Congenital Contractural Arachnodactyly Research Articles

Spine deformity surgery in patients with Beals syndrome can be effectively performed but does risk revision surgery.

Beals syndrome or congenital contractual arachnodactyly is a rare disorder characterized by multiple joint contractures, Marfanoid body habitus and crumpled ears and has been associated with scoliosis. This study reports a clinical series of patients with Beals syndrome who have had surgical treatment for their spinal deformity. A retrospective review of all patients at a single institution who had a genetically-confirmed diagnosis of Beals syndrome and had surgical treatment for their scoliosis were reviewed for surgical outcome and complications. There were eight patients who had surgery at an average age of 11.5years, four were female and four had cardiovascular abnormalities requiring treatment. The preoperative coronal Cobb was 82.3° which improved to 42.1°(46.8% correction), and 46.5° (43.5% correction) at final follow-up. Preoperative halo-gravity-traction was used in three patients. Three patients had a posterior instrumentation and fusion (PSFI), 2 a combined anterior/PSFI, 1 had tethering, 1 with PSFI with posteriorly-approached discectomy, and 1 with a PSFI and vertebral column resection. One of the eight patients had a critical intraoperative neuromonitoring event but was normal following appropriate responses and no patient awoke with neurologic deficits. Two had an unplanned return to the operating room for implant dislodgement and each had a successful revision. Scoliosis associated with Beals syndrome can have large curves at the time of surgery and require a variety of surgical approaches to achieve a good result. Revision surgery with return to the operating room is necessary in 25% of patients.

High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

FBN2 pathogenic variants in congenital contractural arachnodactyly with severe cardiovascular manifestations

ABSTRACT Purpose Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene. Materials and Methods Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations. Results The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype. Conclusions This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.

A Novel Splice Site Mutation in the FBN2 Gene in a Chinese Family with Congenital Contractural Arachnodactyly

Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive kyphoscoliosis, pectus deformity and abnormal crumpled ears. FBN2 is the only gene currently known to be associated with CCA. In this study, we report on a prenatal case presented with skeletal, cardiac and spinal malformations. And his father had elongated limbs, contractures of the proximal interphalangeal joints, high myopia and scoliosis. We conducted whole exome sequencing (WES) on the fetus-parental trio and a heterozygous variant (hg19 chr5:127,673,685, c.3598 + 4A > G, NM_001999.4) in intron 27 of the FBN2 gene was successfully identified, inherited from the father. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (126 bp) by disrupting the splice-donor site and destroyed the 17th calcium-binding epidermal growth factor-like (cbEGF) domain. Our research not only finds the etiology of the disease in affected individuals and expands the mutation spectrum of FBN2 gene, but also provides genetic counseling and fertility guidance for this family.

Two cases of Birt-Hogg-Dubé syndrome combined with congenital contractural arachnodactyly.

Two cases of Birt-Hogg-Dubé syndrome combined with congenital contractural arachnodactyly.

Carrying both COL1A2 and FBN2 gene heterozygous mutations results in a severe skeletal clinical phenotype: an affected family

BackgroundOsteogenesis imperfecta (OI) is the most common monogenic disease of the skeletal system and is usually caused by mutations in the COL1A1 or COL1A2 genes. Congenital contractural arachnodactyly syndrome (CCA) is an autosomal dominant hereditary disease of connective tissue. To date, the FBN2 gene is the only gene reported to cause CCA. Researchers found that COL1A2 and FBN2 are both involved in the extracellular matrix organization pathway. These findings suggest that these two genes play an important role in a similar mechanism and may trigger a synergistic effect.MethodsTrio-whole-exome sequencing (Trio-WES) was performed to analyse the underlying genetic cause of a proband with OI in a Chinese family. Sanger sequencing was used to validate the mutations in 3 members of the family with OI with varying degrees of severity of skeletal abnormalities and the members with no clinical signs.ResultA c.3304G > C mutation in the COL1A2 gene (p.Gly1102Arg) and a novel c.4108G > T mutation in the FBN2 gene (p.Glu1370*) were detected in the proband, an affected member of the family. The affected individuals with both mutations present a more severe phenotype, while affected individuals present a milder phenotype if only the mutation in COL1A2 is detected (c.3304G > C). The unaffected individual in this family did not have any mutations in the COL1A2 gene or FBN2 gene.ConclusionOur study is the first clinical report to indicate that patients carrying concomitant mutations in both the COL1A2 and FBN2 genes may present with more severe skeletal abnormalities. Furthermore, our study suggests the possibility of synergistic effects between the COL1A2 and FBN2 genes.

