ABSTRACT
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
Subject(s)
Alleles , Genetic Association Studies , Genetic Predisposition to Disease , Mutation, Missense , Neurofibromatosis 1/diagnosis , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics , Amino Acid Substitution , Cross-Sectional Studies , Heterozygote , Humans , PhenotypeABSTRACT
Tumor growths, migraine headaches, and other health-related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF-related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate-to-severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.
Subject(s)
Neurofibromatosis 1/complications , Pain/etiology , Quality of Life , Severity of Illness Index , Adolescent , Adult , Child , Chronic Disease , Cohort Studies , Cross-Sectional Studies , Female , Humans , Male , Ohio/epidemiology , Pain/epidemiology , Pain/pathology , Pain Measurement , Surveys and Questionnaires , Young AdultABSTRACT
Junctional epidermolysis bullosa (JEB) is a particularly devastating type of epidermolysis bullosa, especially in the newborn period. Data about the number of new cases of JEB in the United States were collected from the records of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) nurse educator. Seventy-one children with JEB were reported to have been born in the 5 years between 2007 and 2011, reflecting an incidence of at least 3.59 per million per year, significantly higher than previously estimated (2.04 per million). There was a high prevalence of morbidity and infant mortality of at least 73%, as 52 of the 71 cases proved fatal by June 2012. These data emphasize the need for future research to develop treatment and ultimately a cure for this disorder.
