Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene.

The WNT1 gene is crucial for bone development and homeostasis. Homozygous mutations in WNT1 cause severe bone fragility known as osteogenesis imperfecta type XV. Moreover, heterozygous WNT1 mutations have been found in adults with early-onset osteoporosis. We identified a 35 year-old Caucasian woman who experienced multiple vertebral fractures two months after her second pregnancy. There was no history of risk factors for secondary osteoporosis or family history of osteoporosis. Dual-energy X-ray absorptiometry confirmed a marked reduction of bone mineral density (BMD) at the lumbar spine (0.734 g/cm2, Z-score -2.8), femoral neck (0.48 g/cm2, Z-score -3.5), and total hip (0.589 g/cm2, Z-score -3.0). Blood tests excluded secondary causes of bone fragility. Genetic analysis revealed a heterozygous missense mutation (p.Leu370Val) in the WNT1 gene. Varsome classified it as a variant of uncertain significance. However, the fact that the Leucine residue at position 370 is highly conserved among vertebrate species and the variant has a very low allelic frequency in the general population would exclude the possibility of a polymorphism. The patient was treated for two years with teriparatide therapy associated with calcium and vitamin D supplements. During the follow-up period she did not report further clinical fractures. After 24 months of teriparatide, BMD increased at lumbar spine (+14.6%), femoral neck (+8.3%) and total hip (+4.9%) compared to baseline. We confirm that the heterozygous WNT1 mutation could cause a variable bone fragility and low turnover osteoporosis. We suggest that teriparatide is one of the most appropriate available therapies for this case.

Pharmacogenetics of anti-estrogen treatment of breast cancer.

A major effort is underway to select genetic polymorphisms potentially relevant to the clinical efficacy and safety of endocrine treatment of breast cancer. Genetic factors of the host that affect the metabolism of tamoxifen, a widely used drug for the adjuvant treatment of breast cancer, have received particular attention. Cytochrome P450 isoform 2D6 (CYP2D6) is a key step in the metabolism of tamoxifen to its active moiety endoxifen. Women with functionally deficient genetic variants of CYP2D6 who are given drugs that inhibit CYP2D6 are exposed to low endoxifen plasma levels and may enjoy reduced benefits from tamoxifen treatment. Therefore, CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; unfortunately, the data are not uniformly concordant, and definitive evidence that would suggest the routine analysis of CYP2D6 before commencing tamoxifen treatment is not yet available. Recent research has focused on the role UDP-glucuronosyltransferases, a family of metabolizing enzymes that play an important role in the metabolic clearance of tamoxifen and of the aromatase inhibitors as well, and how interindividual differences in these enzymes may play a role in the clinical outcome upon administration of anti-estrogen treatment. In conclusion, whether a pharmacogenetic profile should be obtained prior to initiating tamoxifen therapy is currently a matter of debate, although summing up all the scientific evidence available on this issue it appears that the genetic screening would be an useful support for clinical decision making in selected patients.