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Health-related quality of life and psychosocial adjustment in steroid-sensitive nephrotic syndrome
HEALTH-RELATED QUALITY OF LIFE AND PSYCHOSOCIAL ADJUSTMENT IN STEROID-SENSITIVE NEPHROTIC SYNDROME EVA-MARIA RU¨TH, MD, MARKUS A. LANDOLT, PHD, THOMAS J. NEUHAUS, MD, AND MARKUS J. KEMPER, MD
Objectives To evaluate quality of life (QOL) and psychosocial adjustment by standardized tests in well-characterized patients with steroid-sensitive nephrotic syndrome. Study design Forty-five patients were investigated at a median age of 9.8 years (range, 3.4 to 19.8) and 5.9 years (range, 0.1 to 16.3) since diagnosis. Child- and parent-rated QOL was evaluated by the The Netherlands Organization for Applied Scientific Research Academical Medical Center (TNO-AZL) Child Quality of life Questionnaire. Psychosocial adjustment was assessed by the Child Behavior Checklist and the Teacher Report Form. Results In patients, only the QOL subscale ‘‘social functioning’’ was impaired compared with that in control subjects, whereas parents rated 4 of a total of 7 subscales as abnormal. Psychosocial adjustment was impaired at home and at school. Steroid dependency and cytotoxic treatment had a significant negative impact on QOL only, whereas family climate, especially maternal distress, negatively affected both QOL and psychosocial adjustment. Conclusions QOL and psychosocial adjustment are impaired in steroid-sensitive nephrotic syndrome. Both illness-related variables and family climate play an important role. (J Pediatr 2004;145:778-83) ecent data indicate that steroid-sensitive nephrotic syndrome (SSNS) can no longer be regarded as benign1 because up to 50% of patients have frequent relapses requiring long-term immunosuppression, often into adulthood. Therefore, not only the medical but also the psychosocial burden is high for patients, parents, and other care givers.2,3 Most studies in children with chronic disease focus on medical outcome,4 although somatic evaluation should always be supplemented by data on psychosocial and social consequences.5,6 Standardized questionnaires to assess health-related quality of life (QOL) and psychosocial adjustment have been established independent of a specific disease.7,8 Early efforts to describe QOL in children were focused on functional problems, reported by the attending physicians, and only gradually integrated the patient’s and parent’s self-ratings.9 Despite the clinical problems and the adverse effects of medication on the psychological well-being in children with SSNS, QOL or psychosocial adjustment have See related article, p 784. so far not been addressed in detail. The impact of (short-term) steroid treatment on behavior was studied, and one study addressed family structure in SSNS, reporting a significant impact on clinical course in 16 patients.10-12 The aim of our study was therefore a comprehensive evaluation of QOL as well as psychosocial adjustment in children with SSNS, compared with that in healthy control children, by use of standardized questionnaires From the Department of Pediatric for patients, parents, and teachers. Furthermore, we hypothesized that a complicated clinical Nephrology and Department of Psycourse (frequent relapses and need of cytotoxic medication) as well as poor family climate chiatry and Psychosomatics, University Children’s Hospital Zurich, Zurich, were associated with an impairment of QOL and psychosocial adjustment.
R
METHODS Patients Children with SSNS were recruited from the Pediatric Nephrology Clinic at the University Children’s Hospital Zurich, a primary and tertiary care center for SSNS in the greater Zurich area. SSNS was defined according to the International Study of Kidney Diseases in Children (ISKDC).13,14 For methodologic reasons, the required age range was CBCL FRI QOL SSNS
778
Child Behavior Checklist Family Relationship Index Quality of life Steroid-sensitive nephrotic syndrome
TACQOL TNO-AZL Child Quality of Life Questionnaire TNO-AZL The Netherlands Organization for Applied Scientific Research Academical Medical Center
Switzerland; Department of Pediatric Nephrology, University Hospital, Hamburg, Germany. Submitted for publication Apr 5, 2004; last revision received Jun 13, 2004; accepted Aug 4, 2004. Reprint requests: Eva-Maria Rueth, MD, Department of Nephrology, University Children’s Hospital, Steinwiesstr 75, CH-8032 Zurich, Switzerland. E-mail: Eva-Maria.Rueth@ gmx.de. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.08.022
3 to 19 years, and sufficient knowledge of the German language was a prerequisite. Forty-four families (75%) with 45 affected children (31 male subjects, including two brothers in one family) agreed to participate. This study was approved by the local ethics committee. Written informed consent was obtained from the parents. Median age at time of assessment was 9.8 (range, 3.8 to 19.8) years, with a median age at diagnosis of 3.6 (range, 1.2 to 8.4) years. Six of the 45 patients had no relapses, 5 were infrequent, and 9 frequent relapsers; 25 patients had a history of steroid dependency. The median number of relapses was 7 (range, 0 to 30), and 24, 10, and 6 patients were given cyclophosphamide,15 cyclosporine A, and levamisole,16 respectively. Only 2 patients received high-dose prednisone during the study. Relapse was defined as proteinuria (Albustix >21) for >3 consecutive days. Frequent relapses were defined according to the ISKDC criteria (more than 2 relapses in the initial 6 months after presentation or >4 per year during follow-up).17 Steroid dependency was defined according to APN (at least 2 relapses during alternate-day treatment with prednisone or within 2 weeks of cessation).18 The majority of families (30 of 44; 68%) were from the middle class, whereas 8 (18%) and 6 (13%) were from the upper and lower classes, respectively. Socioeconomic status was calculated by means of a 6-point score of both paternal occupation and maternal education.19 Traditional family structure was defined when the child was living with both biological parents. At the time of evaluation, 37 (82%) patients lived in traditional and 8 (18%) in nontraditional families. Thirty, 4, and 9 patients attended primary school, secondary school, and preschool, respectively. Two adolescents were in vocational training.
TNO-AZL Child Quality of Life Questionnaire The Netherlands Organization for Applied Scientific Research Academical Medical Center (TNO-AZL) Child Quality of Life Questionnaire (TACQOL) offers a Child and a Parent Form, designed to assess the health-related QOL in children with chronic diseases.7,20 Both forms contain 5 health status scales: physical complaints (body), basic motor functioning (motor), autonomy (auto), cognitive (cognition), and social functioning (social). Two additional scales assess general mood: positive emotional functioning (EMOPOS) and negative emotional functioning (EMONEG). Maximum domain scores are 32 for the first 5 domains and 16 for the emotional scales. Higher scores represent better QOL. Studies with normal and clinical samples confirmed the internal and external validity for the questionnaires.7,20 Normal values were provided by healthy Dutch children and parents.7
anxiety/depression, thought problems) and externalizing behavior scales (social problems, attention problems, delinquent and aggressive behavior). From these problem scales, a Total Behavioral Problems Score (T-Score) is calculated and compared with age- and sex-matched normative data. Reference values are provided by 2856 healthy German children and adolescents 4 to 18 years of age.21,22
Teacher Report Form The Teacher Report Form provides information of a child’s behavior in school,23 containing the same items as the CBCL and yielding scores for problems in internalizing and externalizing behavior.
