Congenital contractural arachnodactyly is a rare, autosomal dominant connective tissue disorder characterized by contractures, arachnodactyly, scoliosis, and crumpled ears (Hecht and Beals, 1972). It shares overlapping features with Marfan syndrome (154700), which is caused by mutation in the ... Congenital contractural arachnodactyly is a rare, autosomal dominant connective tissue disorder characterized by contractures, arachnodactyly, scoliosis, and crumpled ears (Hecht and Beals, 1972). It shares overlapping features with Marfan syndrome (154700), which is caused by mutation in the gene encoding fibrillin-1 (FBN1; 134797).
Beals and Hecht (1971) described father and 2 sons affected in 1 kindred and father, daughter and son (by different mothers) affected in a second kindred. They proposed that the disorder be called 'contractural arachnodactyly' and further suggested ... Beals and Hecht (1971) described father and 2 sons affected in 1 kindred and father, daughter and son (by different mothers) affected in a second kindred. They proposed that the disorder be called 'contractural arachnodactyly' and further suggested that the patient reported by Marfan (1896) had this disorder rather than the Marfan syndrome (154700) as presently delineated (Hecht and Beals, 1972). They found several other reports, apparently of the same disorder. Beyer et al. (1965) probably described the same condition in a mother and 4 children and some of the reports of combined Marfan syndrome and arthrogryposis multiplex congenita may be further examples (e.g., Reeve et al., 1960; Kingsley-Pillers, 1946). Epstein et al. (1968) described father and son with a connective tissue disorder with some features suggesting the Marfan syndrome and some suggesting osteogenesis imperfecta. Severe kyphoscoliosis, generalized osteopenia, flexion contractures of the fingers and abnormally shaped ears were among the characteristics. Abnormally shaped ('crumpled') ears have been emphasized by other students of CCA. According to Mirise and Shear (1979), the ocular and cardiovascular complications of the Marfan syndrome do not occur in contractural arachnodactyly (Mirise and Shear, 1979). Hence, the correct diagnosis has prognostic significance. Bass et al. (1981) described CCA and Marfan syndrome in the same family. CCA was, however, the predominant finding in 4 generations of the family; the father of the propositus had keratoconus in addition to CCA. Pyeritz (1986) described several patients who had joint contractures and ear changes in the pinna seemingly characteristic of CCA but severe aortic changes typical of the Marfan syndrome. Bawle and Quigg (1992) described a black male with 'crumpled ear' deformity, scoliosis, and arachnodactyly, who had dilatation of the aortic root and ectopia lentis. They pointed to the patient of Reeve et al. (1960), an infant described as having 'Marfan syndrome and arthrogryposis,' who showed ectopia lentis in the right eye and in whom autopsy showed dilatation of the ascending aorta. Anderson et al. (1984) reported a kindred in which many members of 3 generations showed features consistent with CCA. Of the 7 affected persons they examined, 6 had mitral valve prolapse. Family members without CCA did not have mitral valve prolapse. Although enlargement of the aortic root was not found, a 9-year-old girl was said to have 'an aortic diameter at the upper limits of normal.' Gruber et al. (1978) described severe mitral regurgitation in a premature infant with CCA. Reviewing 4 new families and 29 reported ones, Ramos Arroyo et al. (1985) stated that no ocular problems and no aortic problems have been encountered but that congenital heart defects have occurred 'in 14.7%.' Mitral regurgitation is a well-established feature of CCA; involvement of the aorta remains to be documented. Involvement of the eyes is also unclear. Huggon et al. (1990) described an infant girl with CCA complicated by mitral regurgitation. Although slit-lamp biomicroscopy showed no evidence of lens subluxation, the infant had iridodonesis apparently caused by anterior megalophthalmos. Langenskiold (1985) reported a case he followed for 37 years. Currarino and Friedman (1986) described 2 unrelated infants with severe CCA, both of whom died in the first year of life. Cole and Hughes (1992) described an infant with presumed CCA who also had deficiency in the right lower limb. Viljoen et al. (1991) observed 8 affected persons in a family of Asiatic Indian descent. No linkage could be demonstrated with type I collagen probes (120150, 120160). Viljoen (1994) published a review that included at least 40 families with more than 120 affected members with CCA. - Comparison of CCA and Marfan Syndrome Zhang et al. (1994) showed differences of expression of fibrillin-1 and fibrillin-2 in human ear cartilage. They noted that this may account for the fact that abnormally shaped (i.e., crumpled) auricular helices are a hallmark of CCA. Most persons with Marfan syndrome do not have abnormally shaped ears, although some with neonatal Marfan syndrome may have crumpled ears (Godfrey et al., 1995). Similarities between neonatal Marfan syndrome and severe lethal CCA include arachnodactyly, joint contractures, and some facial characteristics. Importantly, although both have severe cardiovascular abnormalities that lead to very early death, the specific cardiac changes are quite different. Wang et al. (1996) tabulated the differences between the 2 syndromes with valvular insufficiency and aortic root dilatation in neonatal Marfan syndrome and structural defects in severe lethal CCA; scoliosis and vertebral anomalies predominantly in CCA; and duodenal atresia, esophageal atresia, and intestinal malrotation only in CCA. Zhang et al. (1995) suggested that expression of fibrillin-2 directs the assembly of elastic fibers during early embryogenesis, whereas fibrillin-1 provides the major structural (i.e., load bearing) function of the microfibrils.
