Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Medial Patellofemoral Ligament Reconstruction in a Revision Setting: Anchor and Interference Screw Fixation

Recurrent patellar instability is a common pathology and typically affects younger and more active patients. To prevent complete lateral dislocation of the patella, several osseous and soft-tissue procedures have been previously described, including reconstruction of the medial patellofemoral ligament (MPFL), which has been identified as the primary medial stabilizer of the patella. Several techniques have been reported for reconstruction of the MPFL, sometimes in conjunction with other procedures, with the majority showing success in the treatment and resolution of patellar instability. However, MPFL reconstruction is not free of complications, with previous reports of recurrence of medial patellar instability and patellar fracture after surgery. The objective of this Technical Note is to describe our preferred technique, comprising anchor as well as interference screw fixation, for reconstruction of the MPFL in a primary or revision setting

Osteochondral Allograft Transplantation for Treatment of Focal Patellar Osteochondral Lesion

Patellar osteochondral lesions are common and particularly disabling injuries that can affect young and highly active patients. If enough functional impairment, ranging from difficulty climbing stairs to pain with squatting, is present, surgical treatment may be warranted. For the treatment of these lesions, various techniques have been described, including autologous osteochondral transplantation, as well as microfracture surgery. However, these are not without disadvantages. Although morbidity is noted in cases of autologous osteochondral transplantation, uncertain and possibly unsustainable results are associated with the microfracture procedure. Therefore, we present an alternative surgical treatment option for this pathology. The objective of this Technical Note is to describe our preferred approach for an osteochondral allograft transplant procedure to treat a focal patellar osteochondral lesion

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 t