In 1974 new forms of hyperphenylalaninemia were described. They were characterized by normal liver phenylalanine hydroxylase activity and were unresponsive to restricted phenylalanine dietary treatment. Since then, many steps were moved on the way to clarify the biochemical basis of these forms, once called ''atypical'' or ''malignant'' phenylketonuria, and now defined as ''tetrahydrobiopterin deficiency''. Three enzymatic defects have been so far identified as leading to tetrahydrobiopterin deficiency: guanosine-triphosphate cyclohydrolase deficiency, pyruvoyl-tetrahydropterin synthase deficiency and dihydropteridine reductase deficiency. Recently a new form of hyperphenylalaninemia was described; it was called primapterinuria and it is characterized by elevated urinary excretion of 7-substituted biopterin. All the variants can be differentiated by means of urinary pterins determination, of tetrahydrobiopterin oral loading test and of various enzymatic activity assays. In our experience, all the hyperphenylalaninemic children must be investigated for tetrahydrobiopterin deficiency
