Therapeutic challenges in a patient with the simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) due to the P30L/I172N genotype.

Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90-95% of all cases with congenital adrenal hyperplasia (CAH). The classical simple virilizing (SV) form of the disease causes virilization of the external genitalia in newborn females and pseudo-precocious puberty in both sexes, due to reactive androgen overproduction. Case presentation We describe a 3.5-year-old girl presenting with pubarche, P2 according to Tanner, advanced bone age of 6 years and 10 months, and high serum levels of 17-hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mother and a severe I172N mutation from her father. Conclusions Although the CAH phenotype is determined by the allele that produces most of the enzyme activity and the mild non-classical (NC) phenotype should be expected, the mild P30L known to be more virilizing probably induced the classical SV phenotype in our patient. A continuous regimen of hydrocortisone at a recommended dose failed to decrease the 17-OHP sufficiently. Careful tapering of the dose did not help, and her pubic hair advanced to P3 according to Tanner. Individually tailored treatment is warranted in this patient.

Range-wide genetic structure of maritime pine predates the last glacial maximum: evidence from nuclear DNA.

Using nuclear simple sequence repeats (nuSSRs), we determined the genetic variability in the natural distribution range of maritime pine (Pinus pinaster) in the western Mediterranean region. We analysed the role of global and significant climatic fluctuations in driving the evolutionary diversification of this species. We attempted to determine the impact of the last glacial maximum (LGM) and human activity on genetic variation and to identify the effect of bottlenecks, admixing, migration, time to the most recent common ancestor (TMRCA), and recent splits. A total of 972 individuals were analysed. The sample represented 27 natural populations from the western Mediterranean region, which encompasses most of the natural range of P. pinaster. Using eight nuSSRs, we analysed genetic diversity indices for each population and group of populations. We also examined the interpopulation structure by the frequency and distance method and investigated genetic barriers, signals of historical demographic fluctuations, phylogeographic structure, admixing, rate of mutation, migration, as well as testing the hypothesis of isolation by distance (IBD). Both cluster analyses showed similar population genetic structure with three genetic barriers that divided the samples into four large groups. Intensive migration was only detected during the period of the last glacial maximum (LGM), which permitted the mutation rate of the markers used to be calculated. The majority of the population was found to exhibit signs of a recent bottleneck and its timing showed a clear northeast-southwest geographic distribution. A clearly defined phylogeographic structure (Nst > Gst and Rst > Gst ) under IBD was established, and showed the highest divergence between groups of populations separated by physical barriers, such as the Strait of Gibraltar, the Mediterranean Sea and the Pyrenees. The high level of intergroup genetic differentiation (ΦIS = 20.26) was attributed to a long historical isolation (which occurred before the last 18 000 years) between the principal maritime pine population groups that occurred due to physical barriers that limited pollen and seed transfer, combined with a minimal effective radius of distribution. The low level of genetic diversity among the populations was combined with genetic drift and a recent bottleneck during the period of human activity. Significant migration across barriers was due to spontaneous phenomena during the LGM, which had no significant impact on the genetic structure owing to its relatively short duration and the fragmented species. The phylogeographic structure under the assumption of IBD was well established for P. pinaster in each of the principal population groups.