Neurodevelopmental problems, general health and academic achievements in a school-based cohort of 11-year-old Swedish children.

AIM: Assessing rates of neurodevelopmental problems (NDPs) in 11-year-old children and possible association with other health complaints and school performance. METHODS: In-school study of 11-year-old children as an add-on assessment to the 4th grade regular health check-up, comprising a structured physical neurodevelopmental examination, neuropsychological assessment, behavioural ratings, maternal interview, review of medical records and academic achievements. RESULTS: Out of 348 children recruited from eight schools, 223 (64%) participated. Any physical condition was found in 102/222 (46%), most commonly atopy (18%). One in five had a BMI z-score >2 standard deviations over the reference mean. One or more NDP was found in 86/221 (40%) children. The number of failed national tests correlated positively with NDP severity rated with the clinical global impression severity instrument (Spearman's r = 0.41, p < 0.001). The majority of participants with failed national tests, also had co-occurring health complaints (≥2 of: stomach or extremity ache, headache, difficulties sleeping, internalising symptoms or obesity) and NDPs. CONCLUSION: Health complaints, physical conditions and NDPs are very common in 11-year-old children and warrant adequately staffed, thoroughly equipped school healthcare services.

Attention-deficit/hyperactivity disorder with developmental coordination disorder: 24-year follow-up of a population-based sample.

BACKGROUND: Although the body of research concerning neurodevelopmental disorders is vast, there is a scarcity of longitudinal studies beyond late adolescence, and of studies taking co-existing disorders into account. The present study aimed to investigate outcome in adulthood for children with attention-deficit/hyperactivity disorder (ADHD) combined with developmental coordination disorder (DCD) diagnosed at 6.6 years of age. METHODS: Out of a screening-based population cohort of 589 individuals, 62 (10 female) diagnosed with ADHD+DCD at mean age 6.6 years naïve to stimulant treatment were followed into adulthood through national registries. Results were compared to a screen- and assessment negative population matched group from the same cohort (PM group, n = 51) and a registry-matched (RM group, n = 410) group of the same county and age. RESULTS: At 30 to 31 years of age, five deaths had occurred; one in the ADHD+DCD group and two each in the comparison groups. In time to event analyses of the composite outcome of any psychiatric disorder, psychotropic prescription, sick pension or criminal sentence, events occurred at a significantly higher rate in the ADHD+DCD group (p = 0.0032, vs PM group p = 0.0115, vs RM group p = 0.0054). The ADHD+DCD group had significantly higher rates of psychiatric diagnoses, prescriptions of psychoactive medications and occurrence of sick pension than both comparison groups. Further, the ADHD+DCD group had significantly lower educational attainment compared to both comparison groups, more years with unemployment, and overall higher welfare recipiency. Rates of pain diagnoses and analgesic prescriptions did not separate the groups. CONCLUSION: ADHD+DCD entailed a less favorable outcome in adulthood compared to a non-clinical comparison group and a registry-matched population. Neurodevelopmental disorder diagnosed upon school entry is of prognostic utility with respect to function in adulthood, and warrants early identification and management.

Adaptive skills are useful for evaluating the effect of pharmacological treatment in children with attention-deficit/hyperactivity disorder.

AIM: There are few long-term studies of adaptive functions as an outcome measure of pharmacological treatment in attention-deficit/hyperactivity disorder (ADHD). This study assessed the adaptive abilities of children with ADHD before and after several years of pharmacological treatment. METHOD: We studied 12 children with a mean age of 15 years - seven boys and five girls - who had continued pharmacological treatment for ADHD for more than four years. The Adaptive Behaviour Assessment Scales - Second Edition ratings by their teachers were compared before and after they had received treatment for ADHD. RESULTS: On a group level, the conceptual, practical and general adaptive composite domains improved significantly between the baseline and follow-up study. There were clear individual variations: more than half of the group increased from an adaptive level far below average to average, a minority displayed no major changes, and one individual deteriorated. The girls tended to have better outcomes than the boys. CONCLUSION: This study was nonrandomised and only analysed within-group changes in a small number of participants. However, the findings suggest that four to five years of stimulant treatment had markedly positive effects on adaptive functioning in more than half of the school-age children with ADHD.

