Heterogeneity of symptomatology in two male siblings with thymine uraciluria

Abstract

We report studies in two brothers found to have thymine uraciluria (McKusick 274270). The diagnosis was initially made during the neonatal period of the younger boy (Y.R.). He was born at term plus 10 days to first-cousin Asian parents, weighing 3.90kg (on the 10th centile). Twenty-one hours after delivery the baby was lethargic and feeding poorly. Tube feeding was necessary for the first three days of life due to poor suck. He had bilateral hydroceles and a large anterior fontanelle. Head circumference was 32.5 cm (below the 3rd centle) and length 52.5 cm (on the 90th centile). He was fel~ to have coarse facial features with a bulbous nose, held his neck in extension and had a feeble cry. Analysis of urinary organic acid excretion led to the discovery of thymine uraciluria. Y.R. has two older siblings, a 6-year-old sister (N.R.) and a 5-yearold brother (H.R.). Both are healthy and attend normal school. H.R., however, has been found to have the same biochemical defect as Y.R. He does not share any of the dysmorphisms and had a normal neonatal history. His head circumference of 53 cm lies between the 50th and 98th centiles for age. His language development appears normal, but he does have problems with phonology for which he is receiving speech therapy. Urinary purines from the siblings have subsequently been quantified by highpressure liquid chromatography. The proband had uracil and thymine excretions of 582 and 519/zmol/mmol creatinine, respectively. His older brother was found to have similarly elevated excretions at 313 and 170/.tmol/mmol creatinine, but the same metabolites were not increased in his 6-year-old sister (15 and 1/.tmol/mmol creatinine). The enzyme dihydropyrimidine dehydrogenase has been measured in leukocytes from Y.R. and his parents. There was no detectable activity in cells from the index case, whereas the parents had activities approximately half those of normal controls: father 2.76, mother 2.45, control 5.0 nmol/h per mg protein. Thymine uraciluria was first described by van Gennip (1981) in a 4-year-old boy with transient seizures, speech retardation and behavioural problems. Since that time, 19 other affected children have been reported, 13 of whom have been from Holland. There has been considerable clinical heterogeneity but with a predominance of neurological abnormality. The more severely affected children often have microcephaly. A number of affected adults have been described who are quite healthy and are detected either during family studies or following a severe neurotoxic reaction to the drug 5-fluorouracil. The enzyme dihydropyrimidine dehydrogenase is necessary for the metabolism of this chemotherapeutic drug. The observations in the family described here clearly illustrate that there can be considerable phenotypic variabilty, even within a family. This is also the first report of this condition among people of Asian origin, and the first case in the United Kingdom.