Congenital Contractural Arachnodactyly
Summary
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 testing and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria for congenital contractural arachnodactyly (CCA) have not been established.
Suggestive Findings
Classic CCA should be suspected in individuals with the following:
- Arachnodactyly with positive wrist and thumb sign
- Flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers
- Kyphoscoliosis (usually progressive)
- Abnormal pinnae ("crumpled" outer helices)
- A marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate)
On rare occasions, infants were reported with the clinical findings of classic CCA as well as the following anomalies [Lipson et al 1974, Currarino & Friedman 1986, Macnab et al 1991, Wang et al 1996, Snape et al 2006]:
- Cardiovascular. Interrupted aortic arch and atrial or ventricular septal defects, and/or severe aortic root dilatation (rare)
- Gastrointestinal. Duodenal or esophageal atresia and/or intestinal malrotation
Although this phenotype has been referred to as "severe/lethal CCA," its molecular basis has not been unequivocally established and a lethal outcome is not certain; the term "severe CCA with cardiovascular and/or gastrointestinal anomalies" more accurately describes this disorder [Author, personal observation].
Establishing the Diagnosis
The diagnosis of CCA is established in a proband with suggestive findings and a heterozygous FBN2 pathogenic variant identified by molecular genetic testing (Table 1). However, locus heterogeneity is likely, given that only 25%-75% of individuals clinically diagnosed with CCA have an identifiable FBN2 pathogenic variant [Gupta et al 2002; Callewaert et al 2009; Nishimura et al 2007; Meerschaut et al 2019; Callewaert et al, unpublished data]. Because CCA is difficult to diagnose clinically, Meerschaut et al [2019] developed a clinical scoring system to facilitate the clinical diagnosis of CCA (Table 2).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of congenital contractural arachnodactyly is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CCA has not been considered because of atypical findings are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of FBN2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
A multigene panel that includes FBN2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Since the differential diagnosis of CCA includes Marfan syndrome and Loeys-Dietz syndrome, clinicians requesting a panel including genes for heritable thoracic aortic aneurysms and dissections (HTAD) should be aware that FBN2 may not be included in some panels based on recent recommendations for HTAD genetic testing [Renard et al 2018]. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For CCA a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of CCA is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is currently the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Congenital Contractural Arachnodactyly
| Gene 1 | Proportion of CCA Attributed to Pathogenic Variants in Gene 2 | Method | Proportion of FBN2 Pathogenic Variants 3 Detectable by Method |
|---|---|---|---|
| FBN2 | 25%-75% | Sequence analysis 4 | ~93% |
| Gene-targeted deletion/duplication analysis 5 | ~7% 6 | ||
| Unknown | 25%-75% | NA | |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
Because the detection rate for FBN2 pathogenic or likely pathogenic variants is low in individuals with a clinically convincing diagnosis of CCA, genetic heterogeneity is likely [Gupta et al 2002; Nishimura et al 2007; Callewaert et al 2009; Meerschaut et al 2019; Callewaert et al, unpublished data].
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of an entire FBN2 deletion and/or deletion of adjacent genes (e.g., those described by Inbar-Feigenberg et al [2014]) may not be detected by these methods.
- 6.
Five known deletion/duplication pathogenic variants include a mosaic deletion of exons 7-34 [Lavillaureix et al 2017], a duplication of exon 23 [Gupta et al 2002], and a deletion of exons 38-48, 43-48, and 45-48 [Meerschaut et al 2019].
Clinical Scoring System
In the absence of a pathogenic or likely pathogenic FBN2 variant and in the absence of intellectual disability, progressive aortic root dilatation, and/or ectopia lentis, a clinical score of ≥7/20 is suggestive for CCA (sensitivity 95.5%; specificity 17.1%) and a score of ≥11/20 makes the diagnosis of CCA likely (sensitivity 75%; specificity 60%) [Meerschaut et al 2019].
Table 2.
Clinical Scoring System
| Clinical Feature | Points | Comments |
|---|---|---|
| Crumpled ears | 3 |
|
| Arachnodactyly | 3 |
|
| Camptodactyly | 3 | |
| Large-joint contractures | 3 | |
| Pectus deformity | 2 | |
| Dolichostenomelia | 2 | Defined as presence of:
|
| Kyphoscoliosis | 1 |
|
| Muscle hypoplasia | 1 | |
| Highly arched palate | 1 | |
| Micrognathia | 1 |
Based on Loeys et al [2010]
US/LS = upper segment to lower segment
- 1.
Positive wrist sign: the tip of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist [Loeys et al 2010].
- 2.
Positive thumb sign: the entire distal phalanx of the adducted thumb extends beyond the ulnar border of the palm with or without the assistance of the patient