ABSTRACT
BACKGROUND: e- and mHealth interventions using self-regulation techniques like action and coping planning have the potential to tackle the worldwide problem of physical inactivity. However, they often use one-week self-regulation cycles, providing support toward an active lifestyle on a weekly basis. This may be too long to anticipate on certain contextual factors that may fluctuate from day to day and may influence physical activity. Consequently, the formulated action and coping plans often lack specificity and instrumentality, which may decrease effectiveness of the intervention. The aim of this study was to evaluate effectiveness of a self-regulation, app-based intervention called 'MyDayPlan'. "MyDayPlan' provides an innovative daily cycle in which users are guided towards more physical activity via self-regulation techniques such as goal setting, action planning, coping planning and self-monitoring of behaviour. METHODS: An ABAB single-case design was conducted in 35 inactive adults between 18 and 58 years (M = 40 years). The A phases (A1 and A2) were the control phases in which the 'MyDayPlan' intervention was not provided. The B phases (B1 and B2) were the intervention phases in which 'MyDayPlan' was used on a daily basis. The length of the four phases varied within and between the participants. Each phase lasted a minimum of 5 days and the total study lasted 32 days for each participant. Participants wore a Fitbit activity tracker during waking hours to assess number of daily steps as an outcome. Single cases were aggregated and data were analysed using multilevel models to test intervention effects and possible carry-over effects. RESULTS: Results showed an average intervention effect with a significant increase in number of daily steps from the control to intervention phases for each AB combination. From A1 to B1, an increase of 1424 steps (95% CI [775.42, 2072.32], t (1082) = 4.31,p < .001), and from A2 to B2, an increase of 1181 steps (95% CI [392.98, 1968.16], t (1082) = 2.94, p = .003) were found. Furthermore, the number of daily steps decreased significantly (1134 steps) when going from the first intervention phase (B1) to the second control phase (A2) (95% CI [- 1755.60, - 512.38], t (1082) = - 3.58, p < .001). We found no evidence for a difference in trend between the two control (95% CI [- 114.59, 197.99], t (1078) = .52, p = .60) and intervention phases (95% CI [- 128.79,284.22], t (1078) = .74, p = .46). This reveals, in contrast to what was hypothesized, no evidence for a carry-over effect after removing the 'MyDayPlan' app after the first intervention phase (B1). CONCLUSION: This study adds evidence that the self-regulation mHealth intervention, 'MyDayPlan' has the capacity to positively influence physical activity levels in an inactive adult population. Furthermore, this study provides evidence for the potential of interventions adopting a daily self-regulation cycle in general.
Subject(s)
Exercise , Telemedicine , Text Messaging , Actigraphy/instrumentation , Actigraphy/methods , Adolescent , Adult , Exercise/physiology , Female , Fitness Trackers , Humans , Male , Middle Aged , Sedentary BehaviorABSTRACT
BACKGROUND: Electronic health (eHealth) and mobile health (mHealth) interventions have the potential to tackle the worldwide problem of physical inactivity. However, they often suffer from large attrition rates. Consequently, feasibility and acceptability of interventions have become important matters in the creation of e- and mHealth interventions. The aim of this study was to evaluate participants' opinions regarding acceptability and feasibility of a self-regulation, app-based intervention called 'MyDayPlan'. 'MyDayPlan' provides an innovative daily cycle providing several self-regulation techniques throughout the day that guide users towards an active lifestyle via various self-regulation techniques. METHODS: Semi-structured interviews were conducted with 20 adults after using the app for 2 weeks. A directed content analysis was performed using NVivo Software. RESULTS: 'MyDayPlan' was well-received and seems to be feasible and acceptable with inactive adults. The straightforward lay out and ease of use of the app were appreciated. Furthermore, the incorporation of the techniques 'action planning', and 'prompting review of behavioral goals' was positively evaluated. However, the users gave some recommendations: implementation of activity trackers to self-monitor physical activity could be of added value. Furthermore, increasing intuitiveness by minimizing text input and providing more preprogrammed options could further increase the ease of use. Finally, users indicated that they would benefit from more guidance during the "coping planning" component (barrier identification/problem solving), for example by receiving more tailored examples. CONCLUSIONS: Based on these findings, adaptations will be made to the 'MyDayPlan' app before evaluating its effectiveness. Furthermore, involving potential end users and evaluating acceptability and feasibility during the development of an e- and mHealth intervention is key. Also, creating interventions with a large ease of use and straightforward layout that provides tailored support during action and coping planning is key.