Putnam and Milewicz (1995) and Wang et al. (1995) identified point mutations in the FBN2 gene in cases of CCA. A mutation in a calcium-binding EGF-like motif (612570.0001) was found by the first authors and a mutation in ... Putnam and Milewicz (1995) and Wang et al. (1995) identified point mutations in the FBN2 gene in cases of CCA. A mutation in a calcium-binding EGF-like motif (612570.0001) was found by the first authors and a mutation in a TGF-binding protein-like motif (612570.0002) by the second group. In the father of 2 sibs affected with CCA, Putnam et al. (1997) demonstrated somatic mosaicism for an FBN2 mutation. The 2 sisters had been reported by Delemarre-van de Waal et al. (1980). The proband had arachnodactyly, contractures, crumpled ears, a highly arched palate, and mild retrognathia evident at birth. From the age of 4 years she had progressive thoracolumbar scoliosis, which required surgical correction at the age of 13 years. At 18 years of age, she was 173 cm tall, had crumpled ears, a preauricular tag on the right side, a low posterior hairline, slight bilateral ptosis, and mild retrognathia. She also had striae on her thighs, mild pectus carinatum, arachnodactyly, and contractures of elbows, knees, and fingers. Echocardiogram and ophthalmologic examinations were normal. The sister showed similar findings at birth. Like the sister she had normal mental development but delayed motor development. At 21 years of age, she was 176 cm tall and had crumpled ears, slight midthoracic scoliosis, striae on the upper thighs, arachnodactyly, and contractures. Echocardiogram and ophthalmologic examinations were normal. Both parents were unaffected. Putnam et al. (1997) noted that the mutation (612570.0005), resulting in abnormal splicing of the exon, was an unusual alteration that disrupted the invariant A in a putative branch point sequence found in the upstream intron. Exon 29 was deleted in the mutant allele. Analysis of FBN2 transcript levels by use of fibroblasts from one of the affected sibs indicated that the allele inherited from the mother, which did not contain the exon splicing mutation, was reduced in expression. This difference in FBN2 allele expression levels was also observed in CCA cell strains with previously characterized mutations, which showed greater expression of the mutated alleles (Putnam et al., 1995). These data expanded the spectrum of mutations that cause CCA. Putnam et al. (1997) suggested that the effects of mutations on fibrillin-2 are similar to those observed in fibrillin-1 and Marfan syndrome. Park et al. (1998) identified FBN2 mutations in 6 of 12 unrelated CCA patient cell strains. All of the identified mutations were clustered in a limited region of the gene, a region corresponding to that in FBN1 where mutations produce the severe, congenital form of Marfan syndrome, so-called neonatal Marfan syndrome. Furthermore, 3 of the identified mutations occurred in the FBN2 locations exactly corresponding to FBN1 mutations that had been reported in cases of neonatal Marfan syndrome. These mutations indicate that this central region of both fibrillins plays a critical role in human embryogenesis. The limited region of FBN2 that can be mutated to cause CCA may also help explain the rarity of CCA compared to Marfan syndrome. Belleh et al. (2000) reported 2 additional FBN2 mutations in CCA: C1141F in exon 26 (612570.0008) and C1252W in exon 29 (612570.0009). As in previous cases, mutations clustered in the region of fibrillin-2 homologous to the so-called neonatal Marfan syndrome region of fibrillin-1 (FBN1; 134797) (Kainulainen et al., 1994). Gupta et al. (2002) noted that all of the identified CCA mutations in FBN2 cluster in a limited region similar to that where severe Marfan syndrome mutations cluster in FBN1, specifically between exons 23 and 34. Gupta et al. (2002) screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single-stranded conformation polymorphism analysis followed by direct sequencing. They successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this region. None of these identified FBN2 mutations alter amino acids in the calcium-binding consensus sequence in the EGF-like domains, whereas many of the FBN1 mutations alter the consensus sequence. Gupta et al. (2002) reviewed the 21 known CAA mutations in the FBN2 gene, along with available clinical information on the probands. They found that 3 of the 21 patients had dilatation of the aortic root. All 3 were young, and the degree of dilatation appeared to have been borderline in all. However, because of the lack of knowledge of the natural history of aortic involvement in CCA, Gupta et al. (2002) recommended that all CCA patients have an echocardiogram. They cited Su et al. (2000) as indicating that approximately 15% of CCA patients have congenital heart defects. Their review did not support this conclusion, instead suggesting that congenital heart defects are only an occasional finding in these patients.
