Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) was described by Beals and Hecht as an autosomal dominant disorder distinct from Marfan syndrome and comprising joint contractures, arachnodactyly, scoliosis, and a distinct “crumpled ear” deformity. While the disorder is similar to Marfan syndrome, it was split from it due to the distinct physical appearance of the patients and, more importantly, the lack of heart and eye findings. Since the original report, several CCA patients have been found to have mitral valve prolapse, structural cardiac anomalies, and occasionally aortic root dilatations similar to those seen in Marfan syndrome. We report on a patient with CCA with bilateral ectopia lentis and aortic root dilatation. Our review of the literature of CCA showed that serial echo-cardiography and careful eye examinations have not become a standard of medical practice in this condition. Partly this may be due to a lack of documented cases of CCA having severe ectopia lentis and cardiac complications. This patient underscores the need for periodic eye and echocardiographic evaluations of all CCA patients.     

Two novel fibrillin-2 mutations in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin-2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin-2 region homologous to the so-called neonatal Marfan syndrome region of fibrillin-1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3' UTR polymorphism is also described.     

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.     

A severe form of congenital contractural arachnodactyly in two newborn infants

Congenital contractural arachnodactyly (CCA) is an uncommon condition characterized by arachnodactyly, dolichostenomelia, kyphoscoliosis, "crumpled" auricles, and flexion contractures at knees, elbows, fingers, and sometimes other joints. The long-term prognosis for affected individuals is usually relatively good. We report on two newborn infants with severe CCA, both of whom died in the first year of life. One child also had other anomalies not generally associated with this disorder. These observations are consistent with the possibility that CCA is an etiologically and clinically heterogeneous disorder.     

Two novel fibrillin‐2 mutations in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin‐2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin‐2 region homologous to the so‐called neonatal Marfan syndrome region of fibrillin‐1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3′ UTR polymorphism is also described. Am. J. Med. Genet. 92:7–12, 2000. © 2000 Wiley‐Liss, Inc.     

Cardiovascular findings in congenital contractural arachnodactyly: Report of an affected kindred

Three generations of a kindred had a history and physical findings consistent with congenital contractural arachnodactyly (CCA) segregating in an autosomal-dominant manner. Six of the seven affected patients we examined had mitral valve prolapse (MVP) diagnosed clinically or by echocardiography. The family members without CCA did not have MVP. This association of cardiac involvement with CCA further lessens the distinction between CCA and the Marfan syndrome. The indication for ophthamologic and echocardiographic follow-up of patients carrying the diagnosis of CCA is stressed.     

Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study.

BACKGROUND. The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5. METHODS. Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders--congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1). RESULTS. Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 10(25.6):1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the fibrillin gene on chromosome 5. There was no linkage of mitral-valve prolapse to the fibrillin gene on chromosome 5; studies of chromosome 15 were not informative. Annuloaortic ectasia was not linked to either fibrillin gene. CONCLUSIONS. The Marfan syndrome appears to be caused by mutations in a single fibrillin gene on chromosome 15. Diagnosis of the Marfan syndrome by genetic linkage and analysis is now feasible in many families.     

FBN2, FBN1, TGFBR1, and TGFBR2 analyses in congenital contractural arachnodactyly

FBN2, FBN1, TGFBR1, and TGFBR2 were analyzed by direct sequencing in 15 probands with suspected congenital contractural arachnodactyly (CCA). A total of four novel FBN2 mutations were found in four probands (27%, 4/15), but remaining the 11 did not show any abnormality in either of the genes. This study indicated that FBN2 mutations were major abnormality in CCA, and TGFBR and FBN1 defects may not be responsible for the disorder. FBN2 mutations were only found at introns 30, 31, and 35 in this study. Thus analysis of a mutational hotspot from exons 22 to 36 (a middle part) of FBN2 should be prioritized in CCA as previously suggested.     

Ectopia lentis phenotypes and the FBN1 gene

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [K?rkk? et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.     

Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype

Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, 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. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients. Hum Mutat 19:39–48, 2002. © 2001 Wiley‐Liss, Inc.     

