging in girls with CAH.org. The presence of a urogenital sinus is illustrated. A. bilateral moderate to severe nonobstructive hydronephrosis in 2. and 13 (81%) had salt wasting.9 Patients who had not had genitourinary imaging were excluded. history of urinary tract infections (UTIs). type of CAH. 39 boys were excluded because they had not had genitourinary imaging. unilateral vesicoureteral reﬂux (VUR) grades 1 to 3 in 2. B. gender. 66 girls) identiﬁed as potential candidates for the study.ONGENITAL ADRENAL HYPERPLASIA (CAH) is one of the most common inherited disorders.5 years (range: 0. RESULTS Of 107 patients (41 boys. Surgeries consisted of bilateral ureteral reimplantation FIGURE 1 VCUG in an 11-month-old girl with CAH. Provided by Indonesia:AAP Sponsored on October 22.16 –5. Downloaded from www. The degree of virilization in girls was assessed using the Prader scale based on the initial physical examination. August 2007 e305 .25 years). with 95% of cases being attributable to 21-hydroxylase deﬁciency. WA) for descriptive statistics and SPSS 11. The genitourinary anomalies were diagnosed at a median age of 0. However. 7 (10%) had simple virilizing 21-hydroxylase deﬁciency. Eligible patients were those in whom genitourinary imaging had been performed. Number 2. Earlier reports were limited by a lack of genitourinary imaging4 and inclusion of just a few patients5. The 2 boys received a diagnosis immediately after birth with ureteropelvic junction obstruction in 1 and a left malrotated kidney with hydronephrosis in the other. which leads to excessive production of adrenal androgens. and bilateral VUR grades 1 to 3 in 7. Figure 1. The boy had surgery for ureteropelvic junction obstruction and hydronephrosis. no systematic studies investigating upper-tract genitourinary anomalies in CAH have been performed. The Prader grading consists of a 5-point scale in which 1 represents minimal virilization and 5 represents fully masculinized external genitalia. whereas 2 boys had imaging because of suspected UTIs in the neonatal period.4 5.58 –18. Chicago. The average age of the patients was 8. and 1 for right duplex collecting system and hydronephrosis.pediatrics. only anecdotal information regarding the presence of upper-tract genitourinary malformations in these patients is available. One girl had surgery for recurrent UTIs. and years of follow-up. None of the genitourinary anomalies was detected prenatally. Redmond. renal function. Fifty-ﬁve (81%) had classic salt-wasting 21-hydroxylase deﬁciency. C METHODS After institutional review board approval. characteristics.7 To date. medical charts of patients who were followed for classic CAH in the pediatric endocrine clinic at Riley Hospital for Children between 1985 and 2005 were reviewed. 2 (3%) had 11-hydroxylase deﬁciency. 2 of these 9 girls had multiple genitourinary tract infections that required hospitalization and intravenous antibiotics despite the prophylaxis.2%) girls. Median was used for data that were widely scattered. girls with classic 21-hydroxylase deﬁciency present at birth with ambiguous genitalia and typically undergo genitourinary imaging as part of the initial diagnostic evaluation. Student’s t test was performed for comparison between groups. Variables that were extracted from the medical charts included age. Data are expressed as means SDs. however. type of genitourinary malformation. and 4 (6%) had late-onset CAH. On the basis of clinical observation. Also included were girls who had CAH and came from other states to our institution to undergo feminizing genitoplasty. The objective of this study was to determine the incidence. we hypothesized that the frequency of genitourinary anomalies in girls with CAH is higher than that seen in the general population. All 66 girls had a voiding cystourethrogram (VCUG) and pelvic ultrasound as part of the initial diagnostic evaluation for ambiguous genitalia.5 (SPSS Inc. degree of virilization. Nine (65%) girls received antibiotic prophylaxis. In contrast. history of genitourinary surgery. 2009 PEDIATRICS Volume 120. Speciﬁc abnormalities consisted of a duplicated collecting system with obstructive hydronephrosis in 1.3 As a result. All girls with a documented initial genital examination (n 63) had signiﬁcant virilization with Prader 3 to 5 genitalia except for 3 who were Prader 1. Genitourinary anomalies were present in 14 (21.6 or a single case.9 years) during a routine workup for ambiguous genitalia. boys have no overt signs of the disease. history of antibiotic prophylaxis. and a urogenital sinus.3 Lower tract genitourinary malformations that occur as a result of virilization of the female external genitalia in CAH include clitoromegaly. Statistical Analysis Statistics were performed using Microsoft Excel 2000 (Microsoft Corp. posterior labial fusion. shows the results of a VCUG in an 11-month-girl with bilateral VUR. Right VUR grade 2 to 3 with calyceal dilation and left VUR grade 2 are shown. unilateral moderate hydronephrosis in 2.8. 1 for worsening grade 3 reﬂux. history of incontinence.71 years (range: 0. IL) for other analyses. 1 boy) required surgical correction of the genitourinary anomalies. All but 1 had 21-hydroxylase deﬁciency.
