CIFASD: Dysmorphology Core Kenneth L. Jones Ludmila Bakhireva Luther K. Robinson H. Eugene Hoyme Miguel del Campo Christina D. Chambers June, 2005 Santa Barbara, CA First of all, I would like to thank my collaborators: …… who encouraged me to pursue this topic and provided valuable feedback during the entire process. I also would like to thank my husband, Alexei Bakhirev, for his support, understanding, and willingness to listen to me as I worked my way through this project

Progress Report of the Dysmorphology Core (DC): DC Exam Form: finalized DC Manual for Pediatricians: finalized Access Data Input Tool: field tested, modified accordingly: Race/ethnicity fields included Country of origin Validation rules implemented Data obtained from 6 sites (N=467 as of April 05) Preliminary data analysis conducted Osteoporosis and atherosclerosis are usually thought to be two independent processes that occur with aging. However, there is an increasing interest that these conditions are associated. Links between the two conditions were first noted more than one hundred years ago by German Pathologist Rudolf Virchow who first reported morphologic similarities between calcified plaque and bone tissue. Roentgenographic studies in the 1970s showed an association between calcification of the abdominal aorta and osteoporosis of the lumbar spine Recent molecular biology studies discovered cells with both osteoblastic and osteoclastic potential in vascular tissue, and bone-related proteins have been identified in calcified arterial and valvular lesions. Historically, this ectopic calcification was considered a degenerative process leading to passive precipitation of calcium phosphate. Molecular biology revealed that artery calcification is in fact an active process which is regulated by biological mechanisms similar to those of bone formation

Clinical Sites which Submitted Data to the Central Repository (N=467) % from total Luther Robinson, Buffalo 93 19.9 Phil May, Rome 213 45.6 Sarah Mattson, San Diego 23 4.9 Sarah Mattson, Moscow 50 10.7 Sarah Mattson, Finland 67 14.3 Sandra Jacobson, South Africa 21 4.3

Number of Children Examined by Each Pediatrician-Dysmorphologist Examiner N % from total Hoyme 138 29.6 Jones 83 17.8 Khaole 21 4.5 Robinson 192 41.1 Del Campo 33 7.1

Description of the Sample (N=467)

Specific Aims: Which cut-off point (≤10th % vs ≤3rd %) for weight, height, and OFC is better predictor of FAS. Define the best cut-off point for PFL. Examine whether PFL is independent from OFC measure. Identify the prevalence of all key and additional structural features among children with FAS.

Specific Aim # 1: Proportion of Growth Deficient Children (among FAS-diagnosed) at Each Cut-off:

Specific Aim # 1 (cont’d): Sensitivity & Specificity of FAS Diagnosis at Each Cut-off for Each Parameter of Growth

Specific Aim # 1 (cont’d): Sensitivity & Specificity of FAS Diagnosis at Each Cut-off for Each Parameter of Growth

Specific Aim # 2 Define Best Cut-off Point for PFL Research question: Among children with FAS (N=113), define a proportion with short PFL at each cut-off point: PFL≤3rd percentile: 47.8% PFL ≤10th percentile: 81.4% PFL ≤25th percentile: 91.2%

Specific Aim # 2 (cont’d) Define Best Cut-off Point for PFL Research question: Estimate the effectiveness of each cut-off point for PFL percentile (0-100) as a continuous measure to discriminate between FAS-positive & FAS-negative children.

Specific Aim # 2 (cont’d) Define Best Cut-off Point for PFL Methods: Receiver Operating Characteristic (ROC) curve was used ROC curve is the plot of sensitivity vs 1-specificity of FAS diagnosis for all possible threshold values of PFL percentile

Specific Aim # 2 (cont’d) Results PFL percentile of ’10’ has the best ability to differentiate between FAS+ & FAS- children PFL%=10: Sensitivity=82%, Specificity=96% PFL%=25 has too low specificity (75%) PFL%=3 has too low sensitivity (48%)

Specific Aim # 3 Examine whether PFL is Independent from OFC Measure. Research question: Among FAS+ kids with normal OFC, what is a proportion of children with short PFL : N= 24 (children w/ FAS who have normal OFC) PFL≤3rd percentile: 20.9% PFL ≤10th percentile: 66.7%

Specific Aim # 3 (cont’d) Correlation b/w OFC & PFL (all children) Correlation Coefficient (R) = 0.54 (p=<0.0001) R2 = 0.29 29% of the variation in PFL can be explained by variation in OFC 71% of the variance in PFL is due to factors other than OFC

Specific Aim # 3 (cont’d) Correlation b/w OFC & PFL (all children)

Specific Aim # 3 (cont’d) Correlation b/w OFC & PFL (FAS children) Correlation Coefficient (R) = 0.32 (p=<0.001) R2 = 0.10 10% of the variation in PFL can be explained by variation in OFC 90% of the variance in PFL is due to factors other than OFC

Specific Aim # 3 (cont’d) Correlation b/w OFC & PFL (FAS children)

Key Structural Feature Specific Aim # 4: Prevalence of Key Structural Features among Children Diagnosed with FAS Key Structural Feature Prevalence (%) PFL≤10th percentile 81.1 Smooth philtrum 83.2 Thin Vermilion border 86.7

Additional Structural Feature Specific Aim # 4 Sensitivities & Specificities of Additional Structural Features Additional Structural Feature Sensitivity (%) Specificity (%) Railroad track configuration of ears 10.6 97.7 Ptosis 13.3 98.1 Camptodactyly 40.7 94.4 Difficulty in pronation/supination of elbows 8.9 Contractures in other joints 4.4 98.6 Hockey stick crease 24.8 91.6 Other altered palmar creases 21.2 93.5 Heart murmur 99.5

Conclusions For Weight, Height, OFC cut-off point at 10th percentile yields much higher sensitivity of FAS diagnosis with very insignificant loss in specificity compared to the 3rd percentile Best cut-off point for PFL in diagnosing FAS is 10th percentile Only 29% variability in PFL can be explained by OFC among all children & only 10% among children with FAS.

Conclusions (cont’d) Among key structural features, thin vermilion border has the highest prevalence among children with FAS. Among additional structural features, camptodactyly occurs with the highest frequency among children with FAS diagnosis followed by altered palmar creases