- Email: [email protected]
Detection of congenital nephrosis by screening program for hypothyroidism
Volume 102 Number 2
Editorial correspondence
phy, severe effusion, or an extremely abnormal otologic examination would have appeared disproportionately in the placebo group is debatable. We believe that the randomization of our subjects by number table should have promoted a well-distributed spectrum of disease. The physicians did use the tympanograms to qualify the patient for entry into the study, not to generate their therapeutic conclusions. In all instances, however, their evaluations remained unchanged after viewing the final tympanograms. This intimated to us that the pediatricians trusted their clinical judgment foremost over tympanometry. The audiologists and physicians were never appraised of the treatment group assignments. The patient was identified on the tympanogram by code number. The audiologists' evaluations were recorded separately in the investigator's records, and the audiologists were not aIIowed access to these records for global assessment. Although the physicians could have cued their final assessment of the presence or absence of coryza, the data do not reflect this: less t h a n 8% of the subjects given Naldecon had congestion at day I4, whereas 40% were evaluated as unsatisfactory, and 32% of the placebo subjects suffered congestion, whereas 54% were considered unsatisfactory. The two subjects dropped from the study were members of the Naldecon group. Both had begun to appear increasingly ill and were given alternate antibiotic therapy within 72 hours of enrollment in the investigation. We view them as antibiotic failures. The mean number of days symptomatic with earache was 2.3 days for subjects in the Naldecon group, compared with 2.8 days reported by the placebo subjects. It may be that otalgia, rather than effusion, is a better marker for acute infection. Clinical experience would suggest that middle ear effusion is not necessarily painful. The letter from Dr. Joffe poses a cautious but well-stated warning to prescribers. Because our follow-up ended at day 14 of therapy, it cannot be stated what long-term benefits were appreciated by patients receiving the antihistamine-decongestant. Although we would like to agree that alteration of the pressurecompliance relationship must confer some therapeutic advantage, the prescribing o f Naldecon will need to remain a matter of personal discretion until the clinical significance of middle ear effusion is better understood.
Donald M. Moran, Pharm.D. Kelly D. Mutchie, Pharm.D. Martin D. Higbee, Pharm.D. The University o f Utah College o f Pharmacy Salt Lake City, UT 84112
Treatment of OTC deficiency To the Editor. The recent article ~describing the treatment of a boy with severe ornithine transcarbamylase (OTC) deficiency who died at age 8~/2 months adds further evidence that sodium benzoate and phenylacetate are of value in prolonging the lives of patients with O T C
321
deficiency. However, despite these drugs, morbidity and mortality remain significant. 2 Keto acid analogues of amino acids have also been used to prolong survival of patients with severe O T C deficiency. The longest known survivor was treated with keto acids until age 31/2 years, at which time sodium benzoate was recognized as being a useful form of treatment. 3 Since that time, both keto acids and sodium benzoate have been given to the patient, who is now 5 years old. There is no evidence that keto acid analogues of amino acids and sodium benzoate cannot be used together for the benefit of patients with O T C deficiency. Until a more successful form of therapy than either keto acid analogues of amino acids or sodium benzoate and phenylacetate becomes available, both treatment modalities should be considered for patients with severe O T C deficiency.
Virginia V. Michels, M.D. Medical Genetics Mayo Clinic Rochester, M N 55905 Arthur L. Beaudet, M.D. Pediatrics Genetics Baylor College o f Medicine Houston, TX 77030 REFERENCES
1.
2.
3.
Brubakk A, Teizema LL, Blom W, Berger R: Successful treatment of severe O T C deficiency. J PEmArR 100:929, I982. Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk A M , Burton BK, Cann HM, Kerr D, M a m u n e s P, Mataton R, Myerberg D, Schafer IA: Treatment of inborn errors of urea synthesis: Activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Mcd 306:1387, 1982. Miche[s VV, Potts E, Walser M, Beaudet AL: Ornithine transcarbamylase deficiency: Long-term survival (in press).
Detection of congenital nephrosis by screening program for hypothyroidism To the Editor." My colleagues and l have reported a patient with congenital nephrosis, detected by a screening program for congenital hypothyroidism] similar to those described by McLean et al. 2 Our patient was initially euthyroid with a normal free thyroxine (T4) concentration; our report stressed the striking clinical and laboratory similarities of congenital nephrosis and congenital hypothyroidism. Our patient did not develop an elevated thyroid-stimulating hormone (TSH) concentration (16.4 /zU/ml) until l lV~ months of age. Urinary loss of T4 and iodine is a plausible mechanism for the hypothyroidism. It is evident that congenital nephrosis can be detected by programs originally developed to detect congenital hypothyroidism, but only if infants with low T4 and normal T S H have
322
Editorial correspondence
additional evaluation of thyroxine-binding globulin (TBG)? All five patients described by McLean et al? had XY karyotypes or were clinically male. Less astute observers might assume that these infants had X-linked TBG deficiency. Although congenital nephrosis is rare in the United States, a routine urinalysis is valuable in the evaluation of an infant with low T4 and normal T S H on routine neonatal screening.