7 these studies along with our data effectively establish an increased incidence of uppertract anomalies in children with CAH compared with the general population. In addition to an isolated case report. Three had resolution of grade 2 to 3 reﬂux. such as frequent infections. n (%) Prader grade 3–4 Prader grade 4–5 Type of genitourinary malformation. the incidence of upper-tract genitourinary anomalies was 21. In 1 girl. simple virilizing. or hypertension thus far. An integral relationship between gonadal and renal development has indeed been suggested by the identiﬁcation of gene defects that cause abnormalities in both organs.2%.9 5. and in 7.14 Thus. n (%) Ureteral reimplantation Ureteral stent placement Age at time of genitourinary surgery. 2009 . UPJ. One explanation is that this may result from abnormally high androgen levels in utero.15 Genetic variations in androgen sensitivity and biosynthesis have also been proposed to inﬂuence expression of signs of androgen excess in girls with CAH16 and therefore could explain why some patients with CAH develop genitourinary anomalies and others do not. a pelvic ultrasound and genitogram are included in the standard evaluation of ambiguous genitalia. VCUGs. and all children who underwent surgery for genitourinary anomalies were followed at our center. 2 of the girls on prophylaxis had recurrent UTIs.27) or degree of virilization based on Prader rating (P . were impossible to determine because 9 girls with anomalies were prescribed prophylactic antibiotics by their pediatric urologist.org. ureteropelvic junction.pediatrics. Some form of surgical intervention was required in 21% of the girls with anomalies and in 1 of the boys. n (%) Girls VUR grades 1–3 Hydronephrosis Duplicated collecting system Boys Right UPJ obstruction with hydronephrosis Left malrotated kidney with hydronephrosis History of antibiotic prophylaxis. n (%) Girls Boys Type of genitourinary surgery. Speciﬁc anomalies and numbers of affected patients in all reports published thus far are summarized in Table 2.75 6. Eight of the 9 patients who were on antibiotic prophylaxis were from our institution. 9 were followed at our institution and 5 were referred from other medical centers.4 In contrast. y Value 14 (20.2 years (range: 0. Of the 14 girls with genitourinary anomalies. Characteristics of patients with CAH and genitourinary malformations are summarized in Table 1. 2 small series reported genitourinary malformations in 40%5 and 80%6 of patients. n (%) Girls Boys Type of CAH. Referred patients were similar in terms of the type of CAH and the nature of the genitourinary anomalies. mean SD (range).10–13 Because they resulted in additional radiographic tests and subspecialty clinic visits. 11-OH. which are a well-established complication of VUR that can result in irreversible kidney damage. in stark contrast to the estimated 2% to 4% of the general population who have similar abnormalities. Patients were followed by a pediatric urologist for an average of 5. This is in contrast to the risk of UTIs in girls who have CAH and do not have upper-tract genitourinary anomalies. Supporting this hypothesis is the observation that implantation of testosterone propionate in female rabbit fetuses results in abnormalities of the mesonephros. after which she underwent bilateral ureteral reimplantation. None of the patients have developed incontinence.(2 patients) and right ureteral double J stent placement (2 patients). or MAG-3 scans. genitourinary abnormalities remained stable. renal insufﬁciency. One ﬂaw of our study is that similar imaging e306 NABHAN. Additional medical sequelae of these malformations. 