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Photographic analysis: A quantitative approach to the evaluation of dysmorphology
The Journal of Pediatrics Volume 129, Number 1
Editor's column
tis. It is increasingly apparent that this deletion may be among the most common of all genetic abnormalities. We are confident that with a high level of clinical suspicion and the ready availability of FISH analysis, new phenotypes associated with 22ql 1 deletions will continue to be described, as with the Opitz GBBB and Shprintzen-Goldberg syndromes. We urge clinicians to become familiar with the dysmorphic features and the highly variable phenotype of this deletion syndrome to allow appropriate referral and testing, definitive diagnosis by the gold standard of FISH, and genetic counseling to assist in long-term treatment. We also believe that clinical awareness of the potential for genetic causes of cardiac malformations will prove essential in the isolation and characterization of the mutant genes.
Mark C. Johnson, MD Michael S. Watson, PhD Department of Pediatrics Arnold W. Strauss, MD Department of Molecular Biology and Pharmacology St. Louis Children's Hospital Washington University School of Medicine St. Louis, MO 63110
3
REFERENCES
1. Webber SA, Hatchwell E, Barber JCK, Daubeney PEF, Crolla JA, Salmon AP, et al. Importance of microdeletions of chromosomal region 22ql 1 in the etiology of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study. J Pediatr 1996;129:26-32. 2. Payne RM, Johnson MC, Grant JW, Strauss AW. Toward a molecular understanding of congenital heart disease. Circulation 1995;91:494-504. 3. Goldmuntz E, Driscoll D, Budarf ML, Zackai EH, McDonaldMcGinn DM, Biegel JA, et al. Microdeletions of chromosomal region 22ql 1 in patients with congenital conotruncal cardiac defects. J Med Genet 1993;807-12. 4. Wilson DI, Goodship JA, Bum J, Cross IE, Scambler PJ. Deletions within chromosome 22ql 1 in familial congenital heart disease. Lancet 1992;340:573-4. 5. Ewart AK, Morris CA, Atkinson D; Jin W, Sternes K, Spallone P, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993;5:116. 6. Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (hand-heart syndrome). N Engl J Med 1994;330:885-91. 7. Amati F, Mari A, Digilio MC, Mingarelli R, Marino B, Giannotti A, et al. 22qll Deletions in isolated mad syndromic patients with tetralogy of Fallot. Hum Genet 1995;95:479-82.
Photographic analysis: A quantitative approach to the evaluation of dysmorphology The article in this issue by Astley and Clarren concerning a photographic screening tool for the fetal alcohol syndrome illustrates many important aspects of phenotypic analysis of facial characteristics. The authors used simple frontal photographs and some moderately complex mathematical formulas to identify, with amazing accuracy (100%), patients with FAS versus control subjects. Why is this important? First, it confirms the clinician's skill in recognizing FAS facial characteristics. Second, it validates by measurements, contour, and depth that such parameters are measurable and accurately reflect the clinician's observations. Third, relatively cheap screening could be done by individuals not necessarily expert in FAS, by computer, or both. This would dramatically improve prevalence data on FAS and pote ntially allow for earlier and more effective intervention strategies. J Pediatr 1996;129:3-4 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74068
Drs. Astley and Clarren are an epidemiologist and a dysmorphologist, respectively. Using a number of facial characteristics of FAS, they found three features that displayed excellent sensitivity and specificity for the discrimination of FAS from their control subjects. These three features were small palpebral fissures, smooth and simple philtmm, and thin upper lip. They quantified the magnitude of expression of these features, which gave additional discrimination ar/d See related article, p. 33.
FAS
Fetal alcohol syndrome
[ 1
accuracy for the diagnosis or exclusion of FAS. They clearly established that these three features formed the minimum cluster of features unique to FAS. They also studied photographs of 10 patients with known multiple congenital anomaly syndromes, of whom 9 (90%) could be classified as not having the facial phenotype of FAS. They have era-
4
Editor's column
barked on another facial phenotype study comparing a larger seiles of known multiple congenital anomaly syndromes with the FAS phenotype. They also readily admit that fm'ther evaluation by themselves and others will be necessary to validate their FAS facial phenotype conclusions by means of the photographic approach, involving the length of the palpebral fissure, simplicity of the philtrum, and thinness of the upper lip. The two major weaknesses of the Astley and Clarren study are that 77% of the test subjects were white and 12% were American Indian. There were few black (5%), Hispanic (2%), or Asian (2%) subjects among the study group. Facial phenotypes of these latter groups have not been studied adequately enough to establish clearly whether their racial and ethnic facial features for the three core features have the same overall accuracy, sensitivity, and specificity to exclude FAS with 100% confidence. The second problem is that the mean age of the control group was 7.9 years (range, 1.5 to 26.7 years) and that of the FAS group 6.5 years (range, from birth to 24.2 years). These ages indicate that relatively few neo-
The JoumaI of Pediatrics July 1996 nates were studied. That is understandable because the criteria for meeting the necessary quality of the utilized photographs would be difficult to achieve in a ueonate because of the presence of facial distortion and edema, commonly related to the birth process, not to mention excess newborn facial fat. Nevertheless, at the one and only time you have a ',captive audience" (the neonate), it might not be possible to achieve the accuracy with photographs that could be achieved later, when ascertainment is erratic and incomplete. Astley and Clarren's findings substantiate an old but not frequently used dysmorphology adage: Never base a clinical judgment on a measurable parameter. They also illustrate, in the very best sense, the value and importance of different disciplines' combining forces for excellent research.