Subject(s)
Exercise/psychology , Health Promotion/methods , Mobile Applications , Patient Acceptance of Health Care/psychology , Telemedicine/methods , Adult , Feasibility Studies , Humans , Male , Qualitative ResearchABSTRACT
It has been hypothesized that the human cortical responses to nociceptive and nonnociceptive somatosensory inputs differ. Supporting this view, somatosensory-evoked potentials (SEPs) elicited by thermal nociceptive stimuli have been suggested to originate from areas 1 and 2 of the contralateral primary somatosensory (S1), operculo-insular, and cingulate cortices, whereas the early components of nonnociceptive SEPs mainly originate from area 3b of S1. However, to avoid producing a burn lesion, and sensitize or fatigue nociceptors, thermonociceptive SEPs are typically obtained by delivering a small number of stimuli with a large and variable interstimulus interval (ISI). In contrast, the early components of nonnociceptive SEPs are usually obtained by applying many stimuli at a rapid rate. Hence, previously reported differences between nociceptive and nonnociceptive SEPs could be due to differences in signal-to-noise ratio and/or differences in the contribution of cognitive processes related, for example, to arousal and attention. Here, using intraepidermal electrical stimulation to selectively activate Aδ-nociceptors at a fast and constant 1-s ISI, we found that the nociceptive SEPs obtained with a long ISI are no longer identified, indicating that these responses are not obligatory for nociception. Furthermore, using a blind source separation, we found that, unlike the obligatory components of nonnociceptive SEPs, the obligatory components of nociceptive SEPs do not receive a significant contribution from a contralateral source possibly originating from S1. Instead, they were best explained by sources compatible with bilateral operculo-insular and/or cingulate locations. Taken together, our results indicate that the obligatory components of nociceptive and nonnociceptive SEPs are fundamentally different.
Subject(s)
Brain/physiology , Evoked Potentials, Somatosensory , Nociception/physiology , Adult , Animals , Electric Stimulation , Female , Humans , Male , Nociceptors/physiology , Young AdultABSTRACT
Ehlers-Danlos (ED) syndrome type VII is characterized by the accumulation of collagen precursors in connective tissues. ED VII A and B are caused by mutations in the genes of alpha 1 and alpha 2 collagen I which result in the disruption of the cleavage site of procollagen I N-proteinase. The existence of ED VII C in humans has been hypothesized on the basis of a disorder in cattle and sheep related to the absence of the enzyme. We now present evidence for the existence of this disease in humans, characterized by skin fragility, altered polymers seen as hieroglyphic pictures with electron microscopy, accumulation of p-N-alpha 1 and p-N-alpha 2 collagen type I in the dermis and absence of processing of the p-N-I polypeptides in fibroblast cultures.
Subject(s)
Cattle Diseases/genetics , Collagen Diseases/veterinary , Ehlers-Danlos Syndrome/genetics , Animals , Cattle , Cattle Diseases/metabolism , Child, Preschool , Collagen/genetics , Collagen/metabolism , Collagen/ultrastructure , Collagen Diseases/genetics , Collagen Diseases/metabolism , Ehlers-Danlos Syndrome/classification , Ehlers-Danlos Syndrome/metabolism , Female , Humans , Microscopy, Electron , Procollagen N-Endopeptidase/deficiency , Procollagen N-Endopeptidase/genetics , Skin/metabolism , Skin/pathologyABSTRACT
Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6).