Brief Symptom Inventory The Brief Symptom Inventory is a 53-item, self-report questionnaire providing normative-based information of adults with distress, anxiety, and depression. In this study, only the Global Severity Index assessing parents’ mental stress was used.24
Family Relationship Index The Family Relationship Index (FRI) is a 27-item questionnaire consisting of 3 subscales of the Family Environment Scale25 assessing expressiveness, cohesion, and conflict within a family. FRI is calculated as the sum of these 3 subscales, with higher scores indicating better family relations.
Procedure German translations of all questionnaires followed published guidelines, including independent back-translation.26 All 38 patients older than 6 years were interviewed (by one of the authors), using the TACQOL-Child Form. Forty of 44 parents (89%) returned the TACQOL-Parent Form and the CBCL. Thirty-two of 34 (94%) teachers sent back the questionnaires of their students.
Statistical Analyses All analyses were performed with 2-sided tests. The null hypothesis tested against was that children with SSNS had an impaired QOL and psychosocial adjustment in comparison to healthy children. A value of P < .05 was considered significant. For comparison between groups, the Student t test or MannWhitney U test, depending on distribution of data, was performed. To evaluate determinants of QOL and psychosocial adjustment, Spearman correlation coefficients and univariate linear regression analyses were computed, using the SPSS statistical software package (Version 11.5, SPSS Inc, Chicago, Ill).
RESULTS
Child Behavior Checklist The Child Behavior Checklist (CBCL) is a standardized measure with excellent psychometric properties providing parental reports of a child’s behavior.8 It consists of 120 items assessing internalizing (withdrawn, somatic complaints,
Quality of Life at Home and at School The patient’s self-report of QOL was normal for all dimensions except social functioning, indicating a significant impairment of social interactions (Table I). In contrast, the
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Table I. Sample means and normative data for quality-of-life measures Normative data*
Sample Measure TACQOL– Child Form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) TACQOL– Parent Form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative)
Table II. Sample means and normative data for psychosocial adjustment
n Mean SD
Mean
SD
Normative data*
Sample P valuey
38 38 38 35 38 38
26.5 29.2 31.6 28.5 28.7 12.9
5.7 4.8 1.1 4.2 2.6 2.0
25.3 30.0 31.3 28.5 29.8 13.6
5.0 3.2 1.9 3.9 2.7 2.5
.20 .34 .12 .34 .01 .10
38
11.4
2.8
11.7
2.7
.77
40 40 40 30 39 40
26.7 29.4 30.7 26.1 28.1 13.4
4.3 4.2 2.8 5.5 3.0 1.9
27.6 31.0 31.4 29.2 30.0 15.0
3.7 2.3 1.6 3.7 2.3 1.8
.20 .02 .13 .01 ,.0001 ,.0001
40
11.1
2.7
11.7
2.3
.16
*Normative data from manual scales.7 yt Tests with normative data.
Measure Child behavior at home CBCL–Total Scorez CBCL– Internalizing Scorez CBCL– Externalizing Scorez Child behavior at school TRF–Total Scorez TRF– Internalizing Scorez TRF– Externalizing Scorez
n Mean SD
Mean
SD
P valuey
40
56.1
10.5
50.0
10.0
,.01
40
57.3
10.7
50.0
10.0
,.0001
40
54.2
9.8
50.0
10.0
.01
32
57.1
11.2
50.0
10.0
,.01
32
57.7
9.7
50.0
10.0
,.0001
32
53.2
9. 7
50.0
10.0
.07
*Normative data from manual scales.8,38 yt Tests with normative data. zT Score.
parents reported a significant impairment of motor, cognitive, social, and global positive emotional functioning (Table I).
autonomy. On the other hand, a high FRI, indicating good family relations, was correlated with autonomy and cognitive functioning.
Psychosocial Adjustment at Home and at School
Determinants of Psychosocial Adjustment
Psychosocial adjustment compared with healthy control children was rated abnormal by both parents (CBCL) and teachers (Teacher Report Form), and a significant decrease of behavioral adjustment in all dimensions was stated except for the externalizing behavior at school (Table II).
Psychosocial adjustment of the patients, as described by the parents, was significantly correlated with family climate but not with illness-related variables (Table III). There was no correlation between variables of both QOL and psychosocial adjustment and sociodemographic data, for example, age, sex, and socioeconomic background.
Determinants of QOL In the self-report (Table III), there was a negative correlation between a complicated course of SSNS (steroid dependency and cytotoxic treatment) and social functioning. Self-reported physical complaints and negative emotions were also correlated to maternal psychological distress. The parental report revealed a significant correlation between QOL and illness-related variables as well as family climate (Table III): Physical and emotional well-being were inversely correlated to steroid dependency and cyclophosphamide therapy in the medical history. Concerning the influence of family climate, maternal distress (Global Severity Index) particularly showed a negative correlation with most of the TACQOL subscales, whereas paternal distress was associated only with physical complaints, motor functioning, and 780
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DISCUSSION We report a comprehensive cross-sectional analysis on quality of life and psychosocial adjustment and their determinants in SSNS by using multiple informants. QOL was impaired, and notably parents evaluated their children’s QOL more pessimistically than did the patients. Psychosocial adjustment was disturbed not only at home but also in school. Although self-reported physical well-being appeared not to be affected, impairment of social functioning, that is, interaction with family members and peers, indicates that QOL in patients with SSNS is not normal. Few data are available on self-reported QOL in children with chronic illnesses, as mostly parents are interviewed to report on their The Journal of Pediatrics December 2004
Table III. Spearman correlation coefficients between variables of QOL and psychosocial adjustment and illness-related variables and family climate (TACQOL Child Form, n = 38, TAQCOL Parent Form, n = 40; CBCL n = 40) Illness-related variables
Family climate
No. of Relapses
Steroid dependency
Cyclophosphamide therapy
FRI
GSI mother
GSI Father
0.07 0.07 0.10 20.07 20.11 0.19 0.16
20.01 0.01 0.00 20.22 20.35* 20.03 20.16
20.08 20.26 20.14 20.29 20.44y 20.13 20.20
0.16 0.13 0.29 0.09 0.33 0.12 0.16
20.37* 20.33 20.31 20.003 20.08 0.001 20.39*
20.02 20.13 20.19 0.12 0.21 0.18 20.29
20.14 0.06 20.05 20.22 20.06 20.27 0.08
20.17 20.002 20.003 20.16 20.19 20.35* 20.10
20.36* 0.04 20.08 20.44* 20.33* 20.31 20.33*
0.25 0.12 0.38* 0.46* 0.33 0.26 0.27
20.65z 20.27 20.39* 20.35 20.48y 20.49y 20.46y
20.38* 20.46z 20.50y 20.28 20.29 20.20 20.29
20.13 20.01 20.16
20.02 0.08 20.03
0.13 0.20 0.06
20.48y 20.41* 20.40*
0.66z 0.72z 0.61z
0.54y 0.52y 0.54y
TAQCOL Child form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) TAQCOL Parent form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) CBCL Total Internalizing Externalizing *P < .05; yP < .01; zP < .001.