Bryan D. Hall, MD Chief Division of Genetics and Dysmorphology Professor of Pediatrics, Department of Pediatrics University of Kentucky Lexington, KY 40536-0284
Rational approach to pharmacologic reduction of cholesterol levels in children The issues surrounding the identification and treatment of cholesterol abnormalities in children have been vexing for pediatricians for a long time. One would hope that in the era of evidence-based medicine, rational approaches to these questions could be developed. The pediatilc guidefines of the National Cholesterol Education Program for Children and Adolescents (NCEP) set forth the recommendations of a panel of experts and provide an approach to the child who may be at risk of coronary artery disease. 1 However, many pediatricians have found that using these guidelines leaves some questions unanswered. Clearly, a major problem in this area is the lack of reliable data to provide the rationale for an evidence-based approach. The article by Tonstad et al. 2 published in this issue of The Joumal provides useful clinical information and recalls some important questions regarding the clinical approach to children with dyslipidemia. Who should be screened for dyslipidemia? This question is relatively important because it has direct bearing on J Pediatr 1996;129:4-7 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74478
who will be identified as needing treatment. The adult treatment panel guidefines suggested that everyone older than 20 years of age should know bis or her cholesterol values) This would provide a baseline risk value from which to decide the extent, if any, of prescribed treatment. The NCEP pediatric guidelines recommended against a universal screening approach and suggested a more targeted approach based on both the presence of major risk factors and certain other discretionary features. The reasons for this approach were predominantly (1) a great concern that overdiagnosis would be See related article, p. 42. problematic, resulting in psychologic labeling, (2) the potential of overzealous use of medications, and (3) less than perfect tracking of childhood cholesterol percentiles into adulthood. The Muscatine smdy revealed that of children with cholesterol values above the 90th percentile, only 75% remained in that category several years later. 4 This indicates that some percentage of those with high cholesterol concentrations in childhood had normal values in adulthood. The Muscatine and Beaver County studies suggest that at least a partial explanation for the change in this subpopulation of
Editor's column
tis. It is increasingly apparent that this deletion may be among the most common of all genetic abnormalities. We are confident that with a high level of clinical suspicion and the ready availability of FISH analysis, new phenotypes associated with 22ql 1 deletions will continue to be described, as with the Opitz GBBB and Shprintzen-Goldberg syndromes. We urge clinicians to become familiar with the dysmorphic features and the highly variable phenotype of this deletion syndrome to allow appropriate referral and testing, definitive diagnosis by the gold standard of FISH, and genetic counseling to assist in long-term treatment. We also believe that clinical awareness of the potential for genetic causes of cardiac malformations will prove essential in the isolation and characterization of the mutant genes.
Mark C. Johnson, MD Michael S. Watson, PhD Department of Pediatrics Arnold W. Strauss, MD Department of Molecular Biology and Pharmacology St. Louis Children's Hospital Washington University School of Medicine St. Louis, MO 63110
3
REFERENCES
1. Webber SA, Hatchwell E, Barber JCK, Daubeney PEF, Crolla JA, Salmon AP, et al. Importance of microdeletions of chromosomal region 22ql 1 in the etiology of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study. J Pediatr 1996;129:26-32. 2. Payne RM, Johnson MC, Grant JW, Strauss AW. Toward a molecular understanding of congenital heart disease. Circulation 1995;91:494-504. 3. Goldmuntz E, Driscoll D, Budarf ML, Zackai EH, McDonaldMcGinn DM, Biegel JA, et al. Microdeletions of chromosomal region 22ql 1 in patients with congenital conotruncal cardiac defects. J Med Genet 1993;807-12. 4. Wilson DI, Goodship JA, Bum J, Cross IE, Scambler PJ. Deletions within chromosome 22ql 1 in familial congenital heart disease. Lancet 1992;340:573-4. 5. Ewart AK, Morris CA, Atkinson D; Jin W, Sternes K, Spallone P, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993;5:116. 6. Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (hand-heart syndrome). N Engl J Med 1994;330:885-91. 7. Amati F, Mari A, Digilio MC, Mingarelli R, Marino B, Giannotti A, et al. 22qll Deletions in isolated mad syndromic patients with tetralogy of Fallot. Hum Genet 1995;95:479-82.
