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ARTICLES: Susan J. Astley Comparison of the 4-Digit Diagnostic Code and the Hoyme Diagnostic Guidelines for Fetal Alcohol Spectrum Disorders Pediatrics 2006; 118: 1532-1545 [Abstract] [Full text] [PDF]

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RESPONSE TO CRITICISMS RAISED BY ASTLEY TO CLARIFICATIONS OF THE IOM DIAGNOSTIC CRITERIA FOR FASD

H. Eugene Hoyme, MD, FAAP, Philip A. May, PhD, Professor of Sociology and Family & Community Medicine, Univ of New Mexico, Albuquerque, NM   (26 February 2007)

RESPONSE TO CRITICISMS RAISED BY ASTLEY TO CLARIFICATIONS OF THE IOM DIAGNOSTIC CRITERIA FOR FASD 26 February 2007
H. Eugene Hoyme, MD, FAAP, Professor and Chief Div of Medical Genetics, Dept of Pediatrics, Stanford Univ School of Medicine, Stanford, CA, Philip A. May, PhD, Professor of Sociology and Family & Community Medicine, Univ of New Mexico, Albuquerque, NM Send letter to journal: Re: RESPONSE TO CRITICISMS RAISED BY ASTLEY TO CLARIFICATIONS OF THE IOM DIAGNOSTIC CRITERIA FOR FASD gene.hoyme{at}stanford.edu H. Eugene Hoyme, MD, FAAP, et al.	TO THE EDITOR: In a recent issue of Pediatrics(1), Dr. Susan Astley reported on a personally conducted comparison of her 4-digit diagnostic system for children prenatally exposed to alcohol with our clarifications of the Institute of Medicine (IOM) criteria for diagnosis of fetal alcohol spectrum disorders (FASD)(2). A thoughtful reading of the entire literature regarding the teratogenicity of ethanol and objective assessment of our system for diagnosis in the FASD continuum reveal that Dr. Astley’s conclusions are inaccurate, based on faulty and misleading data analysis and a narrow understanding of the developmental biology underlying the features of FASD and other dysmorphic syndromes associated with developmental disabilities. We are surprised by the publication in Pediatrics of this attempt to discredit years of clinical and population- based research on the teratogenic effects of alcohol, much of it based on the recommendations of the Institute of Medicine (IOM). In this letter we will address many of the issues raised by Dr. Astley. GENERAL COMMENTS: To begin, Astley assumes that her 4-digit diagnostic system is the “gold standard” for diagnosis in FASD. An assumption that any variance of our criteria from hers leads to incorrect diagnoses is not demonstrated by our data or her analysis. She has chosen to include in her comparison only children diagnosed with full-blown FAS; this invalidates many of her arguments, since the point of our article was to delineate the entire clinical spectrum of FASD. In fact, a comparison of children diagnosed with FAS and Partial FAS by all existing diagnostic systems would more likely display more similarities than differences. As Dr. Astley points out, many investigators have an ongoing interest in this area. We welcome third party evaluation of all diagnostic systems, especially by busy clinicians who routinely evaluate children exposed prenatally to alcohol as part of their clinical practices. It is our opinion that refinement of methods for the clinical characterization of FASD should focus on both accuracy and practical clinical applicability. Fine-tuning the diagnosis of FASD is an important and ongoing process, continually being re- evaluated as new data are analyzed. Rather than the current published work being the end point of such investigation, it should be the beginning. This research should be conducted in a scientific and collegial atmosphere, and we encourage Dr. Astley to add to this discourse in a positive way. Despite arguing the need for a multidisciplinary approach, Astley’s system ultimately rests on the dysmorphology assessment of the face. She contends that “the validity of an FASD diagnosis rests solely on the specificity of the facial phenotype for the exposure (alcohol) and outcome (FAS).” This statement places undue emphasis on features that are not unique to alcohol exposure. Requiring 3 cardinal facial features rather than 2 does not make “the face” any more specific for alcohol teratogenicity. In fact, extensive animal as well as human data indicate that the face of fetal alcohol syndrome is a non-specific part of the holoprosencephaly spectrum, accompanying a midfacial deficiency directly related to an insult to the developing median forebrain that can be either genetic or teratogenic in origin(3-6). Holoprosencephaly can accompany mutation in or downregulation of a number of early developmental genetic pathways in the brain(7-10). Recent research indicates that one important mechanism of alcohol teratogenicity is the downregulation of these genetic pathways(11-13). The