child’s QOL and psychosocial adjustment.22,27 The information obtained by the patients may yield a more realistic reflection. Notably, a previous study emphasized that parent reports cannot substitute for child reports because the TACQOL-Child form represents the patient’s own perception of QOL.28 Interestingly, parents rated their children’s QOL much less optimistically, and both children and parents regarded physical complaints as less important than social interactions. The divergent rating of children and parents is noteworthy. One possible reason is that children rated their QOL too optimistically, because of confounding factors (eg, face-to-face interview, mechanisms of avoidance). On the other hand, the parents may rate their children’s QOL too pessimistically. This might be due to an impairment in the parent’s (especially mother’s) own QOL, reflecting shared variance between mother’s psychological strain and the rating of her child’s QOL, as noted in other disorders.29 These results appear to be in contrast to those of previous studies in children with chronic conditions.21,22 A possible reason for this apparent discrepancy may be that many patients with SSNS and their parents live in constant fear of imminent relapse, and the daily urinary dipstick testing in the morning is
a permanent burden. Therefore, QOL in relapsing diseases (in general and in those responding to steroids) may be different from those in acute or chronic disorders. Pediatric patient groups with juvenile idiopathic arthritis and chronic inflammatory bowel disease rated their QOL as impaired as well.30,31 Impaired psychosocial adjustment in SSNS compared with control subjects at home but also at school may again be related to the chronic relapsing course of SSNS. The abnormal adjustment at home is in contrast to other pediatric patient groups,21,22 including children with other renal disorders.32 Corticosteroid treatment could be one independent variable of children’s behavior and adjustment. These short-term consequences have been demonstrated not only in SSNS10,11 but also in pediatric patients with asthma and hematologic malignancies.33,34 However, since the vast majority of our patients was studied in remission, disturbed psychosocial adjustment at home and in school is not only related to highdose corticosteroid therapy but suggests an impact of the disease itself. The comprehensive investigation identified several determinants of QOL and psychosocial adjustment relevant
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for the care of patients with SSNS. Severity of medical course of SSNS had a significant impact only on QOL but not on psychosocial adjustment. With respect to family climate, the psychological distress of the mother was a negative determinant of QOL and psychosocial adjustment. Mothers were the main care givers, exposed to the adverse effects of disorder and treatment, resulting in a mutual interference between the child’s QOL and psychosocial adjustment and the mother’s psychological distress, as reported previously.29 Conversely, higher family cohesion is protective, a finding that deserves further study and may have practical relevance. For instance, higher family cohesion has been reported to result in fewer hospitalizations in renal patients.35 Family characteristics mentioned above were identified to be crucial for positive adjustment in healthy populations as well as in other clinical conditions.21,36 The relevance of family climate appears to increase, however, when medical care can be considered as state-of-the-art, corresponding to current treatment guidelines. Somatic and medical variables, as tested by TACQOL and other instruments of health-related QOL, appear to be relevant whenever treatment is suboptimal.22 This study represents a rather small and heterogeneous study group with a wide age range. SSNS is, however, a rare disease, and the majority of our patients was included to minimize a selection bias. However, because the study was conducted at a primary and tertiary care center, patients with a more severe course of SSNS may be overrepresented. In addition, few patients with stable remission were reluctant to participate, possibly because of avoidance strategies. This observation has been described in previous clinical trials, causing difficulties in applying the attained information on all patients with a specific disease.37 Appropriateness of Dutch and German norms for our sample of Swiss children can be questioned, too. However, because the Netherlands, Germany, and Switzerland are central European countries with similar social structures, a major cross-cultural bias seems unlikely. By the use of standardized, established methodology, using multiple informants, our results are valid and may stimulate further research in this field. Future studies should be prospective, with repeated, longitudinal assessment, ideally in multicenter patient populations, to conquer the limitations addressed.
REFERENCES 1. Fakhouri F, Bocquet N, Taupin P, Presne C, Gagnadoux MF, Landais P, et al. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am J Kidney Dis 2003;41:550-7. 2. Neuhaus TJ, Fay J, Dillon MJ, Trompeter RS, Barratt TM. Alternative treatment to corticosteroids in steroid sensitive idiopathic nephrotic syndrome. Arch Dis Child 1994;71:522-6. 3. Lewis MA, Baildom EM, Davis N, Houston IB, Postlethwaite RJ. Nephrotic syndrome: from toddlers to twenties. Lancet 1989;1:255-9. 4. Ebrahim S. Clinical and public health perspectives and applications of health-related quality of life. Soc Sci Med 1995;41:1383-94. 5. Eiser C. Making sense of chronic disease: the eleventh Jack Tizard Memorial Lecture. J Child Psychol Psychiatry 1994;35:1373-89. 6. Theunissen NC, Kamp GA, Koopman HM, Zwinderman KA, Vogels T, Wit JM. Quality of life and self-esteem in children treated for idiopathic short stature. J Pediatr 2002;140:507-15.