The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2.

Different pathogenic variants in the fibrillin‐1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin‐2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2‐related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2‐related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the “tall” and “short” fibrillinopathies. The future parallel functional study of both FBN1/2‐related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.

Practical considerations in the anaesthetic management of thoracolumbar scoliosis correction surgery in a child with hecht–beals syndrome

Practical considerations in the anaesthetic management of thoracolumbar scoliosis correction surgery in a child with hecht–beals syndrome - IJCA- Print ISSN No: - 2394-4781 Online ISSN No:- 2394-4994 Article DOI No:- 10.18231/j.ijca.2022.058, Indian Journal of Clinical Anaesthesia-Indian J Clin Anaesth

Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly.

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 FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 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 FBN2 and ANKRD11 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.

Family with congenital contractural arachnodactyly due to a novel multiexon deletion of the FBN2 gene

Congenital contractural arachnodactyly (CCA) is caused by pathogenic FBN2 variants; however, the contributions of copy number variations (CNVs) to CCA are still unknown. Here, we report on a familial case of CCA, in which a novel multiexon deletion of exons 35–39 in FBN2 was identified after simple CNV prediction.

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly.

Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA. Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA. Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient’s family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members. Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively. Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Arachnodactyly represented in art

Arachnodactyly, a term used since 1902 to describe abnormally long (spider-like) fingers, is a pathologic feature of several heritable conditions, notably the Marfan syndrome and congenital contractural arachnodactyly. A number of prominent artists, dating from the 16th to the 20th centuries, have depicted subjects with unusually long fingers, sometime associated with elongation of the body, neck and head. El Greco incorporated this style in many paintings. Little evidence supports any subject in any of these paintings as having a congenital deformity.

Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2

Fibrillin-2, encoded by FBN2, plays an important role in the early process of elastic fiber assembly. To date, heterozygous pathogenic variants in FBN2 have been shown to cause congenital contractural arachnodactyly (CCA; Beals-Hecht syndrome). Classical CCA is characterized by long and slender fingers and toes, ear deformities, joint contractures at birth, clubfeet, muscular hypoplasia and often tall stature. In individuals with a severe CCA form, different cardiovascular or gastrointestinal anomalies have been described. Here, we report on a 15-year-old girl with a severe form of CCA and novel biallelic variants in FBN2. The girl inherited the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother. We could detect only a small amount of FBN2 transcripts harboring the nonsense variant in leukocyte-derived mRNA from the patient and mother suggesting nonsense-mediated mRNA decay. As the father did not show any clinical signs of CCA we hypothesize the missense variant c.3563G > T to be a hypomorphic allele. Taken together, our data suggests that severe CCA can be inherited in an autosomal-recessive manner by compound heterozygosity of a hypomorphic and a null allele of the FBN2 gene.

Based on a cohort of 52,879 microarrays, recurrent intragenic FBN2 deletion encompassing exons 1–8 does not cause Beals syndrome