Daniel C. Postellon, M.D. Wayne State University Children's Hospital of Michigan 390l Beaubien Blvd. Detroit, M1 48201
The Journal of Pediatrics February 1983
Rather, it is to suggest that acknowledgement within the body of the scientific paper that troublesome ethical issues exist would, I believe, have been well received.
Julius Landwirth, M.D. Pr@ssor, Department of Pediatrics University of Connecticut School of Medicine Director, Department of Pediatrics Hartford Hospital Hartford. CT 06115 REFERENCES 1.
REFERENCES
1.
2.
Finnegan JT, Slosberg E J, Postellon DC, Primak WA: Congenital nephrotic syndrome detected by hypothyroid screening. Acta Paediatr Scand 69:705, 1980. McLean RH, Kennedy TL, Rosoulpour M, Ratzan SK, Siegel N J, Kauschansky A, Genel M: Hypothyroidism in the congenital nephrotic syndrome. J PEI~A'rR 101:72, 1982. Dussault JH, Coulombre P, Laberge C, Letarte J, Guyda H, Khoury K: Preliminary report on a mass screening program for neonatal hypothyroidism. J PEDIAXR86:670, 1975.
Ethical aspects of studying child abuse To the Editor: The paucity of prospective studies seeking to validate presumed antecedents of child abuse, as cited by Altemeier et al. 1 is not difficult to understand. In addition to the complex methods required, such studies raise difficult ethical questions. In the study reported, such questions might include the following: 1. Were the mothers completely informed about the purposes of the study? 2. Was a program of interventional counseling offered for mothers whose interviews indicated potentially serious parenting problems, such as violent behavior or unwanted pregnancy? 3. If so, how does the "at risk" identification and the counseling interaction affect the results of the study? 4. Is the ultimate objective of such studies to identify characteristics with predictive value for child abuse that might become elements of a screening instrument? 5. If so, at what level of confidence (if any) would one be willing to override parental child-rearing preferences with mandatory interventional programs? 6. Are such studies in the category of "natural experiments" built on conditions of social deprivation, about which Roffman has commented, "Ng soon as they [researchers] attempt to take advantage o f the social predicament in which the subjects are found, they become accomplices to the problem, not observers of it. ''2 These recurring issues have been dealt with by others{, and undoubtedly received the attention of the vanderbilt Committee on H u m a n Experimentation. Raising such concerns is not to imply a challenge to the value of investigative activity in this vital area.
2. 3.
Altmeir WA, O'Connor S, Vietze PM, Sandier H M , Sherrod KB: Antecedents of child abuse. J PEDIA'rR 100"823, 1982. R o t h m a n D J: Were Tuskeegee and Wilowbrook "studies in nature"? Hastings Cent Rep 12:5, 1982. Brody H, Gaiss B: Basic issues concerning prediction. In Heifer RE, Kempe CH: Child abuse and neglect: The family and community. Cambridge, Mass., 1976, Ballinger, p 372.
Reply To the Editor: Dr. Landwirth has presented m a n y of the ethical questions associated with prospective behavioral research studies. In designing such investigations, both ethical and scientific needs must be considered. Subjects should not be harmed directly by study procedures or indirectly by being excluded from effective treatment; study procedures should interfere as little as possible with measurements of outcome variables. The intent of our study was to prospectively identify antecedents of child maltreatment and to determine whether prediction of these is feasible. Our ultimate goals are to develop a prediction instrument that will allow us to identify high-risk families and then to offer intervention to prevent child maltreatment before it begins. Women who volunteered to participate signed a written consent that indicated that we were studying relationships between mothers and infants to determine characteristics that contribute to "good and bad relationships" and that we wanted to find what can cause "happy mother-child relationships to break down." The mothers were told that we would use their interview answers to predict how many problems we thought they might have with their children and that we would be following up on them after delivery to identify any "breakdown" in their relationships with their children. Child abuse, neglect, and nonorganic failure to thrive were not described more specifically. We considered providing intervention to selected mothers, but were reluctant to do this for several reasons. Selection of candidates based on individual interview questions, as Dr. Landwirth suggests, would have been difficult because rates of negative answers were surprisingly high: 70% of 1,400 volunteers indicated their pregnancy was unplanned, 50% did not want the pregnancy, and 20% had struck someone recently in anger. We could have offered intervention to the group of 273 women predicted to be at high risk by the overall interview process, but decided against this for both ethical and scientific reasons; Offering intervention would have made these mothers and the intervention team aware of the high-risk assignment. At that point, we did not know whether it
Editorial correspondence