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7. Vogels T, Verrips GHW, Koopman HM, Theunissen HCM, Fekkes M, Kamphuis RP. TACQOL manual, Parent Form and Child Form. Leiden: Center for Child Health and Pediatrics LUMC-TNO; 2000. 8. Achenbach T. Manual for Child Behavior Checklist/4-18. Burlington: University of Vermont; 1991. 9. Ditesheim J, Templeton JJ. Short-term versus long-term quality of life in children following repair of high imperforate anus. J Pediatr Surg 1987;22: 581-7. 10. Hall AS, Thorley G, Houtman PN. The effects of corticosteroids on behavior in children with nephrotic syndrome. Pediatr Nephrol 2003;18: 1220-3. 11. Soliday E, Grey S, Lande MB. Behavioral effects of corticosteroids in steroid-sensitive nephrotic syndrome. Pediatrics 1999;104:e51. 12. Soliday E, Lande MB. Family structure and the course of steroidsensitive nephrotic syndrome. Pediatr Nephrol 2002;17:41-4. 13. The primary nephrotic syndrome in children: identification of patients with minimal change nephrotic syndrome from initial response to prednisone: a report of the International Study of Kidney Disease in Children. J Pediatr 1981;98:561-4. 14. Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children: Arbeitsgemeinschaft fur Padiatrische Nephrologie. Lancet 1988;1:380-3. 15. Kemper MJ, Altrogge H, Ludwig K, Timmermann K, Muller-Wiefel DE. Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome. Pediatr Nephrol 2000;14:772-5. 16. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood: British Association for Paediatric Nephrology. Lancet 1991;337: 1555-7. 17. Early identification of frequent relapsers among children with minimal change nephrotic syndrome: a report of the International Study of Kidney Disease in Children. J Pediatr 1982;101:514-8. 18. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of eight week with 12 week course: report of Arbeitsgemeinschaft fur Paediatrische Nephrologie. Arch Dis Child 1987;62:1102-6. 19. Largo RH, Molinari L, Comenale Pinto L, Weber M, Duc G. Language development of term and preterm children during the first five years of life. Dev Med Child Neurol 1986;28:333-50. 20. Verrips EGH, Vogels AGC, Koopman HM, Theunissen NCM, Kamphuis RP, Fekkes M, et al. Measuring health-related quality of life in a child population. Eur J Pub Health 1999;9:114-9. 21. Landolt MA, Nuoffer JM, Steinmann B, Superti-Furga A. Quality of life and psychologic adjustment in children and adolescents with early treated phenylketonuria can be normal. J Pediatr 2002;140:516-21. 22. Landolt MA, Grubenmann S, Meuli M. Family impact greatest: predictors of quality of life and psychological adjustment in pediatric burn survivors. J Trauma 2002;53:1146-51. 23. Achenbach TM. Manual for Teacher Report Form and 1991 Profile. Burlington: University of Vermont, Department of Psychiatry; 1991. 24. Derogatis LR, Lazarus L. SCL-90-R, Brief Symptom Inventory, and matching clinical rating scales. In: Maruish ME, ed. The use of psychological testing for treatment planning and outcome assessment. Hillsdale, NJ: Lawrence Erlbaum Associates; 1994. p. 217-24. 25. Moos RH, Moos BS. Family Environment Scale Manual: Development, Applications, Research. Palo Alto, Calif; 1994. 26. Brislin R, Lonner W, Thorndike R. Cross-cultural research methods. New York: John Wiley & Sons; 1973. 27. Stancin T, Drotar D, Taylor HG, Yeates KO, Wade SL, Minich NM. Health-related quality of life of children and adolescents after traumatic brain injury. Pediatrics 2002;109:E34. 28. Theunissen NCM, Vogels TGC, Koopman HM, Verrips GHW, Zwindermann KAH. The proxy problem: child report versus parent report in health-related quality of life research. Qual Life Res 1998;7:387-97. 29. Manificat S, Dazord A, Cochat P, Morin D, Plainguet F, Debray D. Quality of life of children and adolescents after kidney or liver transplantation: child, parents and caregiver’s point of view. Pediatr Transplant 2003;7:228-35. 30. Loonen HJ, Grootenhuis MA, Last BF, Koopman HM, Derkx HH. Quality of life in paediatric inflammatory bowel disease measured by a generic and a disease-specific questionnaire. Acta Paediatr 2002;91:348-54.
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31. Selvaag AM, Flato B, Lien G, Sorskaar D, Vinje O, Forre O. Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire. J Rheumatol 2003;30: 1602-10. 32. Soliday E, Kool E, Lande MB. Psychosocial adjustment in children with kidney disease. J Pediatr Psychol 2000;25:93-103. 33. Bender BG, Lerner JA, Poland JE. Association between corticosteroids and psychologic change in hospitalized asthmatic children. Ann Allergy 1991; 66:414-9. 34. Harris JC, Carel CA, Rosenberg LA, Joshi P, Leventhal BG. Intermittent high dose corticosteroid treatment in childhood cancer: behavioral and emotional consequences. J Am Acad Child Psychiatry 1986; 25:120-4.
35. Soliday E, Kool E, Lande MB. Family environment, child behavior, and medical indicators in children with kidney disease. Child Psychiatry Hum Dev 2001;31:279-95. 36. Tiet QQ, Bird HR, Davies M, Hoven C, Cohen P, Jensen PS, et al. Adverse life events and resilience. J Am Acad Child Adolesc Psychiatry 1998; 37:1191-200. 37. Caldwell PH, Butow PN, Craig JC. Parents’ attitudes to children’s participation in randomized controlled trials. J Pediatr 2003;142:554-9. 38. Do¨pfner M, Berner W, Lehmkuhl G. Handbuch: Lehrerfragebogen u¨ber das Verhalten von Kindern und Jugendlichen. Forschungser-gebnisse zur deutschen fassung der teacher’s report form (TRF) der child behavior Checklist 4-18. Ko¨ln: Arbeitsgruppe Kinder; Jugend- und Familien diagnostik (KJFD);1994.
50 Years Ago in The Journal of Pediatrics NONADRENAL FEMALE PSEUDOHERMAPHRODITISM: REPORT OF TWO PATIENTS SIMULATING MIXED ADRENAL DISEASE
Papadatos C, Klein R. J Pediatr 1954;45:662-7. The report by Papadatos et al appeared over 50 years ago, and the medical and ethical issues raised by the article are still relevant and important today. The article describes two female infants born with significant clitoromegaly, electrolyte abnormalities consistent with adrenal hyperplasia, and renal disease, whom, on evaluation, did not have adrenal disease. The authors then cite and describe the only two previous reports of ‘‘nonadrenal female pseudohermaphroditism.’’ One of the reports is particularly significant in that the author was Dr Lawson Wilkins. Dr Wilkins established the specialty of pediatric endocrinology in the United States. His clinical descriptions of the endocrine diseases of childhood remain unsurpassed, and his speculations as to origin of disease, remarkably prescient. In this specific article, the authors, attempting to explain the genital and renal findings of their patients, quote Dr Wilkins: ‘‘the concept that the genital anomalies were . due to genetic abnormalities cannot be dismissed.’’ Today we know that the electrolyte abnormalities seen in neonatal renal disease are caused by transient resistance to aldosterone. However, our current theory that the genital abnormalities seen in congenital renal disease are the result of a mutation causing a field defect in the embryonic development of the genitourinary tract is, essentially, a restatement of Dr Wilkins’s observation. The authors classify their patients as having ‘‘female pseudohermaphroditism.’’ This follows the 19th century emphasis on classifying diseases according to similarities in their physical manifestations. By the mid-20th century, it was becoming apparent that similar or identical physical signs could be produced by radically different pathophysiologic mechanisms and a classification system based on similarities in disease origin began to be used. The title of the article reflects the tension between these two systems as it establishes a case of ‘‘nonadrenal’’ (a rudimentary attempt at defining an etiologic basis for the observed physical findings) ‘‘female pseudohermaphroditism’’ (based on physical findings). As our understanding of the molecular basis of disease advance, classification systems based on physical findings are losing their justification and usefulness. Nonetheless, many current disease classification systems, including that used to classify ambiguous genitalia, still use this approach. The ethical issues implicitly contained in the article but not addressed are relevant today. Both patients had significant clitoromegaly. What recommendations were made regarding surgery on the patients’ genitals? The issue of genital reconstruction has been the source of a spirited, often angry, debate over the last 10 years and remains unresolved. Last, one cannot help but comment on the literary style of the article. Our predecessors were writers as well as scientists, and they produced case reports, which, even today, convey the excitement and thrill of scientific discovery. Jorge J. Daaboul, MD Richard Banks, MD The Nemours Children’s Clinic 83 West Columbia St Orlando, FL 32806 YMPD1176 10.1016/j.jpeds.2004.08.057