Classic congenital contractural arachnodactyly (CCA) is diagnosed based on a constellation of clinical findings [Godfrey 2004]. Individuals with CCA typically have the following: ...
DiagnosisClinical DiagnosisClassic congenital contractural arachnodactyly (CCA) is diagnosed based on a constellation of clinical findings [Godfrey 2004]. Individuals with CCA typically have the following: A marfanoid habitus (long, thin limbs, narrow head and body) Flexion contractures of multiple joints including elbows, knees, hips, and fingers Kyphoscoliosis (sometimes severe) Muscular hypoplasia Abnormal pinnae (“crumpled” outer helices) Severe/lethal CCA is a rare form of CCA [Wang et al 1996, Snape et al 2006]. In addition to the typical features described for classic CCA, infants with severe/lethal CCA have the following anomalies: Cardiovascular: atrial or ventricular septal defect, interrupted aortic arch, single umbilical artery, and aortic root dilatation (rare) Gastrointestinal: duodenal or esophageal atresia and intestinal malrotation Molecular Genetic TestingGene. FBN2 is the only gene in which mutations are known to cause congenital contractural arachnodactyly. Evidence for locus heterogeneity. Given that fewer than 100% of individuals with CCA have an identifiable FBN2 mutation, locus heterogeneity is possible [Callewaert et al 2009, Nishimura et al 2007]. Table 1. Summary of Molecular Genetic Testing Used in Congenital Contractural ArachnodactylyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFBN2Sequence analysis Sequence variants 227% 3, 44% 4, 75% 5See footnotes 6 and 7Clinical Deletion / duplication analysis 8Exonic and whole-gene deletions / duplicationsUnknown; none reported 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Nishimura et al [2007] 4. Callewaert et al [2009]5. Carmical et al [2000], Gupta et al [2002] 6. Only a small number of infants with severe/lethal CCA have been reported. A mutation in the same FBN2 region was identified in the one infant analyzed [Snape et al 2006]. 7. Although most clinical laboratories sequence exons and flanking intronic regions from genomic DNA, sequence analysis of cDNA may be possible and has the advantage of easier detection/confirmation of mutations that affect splicing. 8. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and array CGH may be used.9. No deletions or duplications of FBN2 have been reported to cause congenital contractural arachnodactyly. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. Diagnosis of CCA is based on the clinical features present. Molecular analysis can be confirmatory, but as noted in studies in which the entire coding region was sequenced, fewer than half of clinically identified probands have detected FBN2 mutations.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be caused by mutations in FBN2. Because all mutations that cause CCA are clustered in a rather limited region of FBN2 (i.e., exons 24 through 36), one can hypothesize that mutations falling outside of this region may cause disorders or syndromes not yet attributed to FBN2, or may have no phenotypic effect.
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. At the most severe end is “severe/lethal CCA.” This form of CCA is rare, with few cases reported in the literature, one of which has been confirmed using molecular testing. ...