Mild intellectual disability and ADHD; a comparative study of school age children's adaptive abilities.

AIM: To compare adaptive functioning in children with mild intellectual disability (MID) with that of children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Thirty-three children with MID were contrasted with 27 children with ADHD with regard to adaptive functioning as measured by the Adaptive Behaviour Assessment System (ABAS-II). The group with MID was population-based, and the group with ADHD was considered representative of a clinically referred group with that diagnosis. The two groups were subdivided into those ≤11 years and those ≥12 years. RESULTS: The group with ADHD had lower adaptive functioning, but differences were not significant at total group levels. In children 12 years or older, the group with ADHD had significantly lower adaptive functioning. CONCLUSION: Older children with ADHD had poorer adaptive functioning than those with MID, a finding which should be of interest to school and other authorities mapping out education and intervention plans for children with special needs.

Visual and ocular findings in children with fetal alcohol spectrum disorders (FASD): validating the FASD Eye Code in a clinical setting.

OBJECTIVE: Fetal alcohol spectrum disorders (FASD) is an umbrella term covering a spectrum of medical conditions caused by prenatal alcohol exposure. The FASD Eye Code is a new complementary ophthalmological diagnostic tool created to corroborate the complex FASD diagnosis. The aim of this work was to validate the FASD Eye Code by testing it on a second group of children diagnosed with FASD in a clinical setting. METHODS AND ANALYSIS: A clinical study was carried out in a group of 21 children (13 males, 8 females, mean age 13.3 years) investigated for suspected FASD and a healthy sex-matched and age-matched control group (n=21). The participants underwent a detailed ophthalmological examination including visual perception problems (VPPs) assessment. Clinical examination results were compiled, and total scores were calculated according to the FASD Eye Code protocol (range 4-16). RESULTS: The median total score in the FASD group was 8. Eight individuals in the FASD group and none of the controls obtained a total score of ≥9 corresponding to 38% sensitivity and 100% specificity with an area under the curve of 0.90. A cut-off total score of ≥8 showed 52% sensitivity and 95% specificity. One individual in the FASD group versus 12 controls had a total score of 4, representing normal findings. No significant difference between the two groups regarding VPPs was seen. CONCLUSION: The FASD Eye Code can be used as a complementary diagnostic tool for FASD to assist in diagnosis and to detect ophthalmological abnormalities in individuals with suspected FASD.

Attention-deficit/hyperactivity disorder with oppositional defiant disorder in Swedish children - an open study of collaborative problem solving.

AIM: To evaluate collaborative problem solving (CPS) in Swedish 6-13-year-old children with attention-deficit/hyperactivity disorder and oppositional defiant disorder (ODD). METHODS: Seventeen families completed 6-10 sessions of CPS training. Primary outcome measures were SNAP-IV [attention-deficit/hyperactivity disorder (ADHD) and ODD scores] and Clinical Global Impression-Improvement (CGI-I) scores at baseline, post-intervention and 6 months later. Secondary outcome measures were the Conners' 10-item scale and the Family Burden of Illness Module (FBIM). RESULTS: All 17 participants completed the intervention. The whole group had significant reductions in SNAP-IV ODD, ADHD, total Conners' and FBIM scores, both at post-intervention and at 6-month follow-up. Eight of the children, although significantly improved on ODD scores and the Conners' emotional lability subscale at post-intervention, had almost no improvement in hyperactivity/impulsivity. Post-intervention, this group received stimulant medication for their ADHD. CGI-I scores of much improved or very much improved were reached by 53% (9/17) of all at post-intervention, and by 81% (13/16) at 6-month follow-up. CONCLUSION: Collaborative problem solving significantly reduced ODD, ADHD and emotional lability symptoms. A subgroup improved in their ADHD symptoms only after adding stimulant medication.