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Objectives To evaluate quality of life (QOL) and psychosocial adjustment by standardized tests in well-characterized patients with steroid-sensitive nephrotic syndrome. Study design Forty-five patients were investigated at a median age of 9.8 years (range, 3.4 to 19.8) and 5.9 years (range, 0.1 to 16.3) since diagnosis. Child- and parent-rated QOL was evaluated by the The Netherlands Organization for Applied Scientific Research Academical Medical Center (TNO-AZL) Child Quality of life Questionnaire. Psychosocial adjustment was assessed by the Child Behavior Checklist and the Teacher Report Form. Results In patients, only the QOL subscale ‘‘social functioning’’ was impaired compared with that in control subjects, whereas parents rated 4 of a total of 7 subscales as abnormal. Psychosocial adjustment was impaired at home and at school. Steroid dependency and cytotoxic treatment had a significant negative impact on QOL only, whereas family climate, especially maternal distress, negatively affected both QOL and psychosocial adjustment. Conclusions QOL and psychosocial adjustment are impaired in steroid-sensitive nephrotic syndrome. Both illness-related variables and family climate play an important role. (J Pediatr 2004;145:778-83) ecent data indicate that steroid-sensitive nephrotic syndrome (SSNS) can no longer be regarded as benign1 because up to 50% of patients have frequent relapses requiring long-term immunosuppression, often into adulthood. Therefore, not only the medical but also the psychosocial burden is high for patients, parents, and other care givers.2,3 Most studies in children with chronic disease focus on medical outcome,4 although somatic evaluation should always be supplemented by data on psychosocial and social consequences.5,6 Standardized questionnaires to assess health-related quality of life (QOL) and psychosocial adjustment have been established independent of a specific disease.7,8 Early efforts to describe QOL in children were focused on functional problems, reported by the attending physicians, and only gradually integrated the patient’s and parent’s self-ratings.9 Despite the clinical problems and the adverse effects of medication on the psychological well-being in children with SSNS, QOL or psychosocial adjustment have See related article, p 784. so far not been addressed in detail. The impact of (short-term) steroid treatment on behavior was studied, and one study addressed family structure in SSNS, reporting a significant impact on clinical course in 16 patients.10-12 The aim of our study was therefore a comprehensive evaluation of QOL as well as psychosocial adjustment in children with SSNS, compared with that in healthy control children, by use of standardized questionnaires From the Department of Pediatric for patients, parents, and teachers. Furthermore, we hypothesized that a complicated clinical Nephrology and Department of Psycourse (frequent relapses and need of cytotoxic medication) as well as poor family climate chiatry and Psychosomatics, University Children’s Hospital Zurich, Zurich, were associated with an impairment of QOL and psychosocial adjustment.
R
METHODS Patients Children with SSNS were recruited from the Pediatric Nephrology Clinic at the University Children’s Hospital Zurich, a primary and tertiary care center for SSNS in the greater Zurich area. SSNS was defined according to the International Study of Kidney Diseases in Children (ISKDC).13,14 For methodologic reasons, the required age range was CBCL FRI QOL SSNS
778
Child Behavior Checklist Family Relationship Index Quality of life Steroid-sensitive nephrotic syndrome
TACQOL TNO-AZL Child Quality of Life Questionnaire TNO-AZL The Netherlands Organization for Applied Scientific Research Academical Medical Center
Switzerland; Department of Pediatric Nephrology, University Hospital, Hamburg, Germany. Submitted for publication Apr 5, 2004; last revision received Jun 13, 2004; accepted Aug 4, 2004. Reprint requests: Eva-Maria Rueth, MD, Department of Nephrology, University Children’s Hospital, Steinwiesstr 75, CH-8032 Zurich, Switzerland. E-mail: Eva-Maria.Rueth@ gmx.de. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.08.022
3 to 19 years, and sufficient knowledge of the German language was a prerequisite. Forty-four families (75%) with 45 affected children (31 male subjects, including two brothers in one family) agreed to participate. This study was approved by the local ethics committee. Written informed consent was obtained from the parents. Median age at time of assessment was 9.8 (range, 3.8 to 19.8) years, with a median age at diagnosis of 3.6 (range, 1.2 to 8.4) years. Six of the 45 patients had no relapses, 5 were infrequent, and 9 frequent relapsers; 25 patients had a history of steroid dependency. The median number of relapses was 7 (range, 0 to 30), and 24, 10, and 6 patients were given cyclophosphamide,15 cyclosporine A, and levamisole,16 respectively. Only 2 patients received high-dose prednisone during the study. Relapse was defined as proteinuria (Albustix >21) for >3 consecutive days. Frequent relapses were defined according to the ISKDC criteria (more than 2 relapses in the initial 6 months after presentation or >4 per year during follow-up).17 Steroid dependency was defined according to APN (at least 2 relapses during alternate-day treatment with prednisone or within 2 weeks of cessation).18 The majority of families (30 of 44; 68%) were from the middle class, whereas 8 (18%) and 6 (13%) were from the upper and lower classes, respectively. Socioeconomic status was calculated by means of a 6-point score of both paternal occupation and maternal education.19 Traditional family structure was defined when the child was living with both biological parents. At the time of evaluation, 37 (82%) patients lived in traditional and 8 (18%) in nontraditional families. Thirty, 4, and 9 patients attended primary school, secondary school, and preschool, respectively. Two adolescents were in vocational training.
TNO-AZL Child Quality of Life Questionnaire The Netherlands Organization for Applied Scientific Research Academical Medical Center (TNO-AZL) Child Quality of Life Questionnaire (TACQOL) offers a Child and a Parent Form, designed to assess the health-related QOL in children with chronic diseases.7,20 Both forms contain 5 health status scales: physical complaints (body), basic motor functioning (motor), autonomy (auto), cognitive (cognition), and social functioning (social). Two additional scales assess general mood: positive emotional functioning (EMOPOS) and negative emotional functioning (EMONEG). Maximum domain scores are 32 for the first 5 domains and 16 for the emotional scales. Higher scores represent better QOL. Studies with normal and clinical samples confirmed the internal and external validity for the questionnaires.7,20 Normal values were provided by healthy Dutch children and parents.7
anxiety/depression, thought problems) and externalizing behavior scales (social problems, attention problems, delinquent and aggressive behavior). From these problem scales, a Total Behavioral Problems Score (T-Score) is calculated and compared with age- and sex-matched normative data. Reference values are provided by 2856 healthy German children and adolescents 4 to 18 years of age.21,22
Teacher Report Form The Teacher Report Form provides information of a child’s behavior in school,23 containing the same items as the CBCL and yielding scores for problems in internalizing and externalizing behavior.