Subject(s)
ATP-Binding Cassette Transporters/genetics , Mutation/genetics , Pseudoxanthoma Elasticum/genetics , ATP-Binding Cassette Transporters/chemistry , Amino Acid Sequence , Base Sequence , Chromosomes, Human, Pair 16/genetics , Cohort Studies , Consanguinity , DNA Mutational Analysis , Exons/genetics , Female , Fibroblasts/metabolism , Genetic Linkage/genetics , Genotype , Humans , Male , Microsatellite Repeats/genetics , Multidrug Resistance-Associated Proteins , Pedigree , Phenotype , Polymorphism, Single Nucleotide/genetics , Protein Conformation , Pseudoxanthoma Elasticum/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Neuroblastoma is an aggressive embryonal tumor that accounts for â¼15% of childhood cancer deaths. Hitherto, despite the availability of comprehensive genomic data on DNA copy number changes in neuroblastoma, relatively little is known about the genes driving neuroblastoma tumorigenesis. In this study, high resolution array comparative genome hybridization (CGH) was performed on 188 primary neuroblastoma tumors and 33 neuroblastoma cell lines to search for previously undetected recurrent DNA copy number gains and losses. A new recurrent distal chromosome 1q deletion (del(1)(q42.2qter)) was detected in seven cases. Further analysis of available array CGH datasets revealed 13 additional similar distal 1q deletions. The majority of all detected 1q deletions was found in high risk 11q deleted tumors without MYCN amplification (Fisher exact test p = 5.61 × 10(-5) ). Using ultra-high resolution (â¼115 bp resolution) custom arrays covering the breakpoints on 1q for 11 samples, clustering of nine breakpoints was observed within a 12.5-kb region, of which eight were found in a 7-kb copy number variable region, whereas the remaining two breakpoints were colocated 1.4-Mb proximal. The commonly deleted region contains one miRNA (hsa-mir-1537), four transcribed ultra conserved region elements (uc.43-uc.46) and 130 protein coding genes including at least two bona fide tumor suppressor genes, EGLN1 (or PHD2) and FH. This finding further contributes to the delineation of the genomic profile of aggressive neuroblastoma, offers perspectives for the identification of genes contributing to the disease phenotype and may be relevant in the light of assessment of response to new molecular treatments.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 11 , Gene Dosage , Neuroblastoma/genetics , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Cell Line, Tumor , Comparative Genomic Hybridization , Fumarate Hydratase/genetics , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases , N-Myc Proto-Oncogene Protein , Procollagen-Proline Dioxygenase/geneticsABSTRACT
Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.
Subject(s)
DNA-Binding Proteins/genetics , Hereditary Breast and Ovarian Cancer Syndrome/genetics , DNA Mutational Analysis , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Testing , Humans , Male , Mutation, Missense , Pedigree , Polymorphism, Single NucleotideABSTRACT
The Ehlers-Danlos syndromes (EDSs) comprise a heterogeneous group of diseases, characterized by fragility of the soft connective tissues and widespread manifestations in skin, ligaments, joints, blood vessels and internal organs. The clinical spectrum varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. The current Villefranche classification recognizes six subtypes, most of which are linked to mutations in genes encoding fibrillar collagens or enzymes involved in post-translational modification of these proteins. Mutations in type V and type III collagen cause classic or vascular EDS respectively, while mutations involving the processing of type I collagen are involved in the kyphoscoliosis, arthrochalasis and dermatosparaxis type of EDS. Establishing the correct EDS subtype has important implications for genetic counseling and management and is supported by specific biochemical and molecular investigations. Over the last years, several new EDS variants have been characterized which call for a refinement of the Villefranche classification. Moreover, the study of these diseases has brought new insights into the molecular pathogenesis of EDS by implicating genetic defects in the biosynthesis of other extracellular matrix (ECM) molecules, such as proteoglycans and tenascin-X, or genetic defects in molecules involved in intracellular trafficking, secretion and assembly of ECM proteins.
Subject(s)
Ehlers-Danlos Syndrome/genetics , Extracellular Matrix/genetics , Genetic Heterogeneity , Blood Vessels/metabolism , Blood Vessels/pathology , Collagen/genetics , Ehlers-Danlos Syndrome/classification , Ehlers-Danlos Syndrome/diagnosis , Ehlers-Danlos Syndrome/pathology , Genetic Counseling , Humans , Joints/metabolism , Joints/pathology , Mutation , Protein Processing, Post-Translational , Proteoglycans/genetics , Skin/metabolism , Skin/pathology , Tenascin/geneticsABSTRACT
The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.
