PEDIATRICS Vol. 120 No. 2 August 2007, pp. e304-e307 (doi:10.1542/peds.2006-2993)
ARTICLE |
Upper-Tract Genitourinary Malformations in Girls With Congenital Adrenal Hyperplasia
Section of Pediatric Endocrinology/Diabetology, Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
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ABSTRACT |
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OBJECTIVE. The objective of this study was to determine the incidence, specific abnormalities, and clinical significance of upper-tract genitourinary malformations in girls with congenital adrenal hyperplasia.
METHODS. Medical charts of children who received a diagnosis of congenital adrenal hyperplasia between 1985 and 2005 were reviewed.
RESULTS. Of 107 patients with congenital adrenal hyperplasia, 66 girls were identified. Of these, 14 were found to have upper-tract genitourinary abnormalities. The anomalies consisted of vesicoureteral reflux grades 1 to 3 (9), hydronephrosis (4), and duplicated collecting system (1). Two boys with congenital adrenal hyperplasia and known upper-tract genitourinary anomalies were also identified. One had ureteropelvic junction obstruction, and the other had a left malrotated kidney with hydronephrosis. Four patients (1 boy, 3 girls) underwent surgery that consisted of ureteral reimplantation (2) and ureteral stent placement (2). The reflux eventually resolved in 3 patients and worsened in 1. Hydronephrosis improved in 1 patient. None of the patients developed any impairment in renal function.
CONCLUSION. The incidence of upper-tract genitourinary anomalies in girls with congenital adrenal hyperplasia is much higher in our cohort than in the general population (21.2% vs 2%–4%). 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.
Key Words: congenital adrenal hyperplasia • genitourinary malformations • vesicoureteral reflux • ureteral reimplantation
Abbreviations: CAH—congenital adrenal hyperplasia • UTI—urinary tract infection • VCUG—voiding cystourethrogram • VUR—vesicoureteral reflux
Congenital adrenal hyperplasia (CAH) is one of the most common inherited disorders, with >95% of cases being attributable to 21-hydroxylase deficiency.1,2 Affected individuals have defects in cortisol biosynthesis, which leads to excessive production of adrenal androgens.3 As a result, girls with classic 21-hydroxylase deficiency present at birth with ambiguous genitalia and typically undergo genitourinary imaging as part of the initial diagnostic evaluation. In contrast, boys have no overt signs of the disease.3
Lower tract genitourinary malformations that occur as a result of virilization of the female external genitalia in CAH include clitoromegaly, posterior labial fusion, and a urogenital sinus. However, only anecdotal information regarding the presence of upper-tract genitourinary malformations in these patients is available. Earlier reports were limited by a lack of genitourinary imaging4 and inclusion of just a few patients5,6 or a single case.7 To date, no systematic studies investigating upper-tract genitourinary anomalies in CAH have been performed. The objective of this study was to determine the incidence, characteristics, and clinical significance of upper-tract genitourinary anomalies detected during baseline imaging in girls with CAH. On the basis of clinical observation, we hypothesized that the frequency of genitourinary anomalies in girls with CAH is higher than that seen in the general population.
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METHODS |
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After institutional review board approval, 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. Also included were girls who had CAH and came from other states to our institution to undergo feminizing genitoplasty. Eligible patients were those in whom genitourinary imaging had been performed. Variables that were extracted from the medical charts included age, gender, type of CAH, degree of virilization, type of genitourinary malformation, history of urinary tract infections (UTIs), history of incontinence, history of antibiotic prophylaxis, history of genitourinary surgery, renal function, and years of follow-up. The degree of virilization in girls was assessed using the Prader scale based on the initial physical examination. The Prader grading consists of a 5-point scale in which 1 represents minimal virilization and 5 represents fully masculinized external genitalia.8,9 Patients who had not had genitourinary imaging were excluded.