Brief Symptom Inventory The Brief Symptom Inventory is a 53-item, self-report questionnaire providing normative-based information of adults with distress, anxiety, and depression. In this study, only the Global Severity Index assessing parents’ mental stress was used.24
Family Relationship Index The Family Relationship Index (FRI) is a 27-item questionnaire consisting of 3 subscales of the Family Environment Scale25 assessing expressiveness, cohesion, and conflict within a family. FRI is calculated as the sum of these 3 subscales, with higher scores indicating better family relations.
Procedure German translations of all questionnaires followed published guidelines, including independent back-translation.26 All 38 patients older than 6 years were interviewed (by one of the authors), using the TACQOL-Child Form. Forty of 44 parents (89%) returned the TACQOL-Parent Form and the CBCL. Thirty-two of 34 (94%) teachers sent back the questionnaires of their students.
Statistical Analyses All analyses were performed with 2-sided tests. The null hypothesis tested against was that children with SSNS had an impaired QOL and psychosocial adjustment in comparison to healthy children. A value of P < .05 was considered significant. For comparison between groups, the Student t test or MannWhitney U test, depending on distribution of data, was performed. To evaluate determinants of QOL and psychosocial adjustment, Spearman correlation coefficients and univariate linear regression analyses were computed, using the SPSS statistical software package (Version 11.5, SPSS Inc, Chicago, Ill).
RESULTS
Child Behavior Checklist The Child Behavior Checklist (CBCL) is a standardized measure with excellent psychometric properties providing parental reports of a child’s behavior.8 It consists of 120 items assessing internalizing (withdrawn, somatic complaints,
Quality of Life at Home and at School The patient’s self-report of QOL was normal for all dimensions except social functioning, indicating a significant impairment of social interactions (Table I). In contrast, the
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Table I. Sample means and normative data for quality-of-life measures Normative data*
Sample Measure TACQOL– Child Form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) TACQOL– Parent Form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative)
Table II. Sample means and normative data for psychosocial adjustment
n Mean SD
Mean
SD
Normative data*
Sample P valuey
38 38 38 35 38 38
26.5 29.2 31.6 28.5 28.7 12.9
5.7 4.8 1.1 4.2 2.6 2.0
25.3 30.0 31.3 28.5 29.8 13.6
5.0 3.2 1.9 3.9 2.7 2.5
.20 .34 .12 .34 .01 .10
38
11.4
2.8
11.7
2.7
.77
40 40 40 30 39 40
26.7 29.4 30.7 26.1 28.1 13.4
4.3 4.2 2.8 5.5 3.0 1.9
27.6 31.0 31.4 29.2 30.0 15.0
3.7 2.3 1.6 3.7 2.3 1.8
.20 .02 .13 .01 ,.0001 ,.0001
40
11.1
2.7
11.7
2.3
.16
*Normative data from manual scales.7 yt Tests with normative data.
Measure Child behavior at home CBCL–Total Scorez CBCL– Internalizing Scorez CBCL– Externalizing Scorez Child behavior at school TRF–Total Scorez TRF– Internalizing Scorez TRF– Externalizing Scorez
n Mean SD
Mean
SD
P valuey
40
56.1
10.5
50.0
10.0
,.01
40
57.3
10.7
50.0
10.0
,.0001
40
54.2
9.8
50.0
10.0
.01
32
57.1
11.2
50.0
10.0
,.01
32
57.7
9.7
50.0
10.0
,.0001
32
53.2
9. 7
50.0
10.0
.07
*Normative data from manual scales.8,38 yt Tests with normative data. zT Score.
parents reported a significant impairment of motor, cognitive, social, and global positive emotional functioning (Table I).
autonomy. On the other hand, a high FRI, indicating good family relations, was correlated with autonomy and cognitive functioning.
Psychosocial Adjustment at Home and at School
Determinants of Psychosocial Adjustment
Psychosocial adjustment compared with healthy control children was rated abnormal by both parents (CBCL) and teachers (Teacher Report Form), and a significant decrease of behavioral adjustment in all dimensions was stated except for the externalizing behavior at school (Table II).
Psychosocial adjustment of the patients, as described by the parents, was significantly correlated with family climate but not with illness-related variables (Table III). There was no correlation between variables of both QOL and psychosocial adjustment and sociodemographic data, for example, age, sex, and socioeconomic background.
Determinants of QOL In the self-report (Table III), there was a negative correlation between a complicated course of SSNS (steroid dependency and cytotoxic treatment) and social functioning. Self-reported physical complaints and negative emotions were also correlated to maternal psychological distress. The parental report revealed a significant correlation between QOL and illness-related variables as well as family climate (Table III): Physical and emotional well-being were inversely correlated to steroid dependency and cyclophosphamide therapy in the medical history. Concerning the influence of family climate, maternal distress (Global Severity Index) particularly showed a negative correlation with most of the TACQOL subscales, whereas paternal distress was associated only with physical complaints, motor functioning, and 780
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DISCUSSION We report a comprehensive cross-sectional analysis on quality of life and psychosocial adjustment and their determinants in SSNS by using multiple informants. QOL was impaired, and notably parents evaluated their children’s QOL more pessimistically than did the patients. Psychosocial adjustment was disturbed not only at home but also in school. Although self-reported physical well-being appeared not to be affected, impairment of social functioning, that is, interaction with family members and peers, indicates that QOL in patients with SSNS is not normal. Few data are available on self-reported QOL in children with chronic illnesses, as mostly parents are interviewed to report on their The Journal of Pediatrics December 2004
Table III. Spearman correlation coefficients between variables of QOL and psychosocial adjustment and illness-related variables and family climate (TACQOL Child Form, n = 38, TAQCOL Parent Form, n = 40; CBCL n = 40) Illness-related variables
Family climate
No. of Relapses
Steroid dependency
Cyclophosphamide therapy
FRI
GSI mother
GSI Father
0.07 0.07 0.10 20.07 20.11 0.19 0.16
20.01 0.01 0.00 20.22 20.35* 20.03 20.16
20.08 20.26 20.14 20.29 20.44y 20.13 20.20
0.16 0.13 0.29 0.09 0.33 0.12 0.16
20.37* 20.33 20.31 20.003 20.08 0.001 20.39*
20.02 20.13 20.19 0.12 0.21 0.18 20.29
20.14 0.06 20.05 20.22 20.06 20.27 0.08
20.17 20.002 20.003 20.16 20.19 20.35* 20.10
20.36* 0.04 20.08 20.44* 20.33* 20.31 20.33*
0.25 0.12 0.38* 0.46* 0.33 0.26 0.27
20.65z 20.27 20.39* 20.35 20.48y 20.49y 20.46y
20.38* 20.46z 20.50y 20.28 20.29 20.20 20.29
20.13 20.01 20.16
20.02 0.08 20.03
0.13 0.20 0.06
20.48y 20.41* 20.40*
0.66z 0.72z 0.61z
0.54y 0.52y 0.54y
TAQCOL Child form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) TAQCOL Parent form Body Motor Auto Cognition Social Emotion (positive) Emotion (negative) CBCL Total Internalizing Externalizing *P < .05; yP < .01; zP < .001.
