Salt wasting phenotype in a compound heterozigous girl with P482S mutation associated with a novel mutation of CYP21 gene (Q481P)

The arsenal of molecular lesions that are known to cause 21-hydroxylase deficiency (21-OH-D) congenital adrenal hyperplasia (CAH) includes both deletions of CYP 21 gene and single amino acid substitutions in the 21-OH protein, which can result in varying degrees of enzyme activity impairment. Recently , a proline (P) to serine (S) substitution at codon 482 was reported in 7 patients with either non-classical (NC) form of CAH or heterozygous status. In that report such a mutation was found to reduce enzyme activity to approximately 70% and the authors concluded that P482S mutation should be added to the list of mutations that are to be analyzed in cases where the mildest forms of CAH are suspected, especially in subjects of Italian ancestry. Since that report no other cases with the same mutation have been described in the literature. Here we report another Italian patient with the same mutation, who presented with a very severe clinical picture of salt wasting (SW) CAH, as opposed to the cases by Barbaro et al.. The aims of this letter are: a) to confirm the possible occurrence of that mutation even in individuals with classical CAH; b) to report for the first time a novel mutation of CYP21 gene (http://www.imm.ki.se/Cypalleles/cyp21.htm). Our patient had one allele (of maternal origin) with a cytosine (C) to thymine (T) transition, that caused a P to be replaced by an S at codon 482 (P482S). In the other allele (of paternal origin), DNA analysis revealed the presence of the severe intron 2 splice mutation, which is known to be associated with a classical form of CAH in homozygous subjects. Apart from those 2 mutations, however, our patient exhibited an additional mutation, which had never been described hitherto. In fact, in the maternal strand, very contiguous to P482S mutation, our girl had an adenine (A) to C transition that caused a glutamine (Q) to be replaced by a P at codon 481 (Q481P) . The presence of this novel mutation in our patient may probably be responsible for a further, dramatic reduction of 21-OH activity. The coexistence of 2 mutations (P482S and Q481P) on the same strand can probably account for a severe impairment of enzyme activity and, therefore, for the phenotypical expression of CAH observed in our girl. To sum up: a) if associated with other mutations, in the contiguous codon of the same strand, P482S mutation can be responsible for a severe form of CAH; b) Q481P mutation should be added to the list of mutations which are to be analyzed in the patients with CAH. G. Di Pasquale1, M. Wasniewska1, M. Caruso2, G. Salzano1, M. Coco2, F. Lombardo1, and F. De Luca1 1Department of Pediatrics, University of Messina, Messina; 2Department of Pediatrics, University of Catania, Catania, Italy