Congenital contractural arachnodactyly in two double second cousins: possible homozygosity

Bistritzer T, Fried K, Lahat E, Dvir M, Goldberg M. Congenital contractural arachnodactyly in two double second cousins: possible homozygosity.
Clin Genet 1993: 44: 15–19. © Munksgaard, 1993
A Bedouin family with two girls affected by severe congenital contractural arachnodactyly (CCA) is described. The girls were double second cousins. One of the girls also had ambiguous genitalia, an anomaly not generally associated with this disorder. The two children were both the product of first-cousin Bedouin parents from the same family. It is possible that both sets of parents were heterozygous for CCA; thus the infants may have been homozygous for CCA, which is usually an autosomal dominant condition. No instance of homozygous CCA has previously been reported. This family suggests genetic heterogeneity in CCA and that, in some rare families, the mode of inheritance may be autosomal recessive.     

Ectopia lentis in Loeys‐Dietz syndrome type 4

Loeys‐Dietz syndrome is a heritable disorder of the connective tissue leading to multisystem involvement including craniofacial features, skeletal abnormalities, cutaneous findings and early‐onset and aggressive disease of the aorta and its branches. There are multiple types of Loeys‐Dietz syndrome related to pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3. Individuals with Loeys‐Dietz syndrome may be misdiagnosed as having Marfan syndrome due to shared phenotypic features and aortic root dilation. However, ectopia lentis has been an important discriminating feature, being unique to Marfan syndrome and not reported to be associated with Loeys‐Dietz syndrome. We report the case of a 46‐year‐old woman with Loeys‐Dietz syndrome type 4 due to a pathogenic variant in TGFB2 who was diagnosed with ectopia lentis at age 44. The patient underwent whole exome sequencing and no other pathogenic variants were found to explain the ectopia lentis. Our findings indicate that ectopia lentis may be an uncommon finding in Loeys‐Dietz syndrome type 4 and emphasize the importance of genetic testing in familial thoracic aortic aneurysm disease.     

Ectopia lentis et pupillae: the genetic aspects and differential diagnosis.

Two sib pairs and a fifth child are described with autosomal recessive ectopia lentis et pupillae. Patients with this disorder need regular ophthalmic review, but do not have the skeletal and metabolic complications associated with other syndromes with ectopia lentis.     

Ectopia lentis as the presenting and primary feature in Marfan syndrome

Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.     

Congenital contractural arachnodactyly Report of four additional families and review of literature

We report here four families with congenital contractural arachnodactyly (CCA) in which a wide range of phenotypic expression is observed. In one family with a large number of affected individuals the condition is mildly expressed. These individuals usually have crumpled ears, camptodactyly with ulnar deviation of the fingers, adducted thumbs, limited elbow and/or knee extension, and hypoplasia of the calf muscles. Arachnodactyly is not a constant feature. No spinal deformities are present and only the proband has clubfoot deformities. With time, affecteds have experienced spontaneous improvement of their contractures and their condition in adulthood has not interfered with a normal lifestyle. Within this family there is little phenotypic variation between affected individuals. Those affected within each of the other families have had varying degrees of severity of the condition. A review of 29 other kindreds described in the literature with congenital contractural arachnodactyly shows that in this condition the most common features are abnormally formed ears, camptodactyly, arachnodactyly, adducted thumbs, limited movement of the elbows and knees, and underdevelopment of the calf muscles. Spontaneous improvement of the contractures with age is reported in 94% of cases. Kyphosis, scoliosis or kyphoscoliosis occurred in 50% and these defects were present in those who where more severely affected with CCA. No ocular problems have been reported in this syndrome, but congenital heart defects have occurred in 14.7%. Marfan syndrome is the most important condition to differentiate from congenital contractural arachnodactyly since these two conditions are similar phenotypically. However, in the former there are frequently serious ocular and cardiovascular problems which lead to significant morbidity and/or early death.     

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

Beals‐Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23–34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2‐positive patients. In our FBN2‐positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z‐score: 4.09) and his father (z‐score: 2.94), warranting echocardiographic follow‐up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2‐negative patients in this cohort were clinically indistinguishable from all published FBN2‐positive patients harboring a FBN2 mutation, suggesting locus heterogeneity. Hum Mutat 0, 1–8, 2008. © 2008 Wiley‐Liss, Inc.