phy, severe effusion, or an extremely abnormal otologic examination would have appeared disproportionately in the placebo group is debatable. We believe that the randomization of our subjects by number table should have promoted a well-distributed spectrum of disease. The physicians did use the tympanograms to qualify the patient for entry into the study, not to generate their therapeutic conclusions. In all instances, however, their evaluations remained unchanged after viewing the final tympanograms. This intimated to us that the pediatricians trusted their clinical judgment foremost over tympanometry. The audiologists and physicians were never appraised of the treatment group assignments. The patient was identified on the tympanogram by code number. The audiologists' evaluations were recorded separately in the investigator's records, and the audiologists were not aIIowed access to these records for global assessment. Although the physicians could have cued their final assessment of the presence or absence of coryza, the data do not reflect this: less t h a n 8% of the subjects given Naldecon had congestion at day I4, whereas 40% were evaluated as unsatisfactory, and 32% of the placebo subjects suffered congestion, whereas 54% were considered unsatisfactory. The two subjects dropped from the study were members of the Naldecon group. Both had begun to appear increasingly ill and were given alternate antibiotic therapy within 72 hours of enrollment in the investigation. We view them as antibiotic failures. The mean number of days symptomatic with earache was 2.3 days for subjects in the Naldecon group, compared with 2.8 days reported by the placebo subjects. It may be that otalgia, rather than effusion, is a better marker for acute infection. Clinical experience would suggest that middle ear effusion is not necessarily painful. The letter from Dr. Joffe poses a cautious but well-stated warning to prescribers. Because our follow-up ended at day 14 of therapy, it cannot be stated what long-term benefits were appreciated by patients receiving the antihistamine-decongestant. Although we would like to agree that alteration of the pressurecompliance relationship must confer some therapeutic advantage, the prescribing o f Naldecon will need to remain a matter of personal discretion until the clinical significance of middle ear effusion is better understood.
Donald M. Moran, Pharm.D. Kelly D. Mutchie, Pharm.D. Martin D. Higbee, Pharm.D. The University o f Utah College o f Pharmacy Salt Lake City, UT 84112
Treatment of OTC deficiency To the Editor. The recent article ~describing the treatment of a boy with severe ornithine transcarbamylase (OTC) deficiency who died at age 8~/2 months adds further evidence that sodium benzoate and phenylacetate are of value in prolonging the lives of patients with O T C
321
deficiency. However, despite these drugs, morbidity and mortality remain significant. 2 Keto acid analogues of amino acids have also been used to prolong survival of patients with severe O T C deficiency. The longest known survivor was treated with keto acids until age 31/2 years, at which time sodium benzoate was recognized as being a useful form of treatment. 3 Since that time, both keto acids and sodium benzoate have been given to the patient, who is now 5 years old. There is no evidence that keto acid analogues of amino acids and sodium benzoate cannot be used together for the benefit of patients with O T C deficiency. Until a more successful form of therapy than either keto acid analogues of amino acids or sodium benzoate and phenylacetate becomes available, both treatment modalities should be considered for patients with severe O T C deficiency.
Virginia V. Michels, M.D. Medical Genetics Mayo Clinic Rochester, M N 55905 Arthur L. Beaudet, M.D. Pediatrics Genetics Baylor College o f Medicine Houston, TX 77030 REFERENCES
1.
2.
3.
Brubakk A, Teizema LL, Blom W, Berger R: Successful treatment of severe O T C deficiency. J PEmArR 100:929, I982. Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk A M , Burton BK, Cann HM, Kerr D, M a m u n e s P, Mataton R, Myerberg D, Schafer IA: Treatment of inborn errors of urea synthesis: Activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Mcd 306:1387, 1982. Miche[s VV, Potts E, Walser M, Beaudet AL: Ornithine transcarbamylase deficiency: Long-term survival (in press).
Detection of congenital nephrosis by screening program for hypothyroidism To the Editor." My colleagues and l have reported a patient with congenital nephrosis, detected by a screening program for congenital hypothyroidism] similar to those described by McLean et al. 2 Our patient was initially euthyroid with a normal free thyroxine (T4) concentration; our report stressed the striking clinical and laboratory similarities of congenital nephrosis and congenital hypothyroidism. Our patient did not develop an elevated thyroid-stimulating hormone (TSH) concentration (16.4 /zU/ml) until l lV~ months of age. Urinary loss of T4 and iodine is a plausible mechanism for the hypothyroidism. It is evident that congenital nephrosis can be detected by programs originally developed to detect congenital hypothyroidism, but only if infants with low T4 and normal T S H have
322
Editorial correspondence
additional evaluation of thyroxine-binding globulin (TBG)? All five patients described by McLean et al? had XY karyotypes or were clinically male. Less astute observers might assume that these infants had X-linked TBG deficiency. Although congenital nephrosis is rare in the United States, a routine urinalysis is valuable in the evaluation of an infant with low T4 and normal T S H on routine neonatal screening.
