Marfan Syndrome - A Diagnostic Challenge : aspects of a Norwegian cohort study

Marfan syndrom (MFS) er en sjelden arvelig tilstand, som oftest skyldes feil i genet FBN1 som koder for bindevevsproteinet fibrillin 1. Ved et nasjonalt kompetansesenter for sju sjeldne diagnosegrupper (TRS), erfarte vi at mennesker med MFS ofte klager over tretthet og nedsatt fysisk yteevne. Imidlertid var alle de organsystemer som kan være påvirket ved tilstanden ikke undersøkt hos personer med diagnosen. For å undersøke gruppens helserelaterte livskvalitet (HRL) måtte vi først undersøke etter de gjeldende diagnostiske kriteriene (Gent-kriteriene, GC) for å sikre diagnosen. Undersøkelse av 105 voksne med mistenkt MFS viste at 87 fylte GC, og ikke alt som så ut som MFS var MFS. Noen personer med feil (mutasjoner) i 2 gener for vekstfaktorer (TGFBR1 og TGFBR2) fylte kriteriene (tre personer). Flere hadde fått diagnosen uten å fylle kriteriene, deriblant fem personer med mutasjoner i TGFBR2. Ett av hovedkriteriene for MFS er utvidelse i korsryggen av den harde ryggmargshinnen (dura mater) som inneholder ryggmargsvæsken. Ingen av de 105 hadde undersøkt dura mater. Utvidelse av dura mater var til stede hos 91 % av de som fylte kriteriene. Litteraturen sier at nesten alle som har MFS har utvidelse av eller sprekk i den første delen av hovedpulsåren. I vårt materiale hadde kun 53 % av de som fylte GC dette; dette kan bety at leveutsiktene for gruppen som helhet er mer positive enn man hittil har trodd. Mutasjon i FBN1 ble funnet hos 73 personer, som alle fylte GC. Egen-rapportering av HRL (spørreskjema SF-36) viste at mennesker med MFS opplevde redusert HRL. Studien viser at mennesker med MFS trenger tverrfaglig samarbeid for diagnostikk, rådgivning og oppfølging. Som følge av studien har avdeling for medisinsk genetikk ved Oslo Universitetssykehus etablert undersøkelse av genet. Arbeidet bygger på en samarbeidsstudie mellom fagfolk fra 7 spesialiteter, ansatt ved flere avdelinger på 4 sykehus. Samarbeidet og rutinene fra studien brukes nå ved diagnostikk av MFS

Features of Marfan syndrome not listed in the Ghent nosology : the dark side of the disease

Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features. Areas covered: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction. Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome

Photophobia and disability glare in adult patients with Marfan syndrome: a case–control study

Purpose The aim of the present study was to investigate photophobia and disability glare in adult patients with Marfan syndrome (MFS). Methods In this case–control study, 44 patients with MFS (87 eyes) were compared to 44 controls (88 eyes), who were matched for age and sex. The subjects were asked to grade their photophobia and glare using 10-cm visual analogue scales (VAS), which were marked with ‘never’ at zero and ‘always’ at 10 -cm. In addition, disability glare was measured with C-Quant straylight meter. Results The patients with MFS had significantly higher VAS scores than the controls in four out of seven statements related to photophobia and glare. When including cataract, spherical equivalent, iris colour, axial length and corneal curvature, three of the seven statements were still significantly different between the two groups. The mean straylight values were 1.29 ± 0.03 log(s) in the MFS group and 1.01 ± 0.03 log(s) in the control group (p < 0.001, mixed model). These differences remained significant after adjusting for cataract, spherical equivalent, iris colour, axial length and corneal curvature. Conclusion Patients with MFS reported more photophobia and had a higher straylight value than the control group. Awareness of these findings of more photophobia and glare in the MFS patients is important when counselling and treating these patients

Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome

Background Pathogenic mutations in FBN1, encoding the glycoprotein, fibrillin-1, cause Marfan syndrome (MFS) and related connective tissue disorders. In the present study, qualitative and quantitative effects of 16 mutations, identified in FBN1 in MFS patients with systematically described phenotypes, were investigated in vitro. Methods Qualitative analysis was performed with reverse transcription-PCR (RT-PCR) and gel electrophoresis, and quantitative analysis to determine the FBN1 mRNA levels in fibroblasts from the 16 patients with MFS was performed with real-time PCR. Results Qualitative analysis documented that the mutations c.4817-2delA and c.A4925G led to aberrant FBN1 mRNA splicing leading to in frame deletion of exon 39 and in exon 39, respectively. No difference in the mean FBN1 mRNA level was observed between the entire group of cases and controls, nor between the group of patients with missense mutations and controls. The mean expression levels associated with premature termination codon (PTC) and splice site mutations were significantly lower than the levels in patients with missense mutations. A high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in three of his first degree relatives. No association was indicated between the FBN1 transcript level and specific phenotypic manifestations. Conclusions Abnormal FBN1 transcripts were indicated in fibroblasts from patients with the splice site mutation c.4817-2delA and the missense mutation c.A4925G. While the mean FBN1 mRNA expression level in fibroblasts from patients with splice site and PTC mutations were lower than the mean level in patients with missense mutations and controls, inter-individual variability was high. The observation that high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in the family suggests that variable expression of the normal FBN1 allele may contribute to explain the variability in FBN1 mRNA level

Pupillary response in adults with Marfan syndrome and its effect on straylight

Purpose The main objective of this study was to examine the pupillary response in patients with Marfan syndrome (MFS) and secondarily to determine whether changes in the pupillary response are associated with the increased disability glare previously shown in the same patient population. Methods This study included 60 eyes of 34 patients with MFS diagnosed in accordance with the Ghent-2 criteria and 81 eyes of 44 controls. Pupillary response was measured with a pupillograph and disability glare with a straylight meter. Results The patients with MFS had a significantly smaller maximum pupil size than the control group, 4.87 (4.50–5.23) mm versus 5.58 (5.25–5.90) mm (p = 0.01). In addition, they exhibited slower contraction velocities (p = 0.03) and longer re-dilation times (p = 0.01) compared with the control group. The mean straylight value was higher in patients with MFS than controls, even when including pupillary parameters together with lens surgery, cataract, iris colour, axial length and corneal curvature as possible explanatory variables in the analysis. However, when including data from both groups, a significant negative correlation was seen between maximum pupillary diameter and straylight value (p = 0.01). The other pupillary parameters did not correlate with straylight. Conclusion Patients with MFS had a smaller maximum pupil diameter, slower pupillary contraction and longer re-dilation time than the controls. Despite the correlation between pupil size and straylight value, the pupillary response demonstrated in MFS eyes could not explain the increased straylight in these patients

Ocular findings in 87 adults with Ghent-1 verified Marfan syndrome

Purpose To study ocular characteristics in 87 patients with verified Marfan syndrome (MFS) based on the Ghent criteria from 1996 (Ghent-1). Methods The position of the lens was noted by observing the eye in different gaze directions in maximal mydriasis during slit lamp examination. Ectopia lentis (EL) was classified as subluxated (dislocation slightly backwards) or luxated (vertical or horizontal displacement). Corneal curvature, axial length (AL), corneal diameter, central corneal thickness, anterior chamber depth, lens thickness, condition of the iris, intraocular pressure, spherical equivalent and visual acuity were also investigated. Results EL was found in 108 eyes (62.1%). Of the 68 phakic eyes with EL, 43 (63.2%) had subluxation. Mean AL was 24.80 ± 2.57 mm, and the AL was above 23.5 mm in 65.3%. Mean keratometry (K) in phakic eyes was 41.79 ± 1.70 diopters (D), and the K value was <41.5D in 46.8%. Iris hypoplasia was found in 3.4%. Myopia above 3D occurred in 38.4% of the phakic eyes. Mean binocular logMAR was 0.10 ± 0.32. Only five patients (5.7%) had a logMAR more than 0.5. These 5 patients had EL, and 4 of them were amblyopic. Conclusion In this strictly defined MFS group fulfilling the Ghent-1 criteria, the prevalence of EL was 62.1%. In many cases, the dislocation of the lens was subtle. On average, the corneas were flattened and the globe length was increased. Only a few patients were visually impaired. Children with MFS should have a thorough follow up to avoid amblyopia