Subject(s)
Ehlers-Danlos Syndrome/diagnosis , Phenotype , Adolescent , Adult , Base Sequence , Child , Child, Preschool , Collagen Type I/genetics , Exons , Female , Humans , Infant , Infant, Newborn , Male , Mutation , Pedigree , RNA Splice Sites , Young AdultABSTRACT
The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.
Subject(s)
Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Microfilament Proteins/genetics , Mutation , Adolescent , Adult , Child , Fibrillin-1 , Fibrillins , Follow-Up Studies , Humans , Male , Young AdultABSTRACT
A 9-year-old boy with the classical type of Ehlers-Danlos syndrome (EDS) developed a symptomatic aneurysm of the superior mesenteric artery. His EDS diagnosis had been confirmed biochemically and genetically. Vascular complications are known to be associated with the vascular type of EDS, but this is the first report of a child with classical EDS who developed a major vascular complication. Clinicians should be aware that severe vascular complications albeit rare, can also occur in classical EDS.
Subject(s)
Aneurysm/diagnostic imaging , Ehlers-Danlos Syndrome/complications , Mesenteric Artery, Superior/diagnostic imaging , Aneurysm/complications , Angiography , Child , Humans , Male , Mesenteric Artery, Superior/pathology , Tomography, X-Ray ComputedABSTRACT
Mucormycosis is a rare, emerging angioinvasive infection caused by ubiquitous filamentous fungi. In recent decades, an increase in cutaneous or post-traumatic mucormycosis has been reported. We describe two cases of post-traumatic wound infections with Mucor circinelloides, a mucor species only rarely reported as a cause of post-traumatic mucormycosis. Often considered lethal, management required a combination of medical and surgical therapies to achieve a favorable outcome in both cases.
Subject(s)
Ehlers-Danlos Syndrome/diagnosis , von Willebrand Disease, Type 1/diagnosis , Adult , Alleles , Collagen Type V/genetics , Ehlers-Danlos Syndrome/complications , Ehlers-Danlos Syndrome/genetics , Ehlers-Danlos Syndrome/pathology , Factor VIII/analysis , Female , Fibroblasts/cytology , Fibroblasts/pathology , Humans , Metrorrhagia/diagnosis , Metrorrhagia/etiology , Partial Thromboplastin Time , von Willebrand Disease, Type 1/complicationsABSTRACT
Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.
Subject(s)
Blepharophimosis/genetics , DNA Copy Number Variations/genetics , Forkhead Transcription Factors/genetics , Gene Deletion , Mutation/genetics , Adolescent , Child, Preschool , Female , Forkhead Box Protein L2 , Genotype , Humans , Infant , Male , Middle Aged , Pedigree , Phenotype , PrognosisABSTRACT
SUMMARY: While the majority of this session will deal with selected inherited vascular abnormalities that may manifest as a haemorrhagic disorder, the initial discussion by Dr Key will focus on the interplay between the vessel wall and components of the coagulation system, with a focus on haemophilia A and B. Although it is generally accepted that physiological haemostasis is triggered by contact of blood with tissue factor (TF), there remains some controversy regarding the cellular origin of TF in vivo. In addition, the initiation and propagation of thrombin generation are highly dependent on the balance of pro- and anticoagulant functions of endothelium, a profile that varies significantly throughout the vasculature. Drs De Paepe and Malfait address heritable collagen disorders such as the Ehlers-Danlos syndromes (EDS), a heterogeneous group of diseases involving the skin, ligaments and joints, blood vessels and internal organs. Most EDS subtypes are caused by mutations in genes encoding fibrillar collagens, or in genes coding for enzymes involved in posttranslational modifications of collagens. Accurate biochemical and molecular testing is now available for most EDS subtypes and can direct genetic counselling and medical management for these disorders. Dr Shovlin reviews recent developments in hereditary haemorrhagic telengiectasia (HHT), a frequently undiagnosed disorder characterized by arteriovenous malformations in multiple organs. These abnormal blood vessels are the result of mutations in one of a number of genes whose protein products influence TGF-beta signalling in vascular endothelial cells. Several HHT management guidelines have been published and are discussed.
