Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, encoded by CYP21A2 gene, is an autosomal recessive disorder. The CYP21A2 gene, localized in a genetic unit defined RCCX module, is considered one of the most polymorphic of human genes.

We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 33 Italian PKU families. Mutational screening of the known coding region, including conventional intron splice sites, was performed by direct sequencing of the patients' genomic DNA. Thirty-three different disease causing mutations were identified in our patient group, including 19 missense, 6 splicing, 3 nonsense, 5 deletions, with a detection rate of 100%. The most prevalent mutation was the IVS10-11G>A, accounting for 12.1% of PKU alleles studied. Other frequent mutations were: p.R261Q (9.1%), p.P281L (7.6%), and p.R408W (6.1%). We also identified one novel missense mutation, p.H290Q. A spectrum of 31 different genotypes was observed and a genotype based predictions of BH4-responsiveness were assessed. Among all genotypes, 13 were predicted to be BH4-responsive represented by thirteen PKU families. In addition, genotype-phenotype correlations were performed. This study reveals the importance of a full genotyping of PKU patients and the prediction of BH4-responsiveness, not only because of the definitive diagnosis and prediction of the optimal diet, but also to point out those patients that could benefit from new therapeutic approach. They may potentially benefit from BH4 therapy which, combined with a less strict diet, or eventually in special cases as monotherapy, may contribute to reduce nutritional deficiencies and minimize neurological and psychological dysfunctions.

Small supernumerary marker chromosomes (sSMCs) originating from chromosome 10 are rare. A limited number of cases are documented. We report a new diagnosis of a mosaic sSMC (10) in a normal female who asked for genetic evaluation before undergoing controlled ovarian hyperstimulation, in vitro fertilization, and embryo transfer. Chromosome preparations from peripheral lymphocyte cultures were performed according to standard procedures. QFQ-banded chromosomes confirmed the presence of an sSMC: 47,XX,+mar[49]/46,XX[51]. FISH and array CGH analysis showed that the sSMC consisted of chromosome 10 with a gain of the 10p11.1p11.21 (2.5 Mb) chromosomal region. The presence of sSMC (10) was also confirmed in the patient's mother and sister. It did not appear to affect the phenotype of the women who were phenotypically normal and healthy, and at the time of writing the woman became pregnant naturally. Phenotypes associated with an sSMC vary from normal to severely abnormal. It has been shown that variations in the chromosomal region of sSMCs result in observable differences in clinical outcome. The phenotypical consequences of sSMCs are difficult to predict because of differences in euchromatic DNA content, chromosomal origin, and varying degrees of mosaicism. Therefore, the continued investigation of a larger number of sSMC cases, in particular those originating from chromosome 10 that are the infrequently encountered and characterized, and a better understanding of the genetic content is important in order to improve the delineation of karyotype-phenotype correlation, contributing to a more informed prenatal counseling or prognosis.