Deficits in attention, motor control and perception childhood to age 30 years: prospective case-control study of outcome predictors.

OBJECTIVE: Investigate predictors of adverse outcome in children with and without attention-deficit/hyperactivity disorder (ADHD) combined with developmental coordination disorder (DCD) at 6 years of age. DESIGN: Prospective population-based cohort study. SETTING: Western Sweden. PARTICIPANTS: From a screening-based population cohort of 589 individuals, 62 (11 female) diagnosed with ADHD+DCD at mean age 6.6 years, and a comparison group of 51 population-matched (10 female) children were followed prospectively. OUTCOME MEASURES: Drawn from a clinical reassessment at age 9 years of 110 of the 113 individuals, neuropsychiatric symptoms, continuous performance test results and measures of motor function were used as predictors of outcome in linear regression models. Participants were followed in national registers up to 30-31 years of age for outcomes in adulthood. Predictors were regressed onto an adverse outcome score (range 0-7) comprising seven binary endpoints, and when applicable onto each continuous outcome separately (low educational attainment, low occupation level, psychiatric disorder, psychotropic medication prescription, sick pension, high dependence on social benefits and criminal conviction). RESULTS: Of the 110 individuals, 3 had died. In univariable regression onto the adverse outcome score, the strongest predictors at age 9 years were symptoms of conduct disorder, oppositional defiant disorder, ADHD and motor dysfunction, with an R2 around 25%, followed by autistic traits (R2=15%) and depressive symptoms (R2=8%). Combining these six strongest predictors in a multivariable model yielded an adjusted R2=38%. Subgroup analyses were similar, except for a strong association of autistic traits with the adverse outcome score in females (n=20, R2=50%). CONCLUSION: Several neurodevelopmental symptoms, including ADHD severity at age 9 years, accounted for a considerable amount of the variance in terms of adulthood adverse outcome. Broad neurodevelopmental profiling irrespective of diagnostic thresholds should inform research and clinical practice. The study highlights the importance of considering associated comorbidities and problems in ADHD.

Visual perception problems and quality of life in young adults with foetal alcohol spectrum disorders.

PURPOSE: To investigate visual perception problems (VPPs), health-related quality of life (HRQoL) and vision-related quality of life (VRQoL) in young adults with foetal alcohol spectrum disorders (FASD) and to compare the results with healthy controls. METHODS: Thirty young adults with FASD (13 female; mean age 23 years) and 29 controls (20 female; mean age 25 years) participated. Five areas of VPPs were assessed by a structured history-taking. In the FASD group, VPPs were investigated both in childhood (mean age 8 years) and in early adulthood in a prospective follow-up. Health-related quality of life (HRQoL) was investigated with the Pediatric Quality of Life Inventory™ (PedsQL) and VRQoL with the 25-item Visual Function Questionnaire (VFQ-25). RESULTS: Visual perception problems (VPPs) in at least one area were reported by 16/30 FASD participants (53%) and 1/29 controls (3%) (p = 0.0001, Fisher's exact test), with a similar rate in the same individuals in childhood as in early adulthood (8/27 and 15/27, respectively p = 0.09, McNemar's test). PedsQL total score was lower in the FASD group (n = 20; median: 83; 95% confidence interval (CI) 76-88) compared with controls (n = 29; median: 91; 95% CI 90-95; p = 0.0001, Mann-Whitney U-test). VFQ-25 subscale general vision indicated lower VRQoL in the young adults with FASD (n = 19; median: 80; 95% CI 80-100) compared with controls (n = 29; median: 100; 95% CI 100-100; p = 0.003). CONCLUSION: Young adults with FASD in the present study had more VPPs and worse VRQoL and HRQoL than healthy controls. In the FASD group, VPPs were reported in childhood as well as in early adulthood.

