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1 Disclosure Statement I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider of commercial services discussed in this CME activity. I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation. H. Eugene Hoyme, MD, FAAP, FACMG
2 Clinical Diagnosis of Fetal Alcohol Spectrum Disorders: A Practical Approach H. Eugene Hoyme, MD Chief Academic Officer, Sanford Health President and Senior Scientist, Sanford Research Professor of Pediatrics (Medical Genetics) Sanford School of Medicine The University of South Dakota
3 Learning Objectives List the domains that should be assessed in evaluating a child prenatally exposed to alcohol. Describe the dysmorphology examination of a child prenatally exposed to alcohol. Compare and contrast the Revised Institute of Medicine Diagnostic Criteria for fetal alcohol spectrum disorders (FASD) with other diagnostic schemes. Describe progress in determining a specific neurobehavioral phenotype in FASD. Discuss common phenocopies of FASD.
4 Fetal Alcohol Spectrum Disorders Fetal alcohol spectrum disorders (FASD) refers to the continuum of disabilities associated with the adverse effects of prenatal alcohol exposure. According to the 1997 Institute of Medicine report, FASD comprises four diagnostic categories* Fetal alcohol syndrome (FAS) Partial fetal alcohol syndrome (PFAS) Alcohol related birth defects (ARBD) Alcohol related neurodevelopmental disorder (ARND) *Stratton, et al., 1997
5 Diagnostic Systems The FASD clinics of the Center for Disabilities of the Sanford School of Medicine use the Institute of Medicine (IOM) Revised Criteria (Hoyme, et al, 2005). Others are available which are quite similar: Canadian criteria (Chudley, et al, 2006). Centers for Disease Control (2006). (FAS only) Four Digit Code System (Astley).
6 Current Diagnostic Schemes for FASD + Hoyme HE, et al: A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: Clarification of the 1996 Institute of Medicine criteria. Pediatrics 115: 39-47, Washington Criteria CDC Guidelines Revised IOM Criteria + Canadian Guidelines *4 digit code: - Scores assigned for growth deficit, facial phenotype, CNS damage, and prenatal alcohol exposure -yields 256 combinations, collapsing into 22 categories *FAS: -All three cardinal facial features -Growth deficit -CNS dysfunction (structural and/or functional) *FAS (with/without confirmed alcohol exposure): -2 of 3 cardinal facial features -Growth deficit -Structural CNS anomaly (microcephaly and/or other structural CNS defect) *Partial FAS (with/without confirmed alcohol exposure: -Facies as above -One of other major features *ARBD: -Facies as above -Nl growth/development *FAS (with/without confirmed alcohol exposure): -Growth deficit -3 of 3 cardinal facial features ->3 of 11 abnormalities in specific CNS domains *Partial FAS (with confirmed maternal alcohol exposure) -2 of 3 cardinal facial features ->3 of 11 abnormalities in specific CNS domains -Specific malformations *ARND: *ARBD: -Specific malformations -Nl structure/growth -Spec. neurobehavioral profile *ARND: ->3 of 11 abnormalities in specific CNS domains
7 Diagnoses of FASD Should be Multidisciplinary Diagnoses should be assigned after gathering data from multiple sources: Dysmorphology examination Behavioral assessment Psychological/Neuropsycological testing Maternal interview
8 Typical Facial Characteristics of the Fetal Alcohol Syndrome
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10 Importance of Precision in Collection of Dysmorphology Data
11 FASD Dysmorphology Assessment: Tools of the Trade In the dysmorphology examination, in addition to the usual tools used in physical examination, the physician needs a tape measure (ruled in millimeters), a rigid ruler (ruled in millimeters) and the lip/philtrum guide*. * Order from the FAS Diagnostic and Prevention Network, University of Washington: order.pdf
12 Dysmorphology Data Collection The approach to the dysmorphology diagnostic assessment should be structured. Avoid gestalt diagnoses. Height, weight and head circumference should be measured and plotted using population specific growth curves if available. Facial anthropometry should be measured live and centiles calculated. Palpebral fissure length, inner canthal distance, philtrum length
13 Measurement of Head Circumference: 1. Obtain the largest value possible when positioning the tape. 2. Pull snug to flatten down the hair.
14 Facial Anthropometrics to be Measured for Diagnosis and Scoring: 1 Palpebral fissure length (the left is measured by convention) 2 Inner canthal distance 3 Philtrum length Inner canthal distance Palpebral fissure length Philtrum length
15 Normal Facial Proportions: The inner canthal distance is ideally the same as each palpebral fissure length.
16 Technique formeasuring Palpebral Fissure Length: 1 Subject and examiner are seated at the same level, with the subject facing forward. 2 Keeping the chin level, the subject is asked to look up at the ceiling. 3 The measurement is made by bringing the ruler as close to the eye as possible, without touching the lashes. (The bottom of the ruler can be rested on the cheek for stability while recording the measurement).
