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Genetics in Medicine : Official Journal... Jan 2020Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and...
PURPOSE
Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.
METHODS
In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.
RESULTS
The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.
CONCLUSIONS
Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
Topics: Arachnodactyly; Child; Contracture; Diagnosis, Differential; Early Diagnosis; Female; Fibrillin-2; Genetic Testing; Humans; Male; Marfan Syndrome; Phenotype; Retrospective Studies; Sensitivity and Specificity; Sequence Analysis, DNA
PubMed: 31316167
DOI: 10.1038/s41436-019-0609-8 -
Journal of Medical Genetics Aug 1994Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder akin to, but usually less severe than, Marfan syndrome. The clinical features are... (Review)
Review
Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder akin to, but usually less severe than, Marfan syndrome. The clinical features are marfanoid habitus, arachnodactyly, crumpled ears, camptodactyly of the fingers and adducted thumbs, mild contractures of the elbows, knees, and hips, and mild muscle hypoplasia especially of the calf muscles. Many patients have kyphoscoliosis and mitral valve prolapse and, very occasionally, aortic root dilatation and ectopia lentis have been described. Linkage to a gene coding for fibrillin on chromosome 5q23-31 has been shown in several kindreds. The prognosis for a normal lifespan is good and improvement in joint contractures is usual.
Topics: Abnormalities, Multiple; Chromosomes, Human, Pair 5; Contracture; Diagnosis, Differential; Ear, External; Fibrillins; Fingers; Genes, Dominant; Genetic Linkage; Humans; Kyphosis; Marfan Syndrome; Microfilament Proteins; Scoliosis; Syndrome
PubMed: 7815423
DOI: 10.1136/jmg.31.8.640 -
Frontiers in Genetics 2022Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly,...
Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients' blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported variants were identified through exome sequencing. Two variants outside of the neonatal region of gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of and in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.
PubMed: 35360850
DOI: 10.3389/fgene.2022.804202 -
Genetics in Medicine : Official Journal... Feb 2022Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone.
PURPOSE
Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone.
METHODS
We defined the bone phenotype and clinical predictors of low bone density and fracture risk in 77 patients with LDS type 1 to type 5.
RESULTS
Patients with LDS had dual-energy x-ray absorptiometry (DXA) Z-scores significantly < 0, and 50% of children and 9% of adults had Z-scores < -2. Sixty percent of patients had ≥1 fracture, and 24% of patients with spinal x-rays scans showed spinal compression fractures. Lower body mass index, asthma, male sex and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. The count of 5 LDS-associated skeletal features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly) in patients with LDS was correlated with DXA Z-score. Adults with ≥1 skeletal features had DXA Z-scores significantly < 0, and children with >2 features had DXA Z-score significantly < -2. Bone turnover markers suggest accelerated bone resorption. Data from 5 patients treated with bisphosphonates suggest a beneficial effect.
CONCLUSION
All LDS types are associated with reduced bone density and increased risk of fracture, which may be due to increased bone resorption. Clinical features can predict a subgroup of patients at highest risk of low bone density and fracture risk.
Topics: Absorptiometry, Photon; Bone Density; Bone Diseases, Metabolic; Fractures, Bone; Humans; Loeys-Dietz Syndrome; Male
PubMed: 34906513
DOI: 10.1016/j.gim.2021.10.002 -
Italian Journal of Pediatrics Jun 2022Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity,... (Review)
Review
BACKGROUND
Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity, craniofacial and skeletal features, joint laxity or contractures, skin abnormalities, hypotonia and motor delay. Its diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes. In newborns and toddlers, vascular complications such as aneurism rupture, aortic dissection, and intracerebral incidents, can occur already in the weeks of life. To avoid these events, it is crucial to precociously identify this condition and to start an apunderwent a surgical procedurepropriate treatment which, depending on the severity of the vascular involvement, might be medical or surgical.
CASE PRESENTATION
We report two cases of Loeys-Dietz syndrome precociously diagnosed. The first describes a male, born at 38 + 1 weeks of gestation, with hypotonia, joint hypermobility, arachnodactyly, and fingers joint contractures, as well as senile appearance and facial dysmorphisms. In the suspect of a connective tissue disorder, an echocardiography was performed and revealed an aortic root dilatation of 13 mm (Z score + 3). A trio based Whole Exome Sequencing found a novel de novo variant in the TGFBR2 gene. Despite the onset of a low-dose angiotensin receptor blocker therapy, the aneurysm progressed. The second case describes a female, born at 41 + 3 weeks of gestation. During the neonatal examination a cleft palate was noticed, as well as minor dysmorphisms. Since the family history was suspicious for connective tissue disorders, a genetic panel was performed and identified a pathogenetic variant in TGFB3 gene. In this case, the echocardiography revealed no abnormalities.
CONCLUSIONS
In addition to our cases, we identified 14 subjects with neonatal LDS in the medical literature. All of them had aortic involvement. Skeletal and face abnormalities, including eyes and palate malformations, were also highly frequent. Overall, 10 subjects required medical therapy to avoid aneurysm progression, and 8 patients underwent surgical procedures. Benefits of an early diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.
