[Late diagnoses of 21-hydroxylase deficiencies in children (after the age of 3 years].

To evaluate the heterogeneity of 21-hydroxylase deficiency with delayed symptoms, clinical and laboratory findings at presentation in 29 patients whose first symptoms occurred after three years of age were analyzed retrospectively. In 12 patients, these data were confronted with the results of molecular CYP21B gene analysis. Age at onset was 7 years on average and was comparable in boys and girls. Premature puberty was the most common presenting symptom [n = 24], whereas hirsutism, clitoral enlargement, and menstruation disorders were less frequent. Six cases were diagnosed as the result of routine studies of family members of index patients. The bone age over statural age ratio was greater than 1 in 19 of the 27 patients. Baseline 17-OH-progesterone levels were elevated in 22 of the 27 patients; magnitude of the elevation varied widely. Levels of 17-OH-progesterone after stimulation with immediate-action tetracosactide were closely correlated with baseline values and established the diagnosis in doubtful cases. Four patients had post-stimulation 17-OH-progesterone levels under 10 ng/ml, suggesting that were heterozygous for the disease. An important finding was that the magnitude of the devation in 17-OH-progesterone was not clearly correlated with clinical findings at presentation (age at onset, growth rate, advance in bone age). Molecular CYP21B gene analysis performed in 12 patients disclosed a homozygous 281 Val Leu mutation in 6 cases. This is the most commonly reported mutation in delayed onset forms. Two patients were heterozygous for the 281 Val Leu mutation and had an allele associated with severe disease, suggesting that the least severely affected chromosome governed clinical presentation of the disease. One boy had an allele associated with neonatal onset on both chromosomes; molecular analysis indicated a risk of antenatal masculinization of female fetuses in this family. This study showed that delayed onset 21-hydroxylase deficiency is a heterogeneous entity and that molecular analysis is essential to genetic counseling.