11-hydroxylase.0 years) with serial renal ultrasounds. respectively. n (%) SW 21-OH SV 21-OH SW 11-OH Degree of virilization in girls. these congenital genitourinary anomalies signiﬁcantly added to the disease burden that is incurred with classic CAH. Despite antibiotics. a higher morbidity seems to be a consequence of the upper-tract genitourinary anomalies in these patients. Provided by Indonesia:AAP Sponsored on October 22. reﬂux worsened over a period of 2 years from grade 1 to grade 3.17. SV. The exact cause of this phenomenon is unknown.18 In girls with CAH. Very limited information about upper-tract genitourinary anomalies in CAH has previously been published.5–7 A casual survey of all forms of congenital anomalies in CAH failed to identify any patients with accompanying renal or genitourinary anomalies. 1 had improvement in hydronephrosis. Another possibility is that biochemical abnormalities within the adrenal gland as a result of enzyme deﬁciencies might affect the budding of the ureteric bud from the wolfﬁan duct. DISCUSSION In our girls with CAH.5) 2 (3) 13 (81) 2 (13) 1 (6) 13 (93) 1 (7) 9 (57) 4 (25) 1 (6) 1 (6) 1 (6) 9 (56) 0 2 (13) 2 (13) 5. TABLE 1 Characteristics of Children with CAH and Upper-Tract Genitourinary Malformations Characteristic Gender.5 (0–15) SW indicates salt wasting. which has been found to be no higher than in the general population.18) was found between patients who had genitourinary anomalies and those who did not. EUGSTER Downloaded from www.6 –14. No statistical difference in type of CAH (P .
12:246 –255 Chand DH. An Esp Pediatr. 17. Number 2.9:231–248 Danon M. frequency.16:1839 –1851 Downloaded from www. Urinary tract infections in children with congenital adrenal hyperplasia. Dodge WF. Pediatric Endocrinology. Pathophysiology of ureteropelvic junction obstruction: experimental and clinical observation.89:953–954 Tovar JA.TABLE 2 Review of Reports in the Medical Literature of Children with CAH and Genitourinary Malformations Authors (Year) LaFranchi et al7 (1974) Total No. race and diagnosis. Speiser PW. Incidence and severity of vesicoureteral reﬂux in children related to age. 1972. 1993. Speiser PW. Freidman SC. August 2007 e307 . The Wilms tumor suppressor WT1 regulates early gonad development by activation of SF1. In: Lifshitz F.org. Development. 7. Ambiguous genitalia. or mild incontinence. 11. The prevalence of pyelonephritis in children at autopsy. Cirulli C.10:1527–1535 Rothenpieler UW. as well as additional in vitro and in vivo investigation that focuses on the relationship between genitourinary tract development and hyperandrogenism. Genital ﬁndings in the female pseudo-hermaphroditism of the congenital adrenogenital syndrome: morphology. 2006. Dressler GR. Poe SA. NY: Marcel Dekker. Congenital adrenal hyperplasia. Mol Endocrinol. 12.pediatrics. F. Dupont B. 2 F Tovar et al6 (1982) 10 3 M. Reduced androgen receptor gene expression with ﬁrst exon CAG repeat expansion. 2009 PEDIATRICS Volume 120. Although the underlying pathophysiology of this novel observation has yet to be elucidated. Prospective studies in both genders. 2003. female. Kraus S. Alzueta M. Congenital adrenal hyperplasia. New York.170(pt 2):1548 –1550 Nabhan ZM. gender. J Pediatr. Travis LB.5–7 An additional ﬂaw of our data is that we have no information on rates of subtle urinary symptoms that may not have been documented in the medical chart. hypospadias. Vesicoureteral reﬂux: continuing surgical dilemma. Kemppainen JA. Endocr Rev. such as frequency. 1996. Lippe BM. 16. 