The ESSENCE-Questionnaire in Medical Records Screening for Neurodevelopmental Symptoms/Problems: Utility and Clinical Validity.

Purpose: Determine the prevalence of symptoms of neurodevelopmental problems (NDPs) with a semi-structured review of fourth grade students' medical records, its interrater agreement and validity as compared with clinical assessment. Methods: A school-based sample of 11-year-old children provided child health care (CHC) records and school health care (SHC) records. A pediatric neurologist, child psychiatrist and an adult psychiatrist scored the records, with the "Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire" (ESSENCE-Q, 12 items scored 0-2, summary score range 0-24). Agreement was measured with model-based kappa and intraclass correlation coefficient (ICC). Ratings were validated against a multidisciplinary assessment involving a physician, psychologist, teacher- and parental behavioral rating scales rendering a clinical global impression severity rating (CGI-S, range 1-7) of NDPs. Results: Out of 223 participants, medical charts were available from 201, of whom 169 were rated by all three raters. Kappa agreement was moderate/strong (~0.8) for 7 of the 12 questionnaire items. Measured with the ICC, concordance in the summary score was good for agreement (~0.8) and excellent (~0.9) for consistency. Test-retest reliability was excellent (ICC = ~0.9). Area under the curve for the ESSENCE-Q in predicting clinical-level problems (CGI ≥4) was ~80% for all three raters, albeit with differing optimal cutoffs. Conclusion: Using the ESSENCE-Q as a template, NDPs appear to be common in medical records, are identified reliably, and predict clinical-level concern. Medical records screening may facilitate a structured review of medical records in work-ups or be applied in conjunction with other screening measures for neurodevelopmental disorders. However, differences in calibration currently preclude defining a universal cutoff for using the ESSENCE-Q for medical records screening.

The ESSENCE-Questionnaire for Neurodevelopmental Problems - A Swedish School-Based Validation Study in 11-Year-Old Children.

Purpose: To determine the prevalence of parent-rated developmental concern using the ESSENCE-Q (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire, 12-items, score range 0-24) and to ascertain the predictive validity and optimal cutoff level of the instrument in a school-based sample of 11-year-old children. Methods: In a cross-sectional, school-based study, participants underwent a clinical assessment by a physician and a psychologist, teachers and parents completed the SDQ (Strength and Difficulties Questionnaire), medical health records and national tests were reviewed, and parents independently completed the ESSENCE-Q. In a case-conference outcomes were defined as a) the need for further clinical work-up due to suspected neurodevelopmental problems (NDPs) and b) degree of investigator-rated symptoms/impairment from NDPs on the CGI-S (Clinical Global Impression-Severity instrument, range 1-7, 4-7 defined as clinically symptomatic). Classification and optimal cutoffs of the ESSENCE-Q were determined using ROC (Receiver Operating Characteristic) analysis. Results: Out of 343 eligible children, 223 enrolled, of whom 173 (50% of all eligible) had a parent-rated ESSENCE-Q. At least one of the 12 possible concerns was reported by parents of 36% of participants. Overall, in 101 (57%) participants a work-up was warranted, and 64 (37%) were clinically symptomatic from NDPs. The AUC of the ESSENCE-Q in detecting need for work-up was 0.70 (95% confidence interval [CI] 0.63-0.77), and the AUC in detecting clinically symptomatic participants was 0.82 (95% CI 0.76-0.88). ESSENCE-Q ratings correlated positively with CGI-S scores (r=0.48, p<0.05). A cutoff of ≥3 had the highest accuracy (78%) with a negative predictive value of 82%. Ratings >6 conferred few false positives cases with positive likelihood ratios >10 and positive predictive values of 86% or more. Significance: This study of the ESSENCE-Q in 11-year-old children suggests it might be an acceptable instrument for screening of NDPs in children in middle school, optimally in conjunction with other methods.

Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study.