Photographic analysis: A quantitative approach to the evaluation of dysmorphology The article in this issue by Astley and Clarren concerning a photographic screening tool for the fetal alcohol syndrome illustrates many important aspects of phenotypic analysis of facial characteristics. The authors used simple frontal photographs and some moderately complex mathematical formulas to identify, with amazing accuracy (100%), patients with FAS versus control subjects. Why is this important? First, it confirms the clinician's skill in recognizing FAS facial characteristics. Second, it validates by measurements, contour, and depth that such parameters are measurable and accurately reflect the clinician's observations. Third, relatively cheap screening could be done by individuals not necessarily expert in FAS, by computer, or both. This would dramatically improve prevalence data on FAS and pote ntially allow for earlier and more effective intervention strategies. J Pediatr 1996;129:3-4 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74068
Drs. Astley and Clarren are an epidemiologist and a dysmorphologist, respectively. Using a number of facial characteristics of FAS, they found three features that displayed excellent sensitivity and specificity for the discrimination of FAS from their control subjects. These three features were small palpebral fissures, smooth and simple philtmm, and thin upper lip. They quantified the magnitude of expression of these features, which gave additional discrimination ar/d See related article, p. 33.
FAS
Fetal alcohol syndrome
[ 1
accuracy for the diagnosis or exclusion of FAS. They clearly established that these three features formed the minimum cluster of features unique to FAS. They also studied photographs of 10 patients with known multiple congenital anomaly syndromes, of whom 9 (90%) could be classified as not having the facial phenotype of FAS. They have era-
4
Editor's column
barked on another facial phenotype study comparing a larger seiles of known multiple congenital anomaly syndromes with the FAS phenotype. They also readily admit that fm'ther evaluation by themselves and others will be necessary to validate their FAS facial phenotype conclusions by means of the photographic approach, involving the length of the palpebral fissure, simplicity of the philtrum, and thinness of the upper lip. The two major weaknesses of the Astley and Clarren study are that 77% of the test subjects were white and 12% were American Indian. There were few black (5%), Hispanic (2%), or Asian (2%) subjects among the study group. Facial phenotypes of these latter groups have not been studied adequately enough to establish clearly whether their racial and ethnic facial features for the three core features have the same overall accuracy, sensitivity, and specificity to exclude FAS with 100% confidence. The second problem is that the mean age of the control group was 7.9 years (range, 1.5 to 26.7 years) and that of the FAS group 6.5 years (range, from birth to 24.2 years). These ages indicate that relatively few neo-
The JoumaI of Pediatrics July 1996 nates were studied. That is understandable because the criteria for meeting the necessary quality of the utilized photographs would be difficult to achieve in a ueonate because of the presence of facial distortion and edema, commonly related to the birth process, not to mention excess newborn facial fat. Nevertheless, at the one and only time you have a ',captive audience" (the neonate), it might not be possible to achieve the accuracy with photographs that could be achieved later, when ascertainment is erratic and incomplete. Astley and Clarren's findings substantiate an old but not frequently used dysmorphology adage: Never base a clinical judgment on a measurable parameter. They also illustrate, in the very best sense, the value and importance of different disciplines' combining forces for excellent research.
Bryan D. Hall, MD Chief Division of Genetics and Dysmorphology Professor of Pediatrics, Department of Pediatrics University of Kentucky Lexington, KY 40536-0284
Rational approach to pharmacologic reduction of cholesterol levels in children The issues surrounding the identification and treatment of cholesterol abnormalities in children have been vexing for pediatricians for a long time. One would hope that in the era of evidence-based medicine, rational approaches to these questions could be developed. The pediatilc guidefines of the National Cholesterol Education Program for Children and Adolescents (NCEP) set forth the recommendations of a panel of experts and provide an approach to the child who may be at risk of coronary artery disease. 1 However, many pediatricians have found that using these guidelines leaves some questions unanswered. Clearly, a major problem in this area is the lack of reliable data to provide the rationale for an evidence-based approach. The article by Tonstad et al. 2 published in this issue of The Joumal provides useful clinical information and recalls some important questions regarding the clinical approach to children with dyslipidemia. Who should be screened for dyslipidemia? This question is relatively important because it has direct bearing on J Pediatr 1996;129:4-7 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74478
who will be identified as needing treatment. The adult treatment panel guidefines suggested that everyone older than 20 years of age should know bis or her cholesterol values) This would provide a baseline risk value from which to decide the extent, if any, of prescribed treatment. The NCEP pediatric guidelines recommended against a universal screening approach and suggested a more targeted approach based on both the presence of major risk factors and certain other discretionary features. The reasons for this approach were predominantly (1) a great concern that overdiagnosis would be See related article, p. 42. problematic, resulting in psychologic labeling, (2) the potential of overzealous use of medications, and (3) less than perfect tracking of childhood cholesterol percentiles into adulthood. The Muscatine smdy revealed that of children with cholesterol values above the 90th percentile, only 75% remained in that category several years later. 4 This indicates that some percentage of those with high cholesterol concentrations in childhood had normal values in adulthood. The Muscatine and Beaver County studies suggest that at least a partial explanation for the change in this subpopulation of