17 Note that the ruler is angled slightly to follow the curve of the maxilla
18 Accurate Measurement of Palpebral Fissure Length NOTE: When measuring the palpebral fissure, the ruler must be angled to follow the curve of the maxillary bone. Otherwise a falsely short value will be obtained. B A C Length C is the true palpebral fissure length; Length A is what would be measured from a 2-D photograph. (C 2 =A 2 + B 2 )
19 Difficulties in 2D Photographic Measurement of Palpebral Fissures As illustrated, 2D photographic measurement of palpebral fissure length (PFL) would theoretically consistently undermeasure the true length. In a recent study by Cranston et al*, 2D photometric software measurements consistently measured the PFL smaller than live caliper measurements of the PFL. Live caliper measurements and photometric measurements were concordant only 18% of the time. *Cranston ME et al.: Can J Clin Pharmacol. 16(1):e234-41, 2009.
20 Dysmorphology Data Collection Assess morphology of the philtrum and vermilion border of the upper lip Use racially specific lip/philtrum guide if possible Assess ear morphology Assess neck mobility Perform oral examination Perform cardiac examination Examine extremities Pronation/supination at the elbow Palmar crease morphology Assess for clinodactyly/camptodactyly Assess nail morphology
21 The Lip/Philtrum Guide* Courtesy of M. Muenke, MD, NHGRI *Astley SJ, Clarren SK. Diagnosing the full spectrum of fetal alcohol-exposed individuals: introducing the 4-digit diagnostic code. Alcohol Alcohol. 35(4):400-10, 2000.
22 Use of the Lip Philtrum Guide: 1. Separate scores are assigned for the philtrum and the vermilion border of the upper lip. 2. In this subject, the philtrum scores a 2 and the vermilion a 1.
23 1. In this South African child with FAS, the philtrum scores a 5 and the vermilion a Scores of 4 or 5 are compatible with FASD.
24 **Examination of the face at 45 degrees often allows for better definition of the philtral columns. **The configuration of the ear is recorded.
25 South African Mixed Race Lip/Philtrum Guide* *Hoyme DB, Hoyme HE, Jones KL et al: A South African Mixed Race Lip/Philtrum Guide for Diagnosis of Fetal Alcohol Spectrum Disorders. Western Society for Pediatric Research, Carmel, California, January J Investigative Med, 2010.
26 Arms and Hands are Evaluated for: 1. Pronation/supination at the elbow th finger clinodactyly 3. Camptodactyly 4. Palmar creases 5. Nail anatomy
27 Use of Standards to Assess Anthropometry Once physical examination is complete, use standardized growth references to assess growth. CDC Growth Charts: Anthropometry norms: Greenwood Genetic Center: Growth References (Third Trimester to Adulthood)
28 Common Minor Anomalies in FASD
29 Railroad Track Ear Hockey Stick Palmar Crease 5 th Finger Clinodactyly and Hockey Stick Palmar Creases
30 The Dysmorphology Score (Adapted from Aase) Autti-Rämö I, Fagerlund Å, Ervalahti N, Korkman M, Hoyme HE: AJMG A 140(2):137-43, 2006 Feature Points Feature Points Weight<10% 1 Anteverted Nares 2 Height<10% 2 Long Philtrum 2 OFC<10% 3 Smooth Philtrum 3 ICD<10% 0 Thin Vermilion 3 Palp Fiss<10% 3 Prognathism 0 ADHD 1 Cardiac Murmur 1 Fine Motor Dysfn 1 Hypoplastic Nails 0 Midface Hypoplasia 2 Radioulnar Syn 2 Railroad Track Ears 1 Clinodactyly 1 Strabismus 0 Camptodactyly 1 Ptosis 2 Hockey Stick Creases 1 Epi Folds 1 Hirsutism 1 Flat Nasal Bridge 1 Tot Poss Dys Score 35
31 Utility of the Dysmorphology Score Although not used to make an FASD diagnosis, the Dysmorphology Score is a very useful research tool. A revised Dysmorphology Scoring tool currently is being evaluated based on experience with >1000 children with FASD in the US, Italy and South Africa. The Total Dysmorphology Score correlates with: Maternal drinking (higher score/more EtOH exposure) IQ (higher score/lower IQ) Behavior problems (lower score/more behavior problems) Developmental outcome (higher score/more diffculty in school performance)
32 Case Conference Present dysmorphology/medical data first Specifically rule out other malformation syndromes Is this case FASD plus? Remember that one of the precepts of dysmorphology/clinical genetics is that while children with common malformation syndromes need not have all of the described characteristics of a particular condition, if the child under consideration has a feature undescribed in the disorder, the diagnosis should be questioned.