BACKGROUND: The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. METHODS: Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (V(max)) and affinity constant (K(m)) were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test. RESULTS: The ADHD group had significantly decreased V(max) (p = 0.039) and K(m) (increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher V(max)of alanine transport (p = 0.031), but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group. CONCLUSIONS: Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

Thinner retinal nerve fibre layer in young adults with foetal alcohol spectrum disorders.

BACKGROUND/AIMS: Ophthalmological abnormalities such as ptosis, strabismus, refractive errors and optic nerve hypoplasia have been reported in foetal alcohol spectrum disorders (FASD). The purpose of this study was to investigate whether retinal thickness, retinal nerve fibre layer (RNFL) and optic disc area (ODA) differ between individuals with FASD and healthy controls. METHODS: Best-corrected visual acuity (BCVA) in terms of logarithm of the minimum angle of resolution (logMAR), refraction, and fundus variables measured by optical coherence tomography were obtained from 26 young adults with FASD (12 women, median age 23 years) and 27 controls (18 women, median age 25 years). RESULTS: The total thickness of the peripapillary RNFL was significantly lower in the FASD group than in controls; median (range) in the right/left eye was 96.5 (60-109)/96 (59-107) µm in the FASD group and 105 (95-117)/103 (91-120) µm among controls (p=0.001 and p=0.0001). Macular RNFL and retinal thickness measurements from the FASD group were also lower in most of the nine ETDRS areas, except for the central parts. Median (range) BCVA in the best eye was 0.00 (-0.1-0.3) logMAR in the FASD group and 0.00 (-0.2-0.0) logMAR in controls (p=0.001). No significant differences between the groups were found regarding ODA or refraction. CONCLUSION: Significant differences in peripapillary and macular RNFL, retinal thickness and BCVA were found in this group of young adults with FASD compared with healthy controls. However, there were no differences in the size of the optic disc.

The FASD Eye Code: a complementary diagnostic tool in fetal alcohol spectrum disorders.

OBJECTIVE: To create an easy-to-use complementary ophthalmological tool to support a fetal alcohol spectrum disorder (FASD) diagnosis. METHODS AND ANALYSIS: The FASD Eye Code was derived from 37 children with FASD evaluated along with 65 healthy age-matched and sex-matched controls. Four ophthalmological categories, which are abnormalities commonly found in children with FASD, were ranked independently on a 4-point scale, with 1 reflecting normal finding and 4 a strong presence of an abnormality: visual acuity, refraction, strabismus/binocular function and ocular structural abnormalities. The tool was validated on 33 children with attention deficit/hyperactivity disorder (ADHD), 57 children born moderate-to-late premature (MLP) and 16 children with Silver-Russell syndrome (SRS). Among children with ADHD none was born prematurely or small for gestational age (SGA) or diagnosed with FASD. Among children born MLP none was SGA, had a diagnosis of ADHD or FASD, or a history of retinopathy of prematurity. Children with SRS were all born SGA, half were born preterm and none had FASD. Children with FASD were re-examined as young adults. RESULTS: An FASD Eye Code cut-off total score of ≥10 showed an area under the curve (AUC) of 0.78 (95% CI 0.69 to 0.87), with 94% specificity and 43% sensitivity, in discriminating between FASD and controls, MLP and ADHD, corresponding to a positive likelihood ratio (LR+) of 7.5. Between FASD and controls, an AUC of 0.87 (CI 0.80 to 0.95), with 100% specificity and 43% sensitivity, was found; between FASD and SRS, an AUC of 0.60 (CI 0.45 to 0.75) was found, with 88% specificity and 43% sensitivity. A cut-off score of≥9 showed a specificity of 98% and a sensitivity of 57% for FASD versus controls, corresponding to an LR+ of 36.9. Scores in individuals with FASD were stable into young adulthood. CONCLUSION: The FASD Eye Code has the potential to serve as a complementary tool and help to strengthen an FASD diagnosis.

EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD.

