Congenital contractural arachnodactyly

Clinical characteristics Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families. Diagnosis/testing The diagnosis of CCA can be established in a proband with suggestive findings and a heterozygous FBN2 pathogenic variant identified by molecular genetic testing; however, locus heterogeneity is likely given that only 25%-75% of individuals with clinically diagnosed CCA have an identifiable FBN2 pathogenic variant. Because CCA can be difficult to diagnose clinically, a clinical scoring system based on presence or absence of crumpled ears, musculoskeletal findings, highly arched palate, and micrognathia can be used. Management Treatment of manifestations of classic CCA: Standard management of contractures, clubfeet, kyphoscoliosis including surgical intervention as needed; early physical therapy to improve mobility and occupational therapy to improve camptodactyly. Aortic root dilatation, correction of refractive errors, and palatal abnormalities are managed in a standard manner. Surveillance for classic CCA: Annual evaluation for kyphosis/scoliosis if not present at initial evaluation; routine measurement of aortic root diameter for evidence of aortic dilatation; routine assessment of visual acuity and refractive error; annual assessment of orthodontic needs after age eight years. Agents/circumstances to avoid: Contact sports and activities that stress joints; LASIK eye surgery, which may increase the risk for keratoconus in those with predisposing ocular conditions. Evaluation of relatives at risk: Clarification of the genetic status of apparently asymptomatic or self-reportedly asymptomatic at-risk relatives by molecular genetic testing if the familial FBN2 variant is known, otherwise by clinical examination to identify those with a low – but potential – risk for aortic and/or ocular complications. Pregnancy management: Although no complications related to pregnancy or delivery have been reported in women with CCA, it is advisable to perform an echocardiography preconceptually and to increase cardiac surveillance during pregnancy in women with dilatation of the aortic root. Genetic counseling CCA is inherited in an autosomal dominant manner. While many individuals with CCA have an affected parent, as many as 50% may have a de novo FBN2 pathogenic variant. If a parent of a proband has clinical features of CCA and/or is known to have the FBN2 pathogenic variant identified in the proband, the risk to sibs of the proband is 50%. Because intrafamilial clinical variability is observed in CCA, a heterozygous sib may have a more or less severe phenotypic presentation than the proband. Once the FBN2 pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.