Natural HistoryCongenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. At the most severe end is “severe/lethal CCA.” This form of CCA is rare, with few cases reported in the literature, one of which has been confirmed using molecular testing. Phenotypic expression is variable within and between families. In one report, a mother with somatic mosaicism that affected the germline had features of classic CCA, while her daughter, who inherited the mutant FBN2 allele, had the severe/lethal form of CCA [Wang et al 1996].Classic CCA. The following are seen in individuals with CCA: Marfan syndrome-like appearance characterized by a tall and slender habitus with arm span exceeding height Arachnodactyly (long slender fingers and toes) “Crumpled” ears that present as a folded upper helix of the external ear Joint contractures at birth:Knees (81%) and elbows (86%) are most commonly affected. The proximal interphalangeal joints of the fingers and toes display flexion contractures (i.e., camptodactyly). Hip contractures (26%) are also seen. Adducted thumbs (46%) and club foot may occur. Contractures usually improve with time. Bowed long bones (31%) and muscular hypoplasia (65%) Kyphosis/scoliosisPresent in about 50% of affected individuals Begins as early as infancy and is progressive, causing the greatest morbidity in CCA Aortic root dilatation, documented in individuals with CCA with a characterized FBN2 mutation [Park et al 1998, Carmical et al 1999, Gupta et al 2002, Snape et al 2006, Callewaert et al 2009]. Its frequency is unknown.Additional craniofacial abnormalities (significantly less common): Mild micrognathiaHigh arched palate Scaphocephaly Brachycephaly Dolichocephaly Frontal bossing Severe/lethal CCA. In addition to the typical skeletal findings (arachnodactyly, joint contractures, scoliosis) and abnormally shaped ears of CCA, infants with the severe/lethal form have multiple cardiovascular and gastrointestinal anomalies [Wang et al 1996]. Although data are limited, all individuals with severe/lethal CCA have required surgery for various congenital malformations as early as the first week of life. Respiratory complications have been the cause of death in most. The age of death has ranged from eight days to 11.5 months.
A number of disorders have features that overlap with those of congenital contractural arachnodactyly (CCA)....
Differential DiagnosisA number of disorders have features that overlap with those of congenital contractural arachnodactyly (CCA).The disorder most similar to CCA is the Marfan syndrome, caused by mutations in FBN1. Individuals with Marfan syndrome have lens subluxation, high myopia, and progressive aortic root dilation not characteristic of CCA; they also lack the "crumpled" ears and joint contractures seen at birth in individuals with CCA. Until molecular genetic studies distinguished the two disorders, it was speculated that they could be allelic. Differentiating the two disorders is most important given the severe cardiovascular complications and cardiac monitoring essential in individuals with the Marfan syndrome. The Marfan syndrome and CCA can be distinguished by clinical findings. Diagnosis of either requires the presence of a constellation of clinical features. In both disorders, clinical diagnosis is the gold standard; molecular genetic testing can be used for confirmation of the diagnosis in some instances. The severe/lethal form of CCA may be mistaken for the neonatal Marfan syndrome, the most severe end of the spectrum of the Marfan syndrome, in which the cardiovascular abnormalities include mitral and tricuspid valve anomalies and dilated aorta, while those in severe/lethal CCA include atrial and/or ventricular septal defects and interrupted aortic arch.Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families. At present, no consensus minimal clinical diagnostic criteria exist. Mutations affecting one of three genes (COL2A1, COL11A1, and COL11A2) have been associated with Stickler syndrome. Some individuals with Stickler syndrome have a marfanoid body habitus and typically the fingers are long and gracile, which may suggest the diagnosis of CCA. However, in Stickler syndrome joint laxity is present, as are other findings not typical for CCA, including myopia and retinal detachment, hearing loss that is both conductive and sensorineural, and midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence). Homocystinuria, a multisystem disorder of amino acid metabolism caused by cystathionine β-synthase deficiency, typically affects the skeleton, joints, eye, and central nervous system. Skeletal features are similar to those seen in CCA and Marfan syndrome, and include limited joint mobility, dolichostenomelia, arachnodactyly, and kyphoscoliosis. Homocystinuria is clinically distinguishable from CCA by its other manifestations, such as lens subluxation, osteoporosis, and often developmental delay, as well as predisposition to thromboembolism. It can be definitively diagnosed by serum amino acid analysis. Distal arthrogryposis is a hereditary congenital joint contracture disorder, characterized by involvement of the hands and feet. Typical joint findings are medially overlapping fingers, clenched fists, ulnar deviation of fingers, camptodactyly, positional foot deformities, and clubfoot. Distal arthrogryposis can be clinically distinguished from CCA by absence of marfanoid habitus, arachnodactyly, contractures of knees and elbows, and crumpled ears. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Classic CCASevere/lethal CCA