AIM: Measure efficacy of eicosapentaenoic acid (EPA) in children with attention deficit hyperactivity disorder (ADHD). METHODS: Randomized controlled trial (RCT) of 0.5 g EPA or placebo (15 weeks) in 92 children (7-12 years) with ADHD. Efficacy measure was Conners' Parent/Teacher Rating Scales (CPRS/CTRS). Fatty acids were analysed in serum phospholipids and red blood cell membranes (RBC) at baseline and endpoint with gas chromatography. RESULTS: EPA improved CTRS inattention/cognitive subscale (p = 0.04), but not Conners' total score. In oppositional children (n = 48), CTRS total score improved ≥25% in 48% of the children receiving EPA vs. 9% for placebo [effect size (ES) 0.63, p = 0.01]. In less hyperactive/impulsive children (n = 44), ≥25% improvement was seen in 36% vs. 18% (ES 0.41, n.s.), and with both these types of symptoms 8/13 with EPA vs. 1/9 for placebo improved ≥25% (p = 0.03). Children responding to treatment had lower EPA concentrations (p = 0.02), higher AA/EPA (p = 0.005) and higher AA/DHA ratios (p = 0.03) in serum at baseline. Similarly, AA/EPA (p = 0.01), AA/DHA (p = 0.038) and total omega-6/omega-3 ratios (p = 0.028) were higher in RBC, probably because of higher AA (p = 0.011). CONCLUSION: Two ADHD subgroups (oppositional and less hyperactive/impulsive children) improved after 15-week EPA treatment. Increasing EPA and decreasing omega-6 fatty acid concentrations in phospholipids were related to clinical improvement.

Ophthalmologic Findings in Fetal Alcohol Spectrum Disorders - A Cohort Study From Childhood to Adulthood.

PURPOSE: To investigate whether ophthalmologic findings in children with fetal alcohol spectrum disorders (FASD) persist into young adulthood. DESIGN: Prospective cohort study. METHODS: Thirty children (13 female) adopted from eastern Europe to Sweden in the 1990s and diagnosed with FASD by a multidisciplinary team at the median age of 7.9 years were followed up by the same team 13-18 years later. Visual acuity (VA), refraction, stereoacuity, strabismus, ocular media, and fundus were investigated. RESULTS: Median VA in right/left eye (OD/OS) was 20/32/20/32 (0.2/0.2 logMAR) in childhood and 20/22/20/20 (0.05/0.0 logMAR) in adulthood. Median (range) refraction OD/OS was +0.88/+1.25 (-8.75 to +4.75/-9.38 to +5.25) spherical equivalent diopter (D) in childhood and -0.25/-0.25 (-12 to +2.75/-13.25 to +2.63) in adulthood. Astigmatism (≥1 D) was the most common refractive error, in 13 (40%) and 14 (47%) subjects, respectively. Defective stereoacuity (>60 arc second) was noted in 20 subjects (67%) in childhood and 22 (73%) in adulthood. Heterotropia occurred in 12 subjects (40%) in childhood and 13 (43%) in adulthood. Increased tortuosity of the retinal vessels was found in 8 (27%) subjects in childhood vs 11 (37%) in adulthood. Optic nerve hypoplasia was recorded in 3 children and in 4 young adults. CONCLUSIONS: Ophthalmologic findings such as refractive errors, strabismus, and fundus abnormalities are frequent in children with FASD and persist into early adulthood. The facial features characteristic of FAS diminish with age, making a dysmorphology evaluation in adulthood less reliable. An ophthalmologic examination is an important part of the evaluation of FASD in childhood as well as in young adulthood.

Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature.

Beals-Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23-34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2-positive patients. In our FBN2-positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z-score: 4.09) and his father (z-score: 2.94), warranting echocardiographic follow-up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2-negative patients in this cohort were clinically indistinguishable from all published FBN2-positive patients harboring a FBN2 mutation, suggesting locus heterogeneity.