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

Imaging findings of pelvic venous insufficiency in patients with postural orthostatic tachycardia syndrome

Objectives: Some patients with postural orthostatic tachycardia syndrome (POTS) demonstrate improved dysautonomic symptoms following treatment for pelvic venous insufficiency (PVI). This study assessed the prevalence of significant left common iliac vein (LCIV) compression in POTS patients. Methods: Radiologists retrospectively reviewed CT images of pelvic veins for 216 women (191 with POTS and 25 agecomparable controls). Quantitative vascular analysis identified percent-diameter compression of the LCIV by the right common iliac artery. Significant LCIV compression was defined as >50%. Results: Significant LCIV compression was found in 69% (131/191) of females with POTS versus 40% (10/25) in controls. The hypothesis that venous compression and presence of POTS are independent was rejected (p¼.005). Conclusions: Significant LCIV compression was noted in a majority of female POTS patients, suggesting that incidence of iliac venous obstruction may be higher than the general population. Patients with POTS and symptoms of PVI may benefit from assessment for venous outflow obstruction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175839/1/Knuttinen et al 2021.pdfDescription of Knuttinen et al 2021.pdf : ArticleSEL