Daniel C. Postellon, M.D. Wayne State University Children's Hospital of Michigan 390l Beaubien Blvd. Detroit, M1 48201
The Journal of Pediatrics February 1983
Rather, it is to suggest that acknowledgement within the body of the scientific paper that troublesome ethical issues exist would, I believe, have been well received.
Julius Landwirth, M.D. Pr@ssor, Department of Pediatrics University of Connecticut School of Medicine Director, Department of Pediatrics Hartford Hospital Hartford. CT 06115 REFERENCES 1.
REFERENCES
1.
2.
Finnegan JT, Slosberg E J, Postellon DC, Primak WA: Congenital nephrotic syndrome detected by hypothyroid screening. Acta Paediatr Scand 69:705, 1980. McLean RH, Kennedy TL, Rosoulpour M, Ratzan SK, Siegel N J, Kauschansky A, Genel M: Hypothyroidism in the congenital nephrotic syndrome. J PEI~A'rR 101:72, 1982. Dussault JH, Coulombre P, Laberge C, Letarte J, Guyda H, Khoury K: Preliminary report on a mass screening program for neonatal hypothyroidism. J PEDIAXR86:670, 1975.
Ethical aspects of studying child abuse To the Editor: The paucity of prospective studies seeking to validate presumed antecedents of child abuse, as cited by Altemeier et al. 1 is not difficult to understand. In addition to the complex methods required, such studies raise difficult ethical questions. In the study reported, such questions might include the following: 1. Were the mothers completely informed about the purposes of the study? 2. Was a program of interventional counseling offered for mothers whose interviews indicated potentially serious parenting problems, such as violent behavior or unwanted pregnancy? 3. If so, how does the "at risk" identification and the counseling interaction affect the results of the study? 4. Is the ultimate objective of such studies to identify characteristics with predictive value for child abuse that might become elements of a screening instrument? 5. If so, at what level of confidence (if any) would one be willing to override parental child-rearing preferences with mandatory interventional programs? 6. Are such studies in the category of "natural experiments" built on conditions of social deprivation, about which Roffman has commented, "Ng soon as they [researchers] attempt to take advantage o f the social predicament in which the subjects are found, they become accomplices to the problem, not observers of it. ''2 These recurring issues have been dealt with by others{, and undoubtedly received the attention of the vanderbilt Committee on H u m a n Experimentation. Raising such concerns is not to imply a challenge to the value of investigative activity in this vital area.
2. 3.
Altmeir WA, O'Connor S, Vietze PM, Sandier H M , Sherrod KB: Antecedents of child abuse. J PEDIA'rR 100"823, 1982. R o t h m a n D J: Were Tuskeegee and Wilowbrook "studies in nature"? Hastings Cent Rep 12:5, 1982. Brody H, Gaiss B: Basic issues concerning prediction. In Heifer RE, Kempe CH: Child abuse and neglect: The family and community. Cambridge, Mass., 1976, Ballinger, p 372.
Reply To the Editor: Dr. Landwirth has presented m a n y of the ethical questions associated with prospective behavioral research studies. In designing such investigations, both ethical and scientific needs must be considered. Subjects should not be harmed directly by study procedures or indirectly by being excluded from effective treatment; study procedures should interfere as little as possible with measurements of outcome variables. The intent of our study was to prospectively identify antecedents of child maltreatment and to determine whether prediction of these is feasible. Our ultimate goals are to develop a prediction instrument that will allow us to identify high-risk families and then to offer intervention to prevent child maltreatment before it begins. Women who volunteered to participate signed a written consent that indicated that we were studying relationships between mothers and infants to determine characteristics that contribute to "good and bad relationships" and that we wanted to find what can cause "happy mother-child relationships to break down." The mothers were told that we would use their interview answers to predict how many problems we thought they might have with their children and that we would be following up on them after delivery to identify any "breakdown" in their relationships with their children. Child abuse, neglect, and nonorganic failure to thrive were not described more specifically. We considered providing intervention to selected mothers, but were reluctant to do this for several reasons. Selection of candidates based on individual interview questions, as Dr. Landwirth suggests, would have been difficult because rates of negative answers were surprisingly high: 70% of 1,400 volunteers indicated their pregnancy was unplanned, 50% did not want the pregnancy, and 20% had struck someone recently in anger. We could have offered intervention to the group of 273 women predicted to be at high risk by the overall interview process, but decided against this for both ethical and scientific reasons; Offering intervention would have made these mothers and the intervention team aware of the high-risk assignment. At that point, we did not know whether it