child’s QOL and psychosocial adjustment.22,27 The information obtained by the patients may yield a more realistic reflection. Notably, a previous study emphasized that parent reports cannot substitute for child reports because the TACQOL-Child form represents the patient’s own perception of QOL.28 Interestingly, parents rated their children’s QOL much less optimistically, and both children and parents regarded physical complaints as less important than social interactions. The divergent rating of children and parents is noteworthy. One possible reason is that children rated their QOL too optimistically, because of confounding factors (eg, face-to-face interview, mechanisms of avoidance). On the other hand, the parents may rate their children’s QOL too pessimistically. This might be due to an impairment in the parent’s (especially mother’s) own QOL, reflecting shared variance between mother’s psychological strain and the rating of her child’s QOL, as noted in other disorders.29 These results appear to be in contrast to those of previous studies in children with chronic conditions.21,22 A possible reason for this apparent discrepancy may be that many patients with SSNS and their parents live in constant fear of imminent relapse, and the daily urinary dipstick testing in the morning is
a permanent burden. Therefore, QOL in relapsing diseases (in general and in those responding to steroids) may be different from those in acute or chronic disorders. Pediatric patient groups with juvenile idiopathic arthritis and chronic inflammatory bowel disease rated their QOL as impaired as well.30,31 Impaired psychosocial adjustment in SSNS compared with control subjects at home but also at school may again be related to the chronic relapsing course of SSNS. The abnormal adjustment at home is in contrast to other pediatric patient groups,21,22 including children with other renal disorders.32 Corticosteroid treatment could be one independent variable of children’s behavior and adjustment. These short-term consequences have been demonstrated not only in SSNS10,11 but also in pediatric patients with asthma and hematologic malignancies.33,34 However, since the vast majority of our patients was studied in remission, disturbed psychosocial adjustment at home and in school is not only related to highdose corticosteroid therapy but suggests an impact of the disease itself. The comprehensive investigation identified several determinants of QOL and psychosocial adjustment relevant
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for the care of patients with SSNS. Severity of medical course of SSNS had a significant impact only on QOL but not on psychosocial adjustment. With respect to family climate, the psychological distress of the mother was a negative determinant of QOL and psychosocial adjustment. Mothers were the main care givers, exposed to the adverse effects of disorder and treatment, resulting in a mutual interference between the child’s QOL and psychosocial adjustment and the mother’s psychological distress, as reported previously.29 Conversely, higher family cohesion is protective, a finding that deserves further study and may have practical relevance. For instance, higher family cohesion has been reported to result in fewer hospitalizations in renal patients.35 Family characteristics mentioned above were identified to be crucial for positive adjustment in healthy populations as well as in other clinical conditions.21,36 The relevance of family climate appears to increase, however, when medical care can be considered as state-of-the-art, corresponding to current treatment guidelines. Somatic and medical variables, as tested by TACQOL and other instruments of health-related QOL, appear to be relevant whenever treatment is suboptimal.22 This study represents a rather small and heterogeneous study group with a wide age range. SSNS is, however, a rare disease, and the majority of our patients was included to minimize a selection bias. However, because the study was conducted at a primary and tertiary care center, patients with a more severe course of SSNS may be overrepresented. In addition, few patients with stable remission were reluctant to participate, possibly because of avoidance strategies. This observation has been described in previous clinical trials, causing difficulties in applying the attained information on all patients with a specific disease.37 Appropriateness of Dutch and German norms for our sample of Swiss children can be questioned, too. However, because the Netherlands, Germany, and Switzerland are central European countries with similar social structures, a major cross-cultural bias seems unlikely. By the use of standardized, established methodology, using multiple informants, our results are valid and may stimulate further research in this field. Future studies should be prospective, with repeated, longitudinal assessment, ideally in multicenter patient populations, to conquer the limitations addressed.
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7. Vogels T, Verrips GHW, Koopman HM, Theunissen HCM, Fekkes M, Kamphuis RP. TACQOL manual, Parent Form and Child Form. Leiden: Center for Child Health and Pediatrics LUMC-TNO; 2000. 8. Achenbach T. Manual for Child Behavior Checklist/4-18. Burlington: University of Vermont; 1991. 9. Ditesheim J, Templeton JJ. Short-term versus long-term quality of life in children following repair of high imperforate anus. J Pediatr Surg 1987;22: 581-7. 10. Hall AS, Thorley G, Houtman PN. The effects of corticosteroids on behavior in children with nephrotic syndrome. Pediatr Nephrol 2003;18: 1220-3. 11. Soliday E, Grey S, Lande MB. Behavioral effects of corticosteroids in steroid-sensitive nephrotic syndrome. Pediatrics 1999;104:e51. 12. Soliday E, Lande MB. Family structure and the course of steroidsensitive nephrotic syndrome. Pediatr Nephrol 2002;17:41-4. 13. The primary nephrotic syndrome in children: identification of patients with minimal change nephrotic syndrome from initial response to prednisone: a report of the International Study of Kidney Disease in Children. J Pediatr 1981;98:561-4. 14. Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children: Arbeitsgemeinschaft fur Padiatrische Nephrologie. Lancet 1988;1:380-3. 15. Kemper MJ, Altrogge H, Ludwig K, Timmermann K, Muller-Wiefel DE. Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome. Pediatr Nephrol 2000;14:772-5. 16. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood: British Association for Paediatric Nephrology. Lancet 1991;337: 1555-7. 17. Early identification of frequent relapsers among children with minimal change nephrotic syndrome: a report of the International Study of Kidney Disease in Children. J Pediatr 1982;101:514-8. 18. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of eight week with 12 week course: report of Arbeitsgemeinschaft fur Paediatrische Nephrologie. Arch Dis Child 1987;62:1102-6. 