To establish the extent of disease in an individual diagnosed with congenital contractural arachnodactyly (CCA), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with congenital contractural arachnodactyly (CCA), the following evaluations are recommended:Echocardiogram Musculoskeletal examination for the presence of contractures and kyphosis/scoliosis Medical genetics consultationTreatment of ManifestationsClassic CCAPhysical therapy for joint contractures helps increase joint mobility and ameliorate the effects of muscle hypoplasia (usually calf muscles). This type of therapy is best instituted in childhood. As affected individuals age, spontaneous improvement in camptodactyly is frequently observed. Surgical release of contractures may be necessary. The kyphoscoliosis tends to be progressive, requiring bracing and/or surgical correction. Consultation with an orthopedist is encouraged. Aortic root dilation, if present, is managed in a standard manner. Severe/lethal CCA. no general recommendations exist; findings need to be managed in a standard manner as they arise. SurveillanceThe following are appropriate:Echocardiogram every two years until it is clear that the aorta is not involved At least annual physical examination for evidence of kyphosis/scoliosis Evaluation of Relatives at RiskEstablishing the diagnosis of CCA early in at-risk relatives may permit more careful surveillance of affected individuals (see Surveillance).See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Contractural Arachnodactyly: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFBN25q23.3Fibrillin-2FBN2 @ LOVDFBN2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Contractural Arachnodactyly (View All in OMIM) View in own window 121050ARTHROGRYPOSIS, DISTAL, TYPE 9; DA9 612570FIBRILLIN 2; FBN2Molecular Genetic PathogenesisFibrillin 2 was serendipitously discovered during the search for the molecular basis of the Marfan syndrome and the identification of FBN1. Fibrillin 2 is co-distributed with fibrillin 1 in many tissues of the developing embryo. Fibrillin 2 expression appears to be greatest in matrices rich in elastic fibers. Studies have compared the distribution of fibrillin 1 and fibrillin 2 in tissues. For example, human ear cartilage shows differential expression of the two fibrillins. Abnormally shaped auricular helices are a hallmark of congenital contractural arachnodactyly (CCA). Immunostaining studies of fetal aorta have shown preferential staining of fibrillin 2 in the elastic-rich media, while fibrillin 1 immunostaining was observed in all three aortic layers. In hyaline cartilage, fibrillin 1 was seen throughout the tissue, while fibrillin 2 was localized to the periphery and perichondrium. Fibrillin 2 expression in the lung was also lower than that of fibrillin 1.Given the differential expression of the fibrillins in fetal tissue and the much lower expression of fibrillin 2 versus fibrillin 1 in adult tissues, a general hypothesis has emerged: fibrillin 2 directs the assembly of elastic fibers during early embryogenesis, while fibrillin 1 provides the major structural (i.e., "load-bearing") function of the microfibrils [Robinson & Godfrey 2000].Normal allelic variants. FBN2 is highly homologous to FBN1, mutations in which are known to cause the Marfan syndrome. The structure of FBN2 has been described by Zhang et al [1994]. It encodes a multidomain protein with five distinct structural regions comprising 65 exons. The largest of these structural regions contains 41 calcium binding-epidermal growth factor (cb-EGF)-like domains. The single longest stretch of cb-EGF-like domains is 12; it is here that all mutations causing CCA have been found to date. This is also the region of greatest homology between the fibrillins. Upstream from this region of high homology is a region (encoded by a single exon) with the most divergence. This highly divergent region is proline rich in fibrillin 1 and glycine rich in fibrillin 2. Pathologic allelic variants. Table 2 (pdf) lists selected FBN2 mutations. Most mutations identified to date cluster in the single longest stretch of cb-EGF-like domains of FBN2 [Park et al 1998, Gupta et al 2002, Frédéric et al 2009, Callewaert et al 2009].Normal gene product. Fibrillin 2 is a glycoprotein of the extracellular matrix microfibrils. Abnormal gene product. The precise function of fibrillin 2 is not known. Therefore, the mechanism of an abnormal gene product in contributing to the pathophysiology of CCA is not known. Of note, mice lacking Fbn2 or having a mutation in that gene have syndactyly. This finding suggests that FBN2 mutations outside the "neonatal region" may cause non-CCA phenotypes in humans [Arteaga-Solis et al 2001, Chaudhry et al 2001].