facial features observed in animal models are also highly variable depending on timing of the insult(3). Thus, stating that the three cardinal facial features are 100% specific for FAS is neither borne out by the literature nor clinical experience. Despite Dr. Astley’s assertion that “an astute clinician would not mistake FAS for William’s [sic] syndrome,” many malformation syndromes are phenotypically variable, including Williams syndrome(14,15) and FASD. Astley’s comments about the absolute specificity of the face of FAS reflect a general lack of appreciation of the entire field of developmental disabilities and the causation and variability of malformation syndromes. Although alcohol may contribute to the phenotype of a child with a known genetically determined malformation syndrome, such data are lacking in the literature. In fact, the non-specificity of the facial phenotype implies the absolute necessity of a multidisciplinary diagnostic approach, including input from a pediatrician knowledgeable in the entire spectrum of developmental disabilities. ERRORS IN FACT: While there are many factual errors in Astley's paper, we will highlight only a recurring few. First, she writes that “Hoyme, et al. refer to their diagnostic guidelines as a clarification of the 1996 IOM criteria. The two sets of guidelines are authored by separate groups, however.” In fact, the second author of our paper (May), who is also the principal investigator on the NIAAA grants that have produced much of the data leading to development of the diagnostic system in question, was a member of the IOM committee on FAS for its entire existence, 1994-1996, and authored several sections of the report16. Second, in numerous places in her article, Dr. Astley fails to mention that our diagnostic scheme is a more clinically-specific version of the exact four-category classification system that was recommended by the IOM. Third, Astley repeatedly calls our diagnostic methods a “gestalt” diagnostic technique, which is meant to imply minimal organization and quantification of FASD diagnoses. In fact our approach is well structured and quantified, based on three decades of clinical experience of each of our senior dysmorphologists working on research projects in populations throughout the world. Fourth, she writes that one validation of the 4-digit facial classification system is that it has produced high correlations with the “most disabling feature” of FAS, significant cognitive and behavioral impairments. Our IOM-based system provides for evaluation of not only facial features, but also of other clinical features associated with FASD through a structured, total dysmorphology score. This score has produced higher, more significant correlations with low intelligence and behavioral traits characteristic of FASD(17,18) than 4-digit studies of the face alone(19).Total IQ, Verbal IQ, Performance IQ and behavioral problems have also been significantly linked to specific aspects of our dysmorphology assessments through highly significant correlations with a series of measures of quantity, frequency, and timing of drinking in populations where complete and accurate reporting has been achieved (20,21). Yet Astley argues that it is nearly impossible to link alcohol quantity and frequency to specific prenatal alcohol damage and that our system requires “excessive” documentation of maternal drinking. Is the fact that the 4 -digit system requires a lower extent and lower quality of evidence for quantity, frequency and timing of prenatal alcohol consumption a good thing? CONTRADICTIONS: In addition to inaccuracies, Dr. Astley’s arguments are circular and contradictory. First, at one point in the paper she writes that “since the [Hoyme et al.] diagnosis is based solely on the physical features of growth, facial anomalies and structural brain abnormalities…an interdisciplinary clinical team…would have no role in the derivation of an FAS diagnosis.” Second, she states that we use the “gestalt” method of diagnosis, stating that we have not standardized our clinical procedures and observations in studies of the various populations in which we work. Third, Astley writes in multiple places that the data used to illustrate our diagnostic system in our paper are from “a non-representative population base” (South Africans and Native Americans). None of these assertions are accurate, and later she contradicts all three of them by writing that “key strengths” of our study design and methods used to formulate the diagnostic guidelines “include the use of skilled multidisciplinary teams led by experts in the field of FASD diagnosis; use of standardized objective measurement tools to enhance