Topics: Connective Tissue Diseases; Contracture; Female; Humans; Infant, Newborn; Loeys-Dietz Syndrome; Male; Muscle Hypotonia; Receptor, Transforming Growth Factor-beta Type II; Transforming Growth Factor beta3
PubMed: 35668506
DOI: 10.1186/s13052-022-01281-y -
Orphanet Journal of Rare Diseases Aug 2019Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50-60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power.
RESULTS
Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (OR: 0.654 [0.408-1.046]; OR : 1.291 [0.860-1.939]) or palate anomalies (OR: 1.731 [0.708-4.234]; OR : 0.628 [0.286-1.382]).
CONCLUSIONS
The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
Topics: Arachnodactyly; Chromosome Deletion; Craniosynostoses; Humans; Marfan Syndrome; Phenotype
PubMed: 31399107
DOI: 10.1186/s13023-019-1170-x -
British Medical Journal Oct 1958
Topics: Arachnodactyly; Humans; Marfan Syndrome
PubMed: 13572946
DOI: No ID Found -
Brain and Behavior Aug 2021Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and...
Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and interpretation, and IQ scores do not translate into insights on implicated brain systems that can link genes to behavior. Individuals with 22q11.2 deletion syndrome (22q11.2DS) often undergo IQ testing to address special needs, but access to testing in resource-limited settings is challenging. The brief Penn Computerized Neurocognitive Battery (CNB) provides measures of cognitive abilities related to brain systems and can screen for cognitive dysfunction. To examine the relation between CNB measures and IQ, we evaluated participants with the 22q11.2DS from Philadelphia and Tel Aviv (N = 117; 52 females; mean age 18.8) who performed both an IQ test and the CNB with a maximum of 5 years between administrations and a subsample (n = 24) who had both IQ and CNB assessments at two time points. We estimated domain-level CNB scores using exploratory factor analysis (including bifactor for overall scores) and related those scores (intraclass correlations (ICCs)) to the IQ scores. We found that the overall CNB accuracy score showed similar correlations between time 1 and time 2 as IQ (0.775 for IQ and 0.721 for CNB accuracy), correlated well with the IQ scores (ICC = 0.565 and 0.593 for time 1 and time 2, respectively), and correlated similarly with adaptive functioning (0.165 and 0.172 for IQ and CNB, respectively). We provide a crosswalk (from linear equating) between standardized CNB and IQ scores. Results suggest that one can substitute the CNB for IQ testing in future genetic studies that aim to probe specific domains of brain-behavior relations beyond IQ.
Topics: Adolescent; Arachnodactyly; DiGeorge Syndrome; Female; Humans; Intelligence; Intelligence Tests; Marfan Syndrome
PubMed: 34213087
DOI: 10.1002/brb3.2221 -
The Western Journal of Medicine Jan 1974
Topics: Abnormalities, Multiple; Child, Preschool; Contracture; Female; Humans; Infant; Marfan Syndrome
PubMed: 4812212
DOI: No ID Found -
Nagoya Journal of Medical Science Aug 2013Cohen syndrome is a very rare disease. Complication by spinal deformity has been reported, but management and surgery for spinal deformity in Cohen syndrome has not been... (Review)
Review
Cohen syndrome is a very rare disease. Complication by spinal deformity has been reported, but management and surgery for spinal deformity in Cohen syndrome has not been previously described. The objective of this study was to examine the outcome of surgical treatment for kyphoscoliosis of Cohen syndrome with a literature review. The patient was a 14-year-old male with the characteristics of Cohen syndrome: truncal obesity, mental retardation, arachnodactyly, microcephalia, and a facial malformation. Scoliosis was conservatively treated with a brace at 13 years of age, but the spinal deformity rapidly progressed within a year. Plain radiographs before surgery showed scoliosis of 47 degrees (T5-T11) and 79 degrees (T11-L3), and kyphosis of 86 degrees (T7-L1). One-stage anteroposterior corrective fusion of T4-L3 was scheduled after 2-week Halo traction. Postoperative respiratory management was carefully performed because of Cohen syndrome-associated facial malformation, obesity, and reduced muscle tonus. Respiration was managed with intubation until the following day and no respiratory problems occurred. After surgery, thoracolumbar scoliosis was 28 degrees (correction rate: 65%). Kyphosis was markedly improved from 86 degrees to 20 degrees, achieving a favorable balance of the trunk. The outcome is favorable at 6.5 years after surgery. In conclusion, Cohen syndrome is often complicated by spinal deformity, particularly kyphosis, that is likely to progress even in adulthood. In our patient, spinal deformity progressed within a short period, even with brace treatment. Surgery should be required before progression to the severe spinal deformity with careful attention to general anesthesia.
Topics: Adolescent; Anesthesia, General; Developmental Disabilities; Female; Fingers; Humans; Intellectual Disability; Kyphosis; Male; Microcephaly; Muscle Hypotonia; Myopia; Obesity; Retinal Degeneration; Scoliosis; Surgical Procedures, Operative; Treatment Outcome
PubMed: 24640185
DOI: No ID Found