Chronic pain and fatigue in adults with congenital unilateral upper limb deficiency in Norway. A cross-sectional study

Purpose: To describe Norwegian adults with congenital unilateral upper limb deficiency (CUULD) regarding self-reported chronic pain (intensity, locations, impact on daily life) and fatigue. Analyze associations between chronic pain and demographic/clinical factors and associations between fatigue and demographic/ clinical factors. Materials and methods: Cross-sectional study. In 2012, a postal questionnaire was sent to 186 persons with congenital limb deficiency, age ≥ 20 years. Seventy seven persons with CUULD responded and are included in this paper. The questionnaire included questions on demographic and clinical factors, chronic pain (Brief Pain Inventory, Standardized Nordic Questionnaire) and fatigue (Fatigue severity scale (FSS)). Results: Mean age was 42.7 (SD 16.0), 71% were women. Sixty tree % reported chronic pain, many had bilateral pain, most common pain locations were neck (78%) and shoulder/upper arm (78%). However, reported mean pain intensity (3.3 (SD 2.8)) and mean number of pain locations (3.0 (SD 2.5)) were moderate to low. Thirty seven persons reported that pain started in adult age (≥ 19 years). One third reported severe fatigue (FSS ≥ 5). Persons reporting cold sensitivity and severe fatigue were most likely to have chronic pain. Conclusions: Congenital upper limb deficiency increases the risk of self-reported pain in neck, shoulder/upper arm, cold sensitivity and severe fatigue. Pain, fatigue and cold sensitivity may individually affect function, and may together reinforce functional problems. This should be to taken into account when rehabilitation programs are developed. Further studies of more representative samples should be conducted to confirm our findings

Education and work participation among adults with congenital unilateral upper limb deficiency in Norway: A cross-sectional study.

ObjectivesTo describe level of education and work participation among adults with congenital unilateral upper limb deficiency (CUULD) in Norway and to explore associations between work participation and demographic and clinical factors.MethodsCross-sectional study. In 2012, a postal questionnaire was sent to 186 persons with congenital limb deficiency (CLD), age ≥ 20 years, registered at the TRS National Resource Center for Rare Disorders. In the original CLD study, 77 persons with CUULD responded. In this paper 64 persons with CUULD of working age (20-67 years) are included. Data on demographic factors as education level and work participation, and clinical factors including limb deficiency characteristics, chronic pain (Standardized Nordic Questionnaire), fatigue (Fatigue Severity Scale), physical and mental health (SF-36) were analyzed through descriptive and comparable statistics and logistic regression analyses.ResultsSixty-four persons participated, mean age 43.4 (SD 13.7; range 20-67 years), 45 were women. Education level >13 years was reported by 34. Forty- three of the 64 participants were employed, 21 were prematurely retired (disability benefits). 11 of the 43 employed, and 6 of the 21 prematurely retired had completed vocational education. Physically demanding occupations (work activities that required standing, walking and lifting) were reported by 25 of the 43 employed and 13 of the 21 prematurely retired. 17 of the 64 reported need for further adaptions in their workplaces. The strongest predictors of work participation were younger age (OR 0.86) and good physical health (OR 1.21).ConclusionTwo thirds of persons with CUULD were employed; while one third was prematurely retired and had left work earlier than expected. This suggests that persons with CUULD may experience challenges in work participation. Although levels of education were relatively high, several had chosen careers that required physical strain. Younger age and good physical health were the most important factors mediating work participation