reliability; and access to a reasonably large, population-based study sample.” Regarding the populations we have studied, these populations are non-representative to whom? These two populations exhibit rates of FASD that are among the highest in the world and have proven to provide high degrees of candor/honesty in reporting alcohol use and other maternal risk factors (22,20). Although there are others, the fourth and last contradiction is criticism of our adoption and use of Astley’s lip-philtrum guide to quantify midfacial morphology. Speculating, Dr. Astley states that we must have used the Caucasian version in South Africa, implying that the African American guide would have been more appropriate. We did use the Caucasian version in South Africa and the Plains, feeling it was the best guide available, since both populations have experienced substantial degrees of racial admixture with Caucasians. She also contradicts herself by writing that the “direction of error [using the Caucasian scale] would be to underestimate the prevalence of the FAS facial phenotype.” But later she writes: “The extraordinarily high FAS prevalence rates (40.5 - 46.4 cases per 1000 subjects) reported by May et al. for a South African community were based on FAS diagnoses that Hoyme et al. reported were inaccurate and overestimated.” What Dr. Astley fails to recognize is that all of our studies of other populations utilize normal control groups of children and mothers randomly selected from those same populations. These control groups provide the standardization that she said should be done through adaptation of tools for the specific population. It is equally legitimate and accurate, and preferable due to time, sampling, and cost efficiency, to compare both subpopulations (FASD and random controls) to a common standard whether or not the standard was developed specifically from that exact population(23). CONCLUSIONS: Rather than setting a standard for FAS diagnosis, the 4-digit system tends to eliminate the value of clinical judgment beyond that which is applied to a series of Likert-scaled items. The bar is set so high in terms of facial morphology (three cardinal features) and head circumference (< 2 1/2 percentile) that it is no surprise that Astley and colleagues claim a specificity of 100% when using these cut points. But one might ask how many true positive FAS cases are missed, particularly among offspring of binge drinkers who produce exposed children with facial features that are not always as consistent as required by the 4-digit system. Seventy percent of FAS cases that we diagnose in most populations have all three key facial features along with meeting other physical, behavioral, intelligence and maternal exposure criteria. And we wonder how many false negative FAS cases the 4- digit system would produce in individuals from populations with a normally large head size (e.g. American Indians)(24-26). The 4-digit system is hardly without flaws in spite of the statistical measures employed by Astley. Therefore to hold up the 4-digit system as superior to our system is unjustified. Our criteria for diagnosis of FASD, which Dr. Astley refers to as the “Hoyme” methodology, were indeed coauthored by a truly interdisciplinary research team, including representatives from the disciplines of dysmorphology, human genetics, epidemiology, psychology, neuropsychology, educational diagnostics, special education, and social work. All have worked extensively with diverse populations on three continents. Not only does our critic need to review more carefully the total body of published literature in this area, but she needs to spend more time with an interdisciplinary team of clinicians, practice more “shoe leather” epidemiology in the field with diverse populations, and be more understanding of the many possible faces and variations of FAS and other FASD. This might help her appreciate the need for more sensitivity in accommodating ethnic and racial variation, unique patterns from binge drinking, and minor differentiation arising from other real world variables. The key is to understand and accommodate substantial human phenotypic diversity due to prenatal and postnatal factors without losing accuracy of diagnosis in FASD. REFERENCES: 1. Astley SJ. Comparison of the 4-digit diagnostic code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders. Pediatrics. 2006;118:1532-1545 2. Hoyme HE, May PA, Kalberg WO, Kodituwakku P, Gossage JP, Trujillo PM, Buckley DG, Miller JH, Aragon, AS, Khaole N, Viljoen DL, Jones KL, Robinson LK. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. Pediatrics 2005;115:39-47 3. Sulik KK. Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med. 2005;230:366-375 4. Sulik KK, Johnston MC. Embryonic origin of holoprosencephaly: interrelationship of the developing brain and face. Scan Electron Microsc. 1982; 309-322 5. Webster TA, Gibson BW, Keng T, Biemann K, Schimmel P. Primary structures of both subunits of Escherichia coli glycyl-tRNA synthetase. J Biol Chem. 1983;258:10637-10641 6. Edison R, Muenke M. The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol. Congenit Anom (Kyoto). 2003;43:1-21 7. Ribeiro V, Reis H, Teixeira JF, Xavier JA, Cruz R. Middle interhemispheric variant of holoprosencephaly: a case report. Rev Neurol. 2006;42:245-246 8. El Jaick KB, Powers SE, Bartholin L, Myers, KR, Hahn J, Orioli IM, Ouspenskaia M, Lacbawan F, Roessler E, Wotton D, Muenke M. Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab. 2006 9. Ming Z, Griffith BL, Breese GR, Mueller RA, Criswell HE. Changes in the effect of isoflurane on N-methyl-D-aspartic acid-gated currents in cultured cerebral cortical neurons with time in culture: evidence for subunit specificity. Anesthesiology, 2002;97:856-867 10. Wallis DE, Muenke M. Mutations in holoprosencephaly. Hum Mutat. 2000;16:99-108 11. Ahlgren SC, Thakur V, Bronner-Fraser M. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sc USA. 2002;99;10476-10481 12. Eagleson GW, Dempewolf RD. The role of the anterior neural ridge and Fgf-8 in early forebrain patterning and regionalization in Xenopus laevis. Comp Biochem Physiol B Biochem Mol Bio. 2002;132:179-189 13. Tyas DA, Pearson H, Rashbass P, Price DJ. Pax6 regulates cell adhesion during cortical development. Cereb Cortex, 2003;13:612-619 14. von Beust G, Laccone FA, del Pilar AM, Wessel A. Clinical aspects and genetics of Williams-Beuren syndrome. Clinical and molecular genetic study of 44 patients with suspected Williams-Beuren syndrome. Klin Padiatr. 2000;212:299-307 15. Joyce CA, Zorich B, Pike SJ, Barber JC, Dennis NR. Williams- Beuren syndrome: phenotypic variability and deletions of chromosomes 7, 11, and 22 in a series of 52 patients. J Med Genet. 1996;33:986-992 16. Stratton KR, Howe CJ, Battaglia FC. Institute of Medicine, Division of Biobehavioral Sciences and Mental Disorders, Committee to Study Fetal Alcohol Syndrome, & National Institute on Alcohol Abuse and Alcoholism. Fetal alcohol syndrome diagnosis, epidemiology, prevention, and treatment. Washington, D.C: National Academy Press; 1996 17. Kodituwakku P, Coriale G, Fiorentino D, Aragon AS, Kalberg WO, Buckley D, Gossage JP, Ceccanti M, May PA. Neurobehavioral characteristics of children with fetal alcohol spectrum disorders in communities from Italy: Preliminary results. Alcohol Clin Exp Res. 2006;30:1551-1561 18. Hoyme HE, Ervalahti N, Fagerlund Å, Autti-Rämö I, Loimu L and Korkman M. Relationship between dysmorphic features and general cognitive functioning in children with fetal alcohol spectrum disorders. David W. Smith Morphogenesis and Malformations Workshop, Lake Arrowhead, CA, September, 2006. Proceedings of the Greenwood Genetic Center (in press). 19. Astley SJ, Clarren SK. Measuring the facial phenotype of individuals with prenatal alcohol exposure: correlations with brain dysfunction. Alcohol Alcohol. 2001;36:147-159 20. May PA, Gossage JP, Brooke LE, Snell CL, Marais AS, Hendricks LS, Croxford JA, Viljoen DL. Maternal risk factors for fetal alcohol syndrome in the Western Cape Province of South Africa: a population-based study. Am J Public Health 2005;95:1190-1199 21. May PA, Gossage JP, Marais AS, Adnams CM, Hoyme HE, Jones KL, Robinson LK, Khaole NCO, Snell C, Kalberg WO, Hendricks L, Brooke L, Stellavato C, Viljoen DL. The epidemiology of fetal alcohol syndrome (FAS) and partial FAS in a South African Community: A third study of a very high prevalence area. Drug Alcohol Dep 2006; (in press) 22. Viljoen D, Croxford J, Gossage JP, Kodituwakku PW, May PA. Characteristics of mothers of children with fetal alcohol syndrome in the Western Cape Province of South Africa: a case control study. J Stud Alcohol. 2002;63:6-17 23. May PA, Brooke L, Gossage JP, Croxford J, Adnams C, Jones KL, Robinson L, Viljoen D. Epidemiology of fetal alcohol syndrome in a South African community in the Western Cape Province. Am J Public Health. 2000;90:1905-1912 24. Adams MS, Niswander JD. Birth weight of North American Indians. Hum Biol 1968;40:226-234. 25. Adams MS, Niswander JD. Birth weight of North American Indians: A correction and amplification. Hum Biol 1973;45:351-357 26. Maynard JE, Hammes LM. A study of the growth, morbidity and mortality among Eskimo infants of western Alaska. Bull World Health Org. 1970;42:613-622. Conflict of Interest: None declared

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