19. Largo RH, Molinari L, Comenale Pinto L, Weber M, Duc G. Language development of term and preterm children during the first five years of life. Dev Med Child Neurol 1986;28:333-50. 20. Verrips EGH, Vogels AGC, Koopman HM, Theunissen NCM, Kamphuis RP, Fekkes M, et al. Measuring health-related quality of life in a child population. Eur J Pub Health 1999;9:114-9. 21. Landolt MA, Nuoffer JM, Steinmann B, Superti-Furga A. Quality of life and psychologic adjustment in children and adolescents with early treated phenylketonuria can be normal. J Pediatr 2002;140:516-21. 22. Landolt MA, Grubenmann S, Meuli M. Family impact greatest: predictors of quality of life and psychological adjustment in pediatric burn survivors. J Trauma 2002;53:1146-51. 23. Achenbach TM. Manual for Teacher Report Form and 1991 Profile. Burlington: University of Vermont, Department of Psychiatry; 1991. 24. Derogatis LR, Lazarus L. SCL-90-R, Brief Symptom Inventory, and matching clinical rating scales. In: Maruish ME, ed. The use of psychological testing for treatment planning and outcome assessment. Hillsdale, NJ: Lawrence Erlbaum Associates; 1994. p. 217-24. 25. Moos RH, Moos BS. Family Environment Scale Manual: Development, Applications, Research. Palo Alto, Calif; 1994. 26. Brislin R, Lonner W, Thorndike R. Cross-cultural research methods. New York: John Wiley & Sons; 1973. 27. Stancin T, Drotar D, Taylor HG, Yeates KO, Wade SL, Minich NM. Health-related quality of life of children and adolescents after traumatic brain injury. Pediatrics 2002;109:E34. 28. Theunissen NCM, Vogels TGC, Koopman HM, Verrips GHW, Zwindermann KAH. The proxy problem: child report versus parent report in health-related quality of life research. Qual Life Res 1998;7:387-97. 29. Manificat S, Dazord A, Cochat P, Morin D, Plainguet F, Debray D. Quality of life of children and adolescents after kidney or liver transplantation: child, parents and caregiver’s point of view. Pediatr Transplant 2003;7:228-35. 30. Loonen HJ, Grootenhuis MA, Last BF, Koopman HM, Derkx HH. Quality of life in paediatric inflammatory bowel disease measured by a generic and a disease-specific questionnaire. Acta Paediatr 2002;91:348-54.
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31. Selvaag AM, Flato B, Lien G, Sorskaar D, Vinje O, Forre O. Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire. J Rheumatol 2003;30: 1602-10. 32. Soliday E, Kool E, Lande MB. Psychosocial adjustment in children with kidney disease. J Pediatr Psychol 2000;25:93-103. 33. Bender BG, Lerner JA, Poland JE. Association between corticosteroids and psychologic change in hospitalized asthmatic children. Ann Allergy 1991; 66:414-9. 34. Harris JC, Carel CA, Rosenberg LA, Joshi P, Leventhal BG. Intermittent high dose corticosteroid treatment in childhood cancer: behavioral and emotional consequences. J Am Acad Child Psychiatry 1986; 25:120-4.
35. Soliday E, Kool E, Lande MB. Family environment, child behavior, and medical indicators in children with kidney disease. Child Psychiatry Hum Dev 2001;31:279-95. 36. Tiet QQ, Bird HR, Davies M, Hoven C, Cohen P, Jensen PS, et al. Adverse life events and resilience. J Am Acad Child Adolesc Psychiatry 1998; 37:1191-200. 37. Caldwell PH, Butow PN, Craig JC. Parents’ attitudes to children’s participation in randomized controlled trials. J Pediatr 2003;142:554-9. 38. Do¨pfner M, Berner W, Lehmkuhl G. Handbuch: Lehrerfragebogen u¨ber das Verhalten von Kindern und Jugendlichen. Forschungser-gebnisse zur deutschen fassung der teacher’s report form (TRF) der child behavior Checklist 4-18. Ko¨ln: Arbeitsgruppe Kinder; Jugend- und Familien diagnostik (KJFD);1994.
50 Years Ago in The Journal of Pediatrics NONADRENAL FEMALE PSEUDOHERMAPHRODITISM: REPORT OF TWO PATIENTS SIMULATING MIXED ADRENAL DISEASE
Papadatos C, Klein R. J Pediatr 1954;45:662-7. The report by Papadatos et al appeared over 50 years ago, and the medical and ethical issues raised by the article are still relevant and important today. The article describes two female infants born with significant clitoromegaly, electrolyte abnormalities consistent with adrenal hyperplasia, and renal disease, whom, on evaluation, did not have adrenal disease. The authors then cite and describe the only two previous reports of ‘‘nonadrenal female pseudohermaphroditism.’’ One of the reports is particularly significant in that the author was Dr Lawson Wilkins. Dr Wilkins established the specialty of pediatric endocrinology in the United States. His clinical descriptions of the endocrine diseases of childhood remain unsurpassed, and his speculations as to origin of disease, remarkably prescient. In this specific article, the authors, attempting to explain the genital and renal findings of their patients, quote Dr Wilkins: ‘‘the concept that the genital anomalies were . due to genetic abnormalities cannot be dismissed.’’ Today we know that the electrolyte abnormalities seen in neonatal renal disease are caused by transient resistance to aldosterone. However, our current theory that the genital abnormalities seen in congenital renal disease are the result of a mutation causing a field defect in the embryonic development of the genitourinary tract is, essentially, a restatement of Dr Wilkins’s observation. The authors classify their patients as having ‘‘female pseudohermaphroditism.’’ This follows the 19th century emphasis on classifying diseases according to similarities in their physical manifestations. By the mid-20th century, it was becoming apparent that similar or identical physical signs could be produced by radically different pathophysiologic mechanisms and a classification system based on similarities in disease origin began to be used. The title of the article reflects the tension between these two systems as it establishes a case of ‘‘nonadrenal’’ (a rudimentary attempt at defining an etiologic basis for the observed physical findings) ‘‘female pseudohermaphroditism’’ (based on physical findings). As our understanding of the molecular basis of disease advance, classification systems based on physical findings are losing their justification and usefulness. Nonetheless, many current disease classification systems, including that used to classify ambiguous genitalia, still use this approach. The ethical issues implicitly contained in the article but not addressed are relevant today. Both patients had significant clitoromegaly. What recommendations were made regarding surgery on the patients’ genitals? The issue of genital reconstruction has been the source of a spirited, often angry, debate over the last 10 years and remains unresolved. Last, one cannot help but comment on the literary style of the article. Our predecessors were writers as well as scientists, and they produced case reports, which, even today, convey the excitement and thrill of scientific discovery. Jorge J. Daaboul, MD Richard Banks, MD The Nemours Children’s Clinic 83 West Columbia St Orlando, FL 32806 YMPD1176 10.1016/j.jpeds.2004.08.057
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