Statistical Analysis
Statistics were performed using Microsoft Excel 2000 (Microsoft Corp, Redmond, WA) for descriptive statistics and SPSS 11.5 (SPSS Inc, Chicago, IL) for other analyses. Data are expressed as means ± SDs. Median was used for data that were widely scattered. Student's t test was performed for comparison between groups.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of 107 patients (41 boys, 66 girls) identified as potential candidates for the study, 39 boys were excluded because they had not had genitourinary imaging. All 66 girls had a voiding cystourethrogram (VCUG) and pelvic ultrasound as part of the initial diagnostic evaluation for ambiguous genitalia, whereas 2 boys had imaging because of suspected UTIs in the neonatal period. None of the genitourinary anomalies was detected prenatally. The average age of the patients was 8.4 ± 5.5 years (range: 0.58–18.25 years). Fifty-five (81%) had classic salt-wasting 21-hydroxylase deficiency, 7 (10%) had simple virilizing 21-hydroxylase deficiency, 2 (3%) had 11-hydroxylase deficiency, and 4 (6%) had late-onset CAH. 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 (21.2%) girls. All but 1 had 21-hydroxylase deficiency, and 13 (81%) had salt wasting. The genitourinary anomalies were diagnosed at a median age of 0.71 years (range: 0.16–5.9 years) during a routine workup for ambiguous genitalia. Specific abnormalities consisted of a duplicated collecting system with obstructive hydronephrosis in 1, unilateral moderate hydronephrosis in 2, bilateral moderate to severe nonobstructive hydronephrosis in 2, unilateral vesicoureteral reflux (VUR) grades 1 to 3 in 2, and bilateral VUR grades 1 to 3 in 7. Figure 1. shows the results of a VCUG in an 11-month-girl with bilateral VUR. 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. Nine (65%) girls received antibiotic prophylaxis; however, 2 of these 9 girls had multiple genitourinary tract infections that required hospitalization and intravenous antibiotics despite the prophylaxis. Four patients (3 girls, 1 boy) required surgical correction of the genitourinary anomalies. One girl had surgery for recurrent UTIs, 1 for worsening grade 3 reflux, and 1 for right duplex collecting system and hydronephrosis. The boy had surgery for ureteropelvic junction obstruction and hydronephrosis. Surgeries consisted of bilateral ureteral reimplantation (2 patients) and right ureteral double J stent placement (2 patients). Of the 14 girls with genitourinary anomalies, 9 were followed at our institution and 5 were referred from other medical centers. Referred patients were similar in terms of the type of CAH and the nature of the genitourinary anomalies. Eight of the 9 patients who were on antibiotic prophylaxis were from our institution, and all children who underwent surgery for genitourinary anomalies were followed at our center.
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Patients were followed by a pediatric urologist for an average of 5.9 ± 5.2 years (range: 0.6–14.0 years) with serial renal ultrasounds, VCUGs, or MAG-3 scans. Three had resolution of grade 2 to 3 reflux; 1 had improvement in hydronephrosis; and in 7, genitourinary abnormalities remained stable. In 1 girl, reflux worsened over a period of 2 years from grade 1 to grade 3, after which she underwent bilateral ureteral reimplantation. None of the patients have developed incontinence, renal insufficiency, or hypertension thus far. No statistical difference in type of CAH (P = .27) or degree of virilization based on Prader rating (P = .18) was found between patients who had genitourinary anomalies and those who did not. Characteristics of patients with CAH and genitourinary malformations are summarized in Table 1.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In our girls with CAH, the incidence of upper-tract genitourinary anomalies was 21.2%, in stark contrast to the estimated 2% to 4% of the general population who have similar abnormalities.10–13 Because they resulted in additional radiographic tests and subspecialty clinic visits, these congenital genitourinary anomalies significantly added to the disease burden that is incurred with classic CAH. Some form of surgical intervention was required in 21% of the girls with anomalies and in 1 of the boys. Additional medical sequelae of these malformations, such as frequent infections, were impossible to determine because 9 girls with anomalies were prescribed prophylactic antibiotics by their pediatric urologist. Despite antibiotics, 2 of the girls on prophylaxis had recurrent UTIs, which are a well-established complication of VUR that can result in irreversible kidney damage. This is in contrast to the risk of UTIs in girls who have CAH and do not have upper-tract genitourinary anomalies, which has been found to be no higher than in the general population.14 Thus, a higher morbidity seems to be a consequence of the upper-tract genitourinary anomalies in these patients.
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.4 In contrast, 2 small series reported genitourinary malformations in 40%5 and 80%6 of patients, respectively. In addition to an isolated case report,7 these studies along with our data effectively establish an increased incidence of upper-tract anomalies in children with CAH compared with the general population. Specific anomalies and numbers of affected patients in all reports published thus far are summarized in Table 2. The exact cause of this phenomenon is unknown. One explanation is that this may result from abnormally high androgen levels in utero. Supporting this hypothesis is the observation that implantation of testosterone propionate in female rabbit fetuses results in abnormalities of the mesonephros.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. 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. An integral relationship between gonadal and renal development has indeed been suggested by the identification of gene defects that cause abnormalities in both organs.17,18
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In girls with CAH, a pelvic ultrasound and genitogram are included in the standard evaluation of ambiguous genitalia. One flaw of our study is that similar imaging was not available for boys. Whether boys with CAH also have an increased incidence of genitourinary abnormalities is unknown. Although the 2 boys in our study could have been affected as a result of CAH, these congenital abnormalities could also have been coincidental. However, it is interesting that there have been previous reports of genitourinary anomalies in boys with CAH.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, such as frequency, urgency, or mild incontinence. Prospective studies in both genders, as well as additional in vitro and in vivo investigation that focuses on the relationship between genitourinary tract development and hyperandrogenism, will shed additional light on these findings.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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. Although the underlying pathophysiology of this novel observation has yet to be elucidated, these findings provide valuable information for genetic counseling and for clinicians who are involved in the care of children with CAH.
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FOOTNOTES |
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Accepted Jan 26, 2007.
Address correspondence to Zeina M. Nabhan, MD, Department of Pediatric Endocrinology/Diabetology, Riley Hospital for Children, Room 5960, 702 Barnhill Dr, Indianapolis, IN 46202. E-mail: znabhan{at}iupui.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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