IntroductionCongenital contractural arachnodactyly (CCA) is a rare connective tissue disorder, associated with heterozygous mutations in the FBN2 gene. The objective of this study was to evaluate the prevalence of an intragenic deletion encompassing exons 1–8 of FBN2 gene in Israeli population. Materials and methodsA search for intragenic FBN2 microdeletions was performed in two databases of chromosomal microarray analysis (CMA) – genetic laboratory of a tertiary medical center (the primary cohort) and one of the largest Israeli health maintenance organizations (replication cohort). ResultsOverall, 52,879 microarray tests were searched for FBN2 microdeletions. The primary cohort constituted of 18,301 CMA tests, among which 33 intragenic FBN2 microdeletions in unrelated individuals were found (0.18%). Prenatal prevalence of this variant was 0.23% (28/12,604), and specifically in low risk pregnancies - 0.29% (22/7464). Of the 28 cases with known parental origin, 27 (96.4%) were of full or partial Ashkenazi Jewish ethnic background. The approximate allele incidence in the Ashkenazi Jewish origin was 0.4% (18/4961). Combined with the 34,578 CMA tests in the replication cohort, the overall frequency of FBN2 microdeletions was 0.24% (125/52,879). None of the pre- or postnatal cases had any clinical manifestations of CCA. DiscussionIntragenic FBN2 microdeletions are found in one of every 420 CMA analyses in Israeli population, and in particular one of every 340 low-risk pregnancies. Due to high allele incidence in Ashkenazi Jewish population (1:275), we suggest that FBN2 gene deletion detected by CMA among Ashkenazi Jews should be interpreted as benign copy number variant.

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension

To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. Children (n=70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n=7, TBX4 n=8, ACVRL1 n=1, KCNK3 n=1, and EIF2AK4 n=2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.

Are Fibrillin‐Notch Interactions Important in Development and Disease?

In humans, mutations in the gene for fibrillin‐1 (FBN1) cause both the Marfan syndrome as well as several types of acromelic dysplasias. Musculoskeletal features of the Marfan syndrome (long bone overgrowth and arachnodactyly, joint hypermobility, and a muscle wasting phenotype) are the opposite of those in acromelic dysplasias (short stature and brachydactyly, joint stiffness, and a hypermuscular build). How mutations in the same gene can result in opposite phenotypes is poorly understood. Mutations in FBN2 cause congenital contractural arachnodactyly, which features a mixture of related musculoskeletal features (muscle hypoplasia, contractures of the large and small joints and arachnodactyly).The fibrillins are multifunctional glycoproteins that polymerize into extracellular matrix microfibrils. Although we have associated fibrillin microfibril structure with the opposite musculoskeletal features of Marfan syndrome and acromelic dysplasias, we can only speculate that perturbations in growth factor signaling are involved. To begin to address this gap in our understanding, we hypothesize that direct interactions between fibrillin and cells coordinate growth factor signaling. Therefore, we searched for interactions between fibrillin and cellular receptors.Fibrillins, like Notch receptors and Notch ligands, are composed of multiple tandemly repeated cbEGF‐like domains. Each fibrillin contains 43 cbEGF‐like domains. What if Notch receptors or ligands also bind to fibrillins in the extracellular matrix? Our biochemical data imply that fibrillin interactions with Notch receptors or ligands are just as likely to occur in vivo as interactions between Notch receptors and known Notch transmembrane ligands. Human genetic evidence support significant roles for Notch signaling components in vascular and musculoskeletal diseases, tissues primarily affected in the fibrillinopathies.The current concept of Notch signaling is based strictly on cell‐cell communication. Our investigations have the potential to transform current understanding of context‐dependent Notch signaling by introducing the possibility that Notch signaling components also interact with fibrillin extracellular matrix.Support or Funding Informationgrants from the Shriners Hospitals for Children to Lynn Y. Sakai

A clinical scoring system for congenital contractural arachnodactyly

PurposeCongenital 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. MethodsIn 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. ResultsThe 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. ConclusionsOur clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies.

Genome‐scale high‐throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population‐based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal‐dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co‐occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal‐dominant disorders, enabling the estimation of variant‐filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co‐occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co‐occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.

Establishment of a Beals syndrome patient-derived human induced pluripotent stem cell line HELPi001-A.

The human induced pluripotent stem cell line HELPi001-A was derived from peripheral blood mononuclear cells (PBMC) of a 35-year-old female Beals syndrome patient carrying a heterozygous FBN2c.728 T > C mutation. HELPi001-A were positive for pluripotent stem cell markers, had a normal karyotype and the ability to differentiate into cells representing all three germ layers. The patient not only demonstrated typical characteristics of Beals syndrome such as joint contractures and crumpled ears, but also demonstrated aortic dissection. HELPi001-A could serve as a platform for exploring the pathogenesis of cardiovascular and connective tissue disorders related to FBN2 mutation.