Sir: Transient neonatal tyrosinaemia is thought to be caused by late maturation of the hepatic enzymes 4-hydroxyphenylpyruvate dioxygenase and tyrosine aminotransferase [4]. In addition to prematurity, high protein intake and ascorbate deficiency are suggested as risk factors [2]. Although transient tyrosinaemia is a benign condition, lethargy and reduced motor activity have been reported in some cases [3]. We recently identified two female preterm newborns who presented with hyperphenylalaninaemia. One was identified at 4 days of age with a plasma phenylalanine level of 545 gmol/1 and the other at 14 days with a phenylalanine level of 1210 btmol/1. Both infants developed transient tyrosinaemia after a challenge with tetrahydrobiopterin (BH4) (20 mg/kg body weight). Phenylalanine concentration in plasma decreased within 4-8 h in response to the challenge (Table 1). Simulta neously, however, plasma tyrosine rose in almost equimolar amounts. A lower dose of BH 4 (5 mg/kg per day) restored plasma tyrosine and phenylalanine to normal levels in both infants. Tyrosine metabolites in urine were increased after administration of 20 mg tetrahydrobiopterin/kg body weight (4-hydroxyphenylpyruvic acid: 90-120 mmol/mol creatinine, 4-hydroxyphenyllactic acid: 210-1100 mmol/mol creatinine, and 4-hydroxyphenylacetic acid: 50-190 mmol/mol creatinine), suggesting immature 4-hydroxyphenylpyruvate dioxygenase in our patients. However, low tyrosine aminotransferase activity cannot be excluded. Both infants were later diagnosed to be deficient in 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the biosynthesis of the cofactor BH4 [1]. Very high urinary and cerebrospinal fluid (CSF) neopterin, absent or very low urinary and CSF biopterin, and absent 6-pyruvoyltetrahydropterin synthase activity in erythrocytes were determined in both infants. The patients are now 2 months, and 3 years 4 months old, on regular diets with supplements of BH4 (5 mg/kg body weight day) in combination with the neurotransmitter precursors L-dopa and 5-hydroxytryptophan. BH 4 challenges are commonly used in the differential diagnosis of hyperphenylalaninaemia. Plasma phenylalanine and tyrosine concentrations in normal and phenylketonuric term infants are not affected after administration of BH4. In contrast, patients with inherited BH 4 deficiencies respond to BH 4 administration by normalizing plasma phenylalanine concentrations usually within 4 h after a challenge and there is only a marginal increase of tyrosine which normalizes in 4 h. In normal premature newborns the initial enzymes in the tyrosine catabolic pathway usually tolerate a protein intake of up to 5 g/kg per day. However, in premature hyperphenylalaninaemic patients, tyrusine tolerance is markedly reduced and therapy with relatively high doses of BH4 seems warranted.