Subject(s)
Collagen Diseases/physiopathology , Ehlers-Danlos Syndrome/physiopathology , Hemophilia A/complications , Hemophilia B/complications , Hemostasis , Collagen/metabolism , Diagnosis, Differential , Ehlers-Danlos Syndrome/diagnosis , Endothelial Cells/physiology , Endothelium/physiology , Epistaxis/genetics , HumansABSTRACT
BACKGROUND: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen alpha1-chains. METHODS: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation. RESULTS: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (17 7/12 years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a "KDEL" endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of alpha1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients. CONCLUSION: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.
Subject(s)
Membrane Glycoproteins/genetics , Mutation , Osteogenesis Imperfecta/genetics , Proteoglycans/genetics , Alternative Splicing , Blotting, Western , Cells, Cultured , Cohort Studies , Collagen Type I/metabolism , Cyclophilins/genetics , Cyclophilins/metabolism , DNA Mutational Analysis , Electrophoresis, Polyacrylamide Gel , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression , Genes, Recessive , Genetic Testing , Humans , Hydroxylation , Immunohistochemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Membrane Glycoproteins/metabolism , Molecular Chaperones , Osteogenesis Imperfecta/diagnosis , Prolyl Hydroxylases , Proteoglycans/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tandem Mass SpectrometryABSTRACT
We describe a 2-year-old male patient with skeletal, neurological, cardiovascular, and connective tissue anomalies. Skeletal anomalies included pectus excavatum, hammer toes and hallux valgus and camptodactyly. The characteristic craniofacial findings of hypertelorism, down slanting palpebral fissures, strabismus, ptosis of eyelids, bifid uvula, high-arched palate and retrognathia were present. The proband has been operated on twice for bilateral inguinal hernia and several times for his foot deformities. Psychomotor development was retarded. At present, echocardiographic findings show aortic root dilation. The patient has important characteristics of Loeys-Dietz syndrome (LDS). Direct sequencing analysis of the transforming growth factor beta receptor I and II (TGFBR1 and 2) genes was performed and was demonstrated heterozygous missense mutation of the TGFBR2 gene in the patient, which confirms the diagnosis of LDS. This is the first Turkish patient with typical clinical signs of LDS. This report also illustrates that LDS and Shprintzen-Goldberg syndrome (SGS) have some common clinical characteristics.
Subject(s)
Aorta/abnormalities , Hand Deformities, Congenital , Loeys-Dietz Syndrome/genetics , Mutation, Missense , Protein Serine-Threonine Kinases/genetics , Receptors, Transforming Growth Factor beta/genetics , Child, Preschool , Craniosynostoses , Dilatation, Pathologic , Hand Deformities, Congenital/genetics , Humans , Male , Receptor, Transforming Growth Factor-beta Type II , TurkeyABSTRACT
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.
Subject(s)
Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Microfilament Proteins/genetics , Adult , Cohort Studies , Ectopia Lentis/diagnosis , Ectopia Lentis/genetics , Ectopia Lentis/pathology , Fibrillin-1 , Fibrillins , Humans , Male , Marfan Syndrome/classification , Marfan Syndrome/pathology , Mutation , PhenotypeABSTRACT
The gene encoding alpha 6(IV) collagen, COL4A6, was identified on the human X chromosome in a head-to-head arrangement and within 452 base pairs of the alpha 5(IV) collagen gene, COL4A5. In earlier studies, intragenic deletions of COL4A5 were detected in a subset of patients with Alport syndrome (AS), a hereditary defect of basement membranes. In some families, AS cosegregates with diffuse leiomyomatosis (DL), a benign smooth muscle tumor diathesis. Here it is shown that patients with AS-DL harbor deletions that disrupt both COL4A5 and COL4A6. Thus, type IV collagen may regulate smooth muscle differentiation and morphogenesis.
Subject(s)
Collagen/genetics , Gene Deletion , Leiomyoma/genetics , Nephritis, Hereditary/genetics , Amino Acid Sequence , Base Sequence , Cell Differentiation , Collagen/chemistry , Exons , Female , Fetus/metabolism , Genetic Linkage , Humans , Male , Molecular Sequence Data , Morphogenesis , Muscle, Smooth/cytology , Mutation , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.