14 F M indicates male. White PC.349:776 –788 4. Daeschner CJ. The incidence of associated anomalies in 105 patients with congenital adrenal hyperplasia. Congenital renal anomalies associated with congenital adrenal hyperplasia.30:737–745 Koff SA. Urology. was not available for boys. 1962. ed. of Patients 1 No. development and heredity of the different genital forms[in German]. micropenis. Clayton GW. Wilson EM. 1953. Urology aspects of adrenogenital syndrome [in Spanish]. CONCLUSIONS The incidence of upper-tract genitourinary anomalies in girls with CAH is 10-fold higher than in the general population and results in potentially serious clinical sequelae. 18. Birdsell DC.199:711–720 Wilhelm D. will shed additional light on these ﬁndings. Whether boys with CAH also have an increased incidence of genitourinary abnormalities is unknown.8:379 Choong CS. Upper 6. Hopps HC. Helv Pediatr Acta. these ﬁndings provide valuable information for genetic counseling and for clinicians who are involved in the care of children with CAH. 8. Rhoades T. 1987.19:815– 820 Jost A. and cryptorchidism. J Pediatr Endocrinol Metab.49:608 – 610 5. 10. 1996:281–304 Spark H. Williams JA. 2003. 14.136:336 –338 Ransley PG. 1974. 9. 1986. N Engl J Med. Pediatrics. Rink RC. 13. Zhou ZX. Provided by Indonesia:AAP Sponsored on October 22. 2000.16:295–301 LaFranchi SH.316:1519 –1524 2. urinary tract anomalies in children with adrenogenital syndrome. 1976. 1978. 4 F Nabhan and Eugster (this article) 68 2 M. Recent Prog Horm Res. 15. it is interesting that there have been previous reports of genitourinary anomalies in boys with CAH. Pediatrics. N Engl J Med. New MI. J Urol. urgency. Areses R. Congenital adrenal hyperplasia due to 21-hydroxylase deﬁciency.21:245–291 3. Paisan L. J Urol. J Pediatr. Shore R. these congenital abnormalities could also have been coincidental. White PC. However. Pax-2 is required for mesenchyme to epithelium conversion during kidney development. 1954. Strife CF. Echeverria J. Eugster EA. Kirkland RT.84:157 Prader A. Genes Dev. Librik L. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Kaplan SA. Englert C. 2002. White PC. 1982. of Patients With Genitourinary Anomalies 1M Type of Genitourinary Malformation (n) Biﬁd right pelvocaliceal system with left multicystic dysplastic kidney (1) Partial duplication of left ureter (1) Duplication right collecting system (1) UPJ obstruction (1) Agenesis of the right kidney (1) Ureteral Duplication (1) Lower urinary obstruction (3) VUR bilateral (4) Hydronephrosis (4) VUR bilateral or unilateral (9) UPJ obstruction (1) Duplicated right collecting system with hydronephrosis (1) Left malrotated kidney with Hydronephrosis (1) McMillan et al5 (1976) 10 2 M. Kirkland JL. REFERENCES 1. Hayden LJ. McArthur RG. Although the 2 boys in our study could have been affected as a result of CAH. McMillan DD.
shtml Information about ordering reprints can be found online: http://www. appears in the following collection(s): Genitourinary Tract http://www.pediatrics.1542/peds.org/misc/Permissions. Eugster Pediatrics 2007.pediatrics.pediatrics. Provided by Indonesia:AAP Sponsored on October 22.e304-e307 DOI: 10.org/cgi/collection/genitourinary_tract Information about reproducing this article in parts (figures. Nabhan and Erica A.Upper-Tract Genitourinary Malformations in Girls With Congenital Adrenal Hyperplasia Zeina M.org/cgi/content/full/120/2/e304 This article cites 16 articles.org/misc/reprints.pediatrics.org. 6 of which you can access for free at: http://www. tables) or in its entirety can be found online at: http://www. along with others on similar topics.2006-2993 Updated Information & Services References including high-resolution figures. 2009 .pediatrics.pediatrics. can be found at: http://www.org/cgi/content/full/120/2/e304#BIBL This article.120.shtml Subspecialty Collections Permissions & Licensing Reprints Downloaded from www.
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