33 Case Conference Present educational/psychological assessment Include review of educational records (if available) Present neuropsychological assessment Assign diagnostic category Other malformation syndrome/medical condition FASD diagnostic category Normal child; not FASD
34 Case Conference Follow-up planning Intervention OT/PT/Speech therapy Classroom modification Behavioral modification Other medical evaluations/consultations e.g., cardiology, audiology, ophthalmology Laboratory/imaging studies Follow-up visits
35 Case Conference for final diagnosis
36 How Well Do the Revised IOM Diagnostic Criteria Demonstrate the Spectrum of FASD? Objective Correlates with Revised IOM Diagnosis: Dysmorphology score (Autti-Rämö et al: AJMG: 14:137-43, 2006) Highest scores: FAS Intermediate scores: PFAS Lowest scores: ARND Maternal alcohol use (Jacobson et al: ACER 32:365-72,2008) Highest: FAS Intermediate: PFAS Lowest: ARND Eyeblink conditioning (Jacobson et al: ACER 32:365-72,2008) a Pavlovian paradigm that in animals prenatally exposed to alcohol accompanies a loss of neurons in the inferior olive and cerebellar cortex and deep nuclei FAS: none conditioned PFAS children: one third conditioned Control children: all conditioned
37 Debated Aspects of the Current Diagnostic Criteria Should 2 or 3 cardinal facial features be required for a diagnosis of FAS? Should the 3 rd centile or the 10 th centile constitute the cutoff for OFC, height and weight in FAS and PFAS? Should the diagnosis of PFAS be made without direct confirmation of maternal drinking? What constitutes the specific neurobehavioral profile diagnostic of an FASD? Should this specific neurobehavioral profile be confirmed to make a diagnosis of FAS or PFAS? Should PFAS, ARBD and ARND be the terms used to describe FASD on the milder end of the continuum? Our approach has been to design criteria that are the most inclusive, taking into account all of the domains evaluated in assessing childrens with prenatal alcohol exposure: quantification of maternal drinking, psychological/neuropsychological profile and dysmorphology.
38 Facial Features and Diagnosis In the first six finalized waves of population-based screening* by May et al using the Revised IOM Criteria: (% with) FAS PFAS Not FASD 3 features features or less * (SA, Italy, and US, n=1001)
39 Sensitivity and Specificity with Three Facial Features If the cut off requires all three facial features for a diagnosis of FAS: Sensitivity = Specificity = Predictive value (in isolation) = Not totally sensitive, but specific. In isolation they are not strong predictors of FAS.
40 Sensitivity and Specificity with Two Facial Features If the cut off required two cardinal features for a diagnosis of FAS: Sensitivity = Specificity = Predictive value (isolated) = Sensitive but not as specific. Again, taken alone they are not adequate predictors of FAS.
41 How Close Are We to a Specific Neuropsychological Profile of FASD? A large cohort of children with FAS, heavily alcoholexposed children (not meeting diagnostic criteria for FAS) and control children were identified through CIFASD* +. All underwent an extensive battery of neuropsychological tests that assessed: Executive function Spatial learning and memory Fine motor speed Visual motor integration *Collaborative Initiative on Fetal Alcohol Spectrum Disorders + Mattson et al: ACER 34: , 2010
42 How Close Are We to a Specific Neuropsychological Profile of FASD? Tests of executive function and spatial reasoning were most predictive of prenatal alcohol exposure. The profile distinguished subjects with FAS from controls with 92% accuracy. The profile distinguished subjects with heavy prenatal alcohol exposure (without FAS) from controls with 85% accuracy. A combination of tests assessing these variables is most likely to be useful in assessing the neurodvelopmental profile of an alcohol exposed subject (along with dysmorphology examination and data on maternal drinking). + Mattson et al: ACER 34: , 2010
43 Phenocopies of FASD Children with other genetic and dysmorphic syndromes are born as frequently to women who abuse alcohol as they are to other women. Avoid automatically assigning an FASD diagnosis to a child with disabilities just because his or her mother drank alcohol in pregnancy. Remember: FASD is a diagnosis of exclusion!
44 Representative Genetic Syndromes Displaying Some of the Features of FASD Williams syndrome/delange Syndrome/VCFS
45 Future Trends in FASD Diagnostic Methodology
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