Aut-dom, Fibrillin defect (scaffolding for elastin formation - stretchy protein for lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava). Connective tissue disorder: skeleton, heart, eyes affected. Tall, long extremities, pectus excavatum, hyperextensive joints, arachnodactyly (long, tapering fingers / toes). Cystic medial necrosis of aorta -> aortic incompetence, dissecting aortic aneurysms; floppy mitral valve; subluxation of lenses. Trisomy 21; MR, flat facies, epicanthal folds, simian crease, gap btwn 1-2nd toes, duodenal atresia, congenital heart dz (esp septum-primum-type ASD), a/w inc risk ALL, Alz dz (>35 y/o). #1 cause congenital MR; #1 chr disorder (1:700). 95% from meiotic nondisjunction of homologous chr (a/w advanced maternal age, 1:25 > 45y/o), also Robertsonian translocation (4%). Screening: pregnancy quad screen (dec AFP, inc B-hCG, dec estriol, inc. inhibin A); U/S: inc. nuchal translucency Aut-rec deficiency of phenylalanine hydroxylase / THB (cofactor), so can't convert phenylalanine to tyrosine. Results: accumulate phenylalanine (excess phenylketones in urine); tyrosine becomes essential AA. Dx: MR, growth retardation, seizures, eczema, musty body odor ("aromatic" amino acids). Tx: don't eat phenylalanine (aspartame=Nutrasweet, etc), increase tyrosine in diet. Screening: 2-3 days after birth. Maternal PKU (no proper diet therapy during pregnancy) - baby has microcephaly, MR, growth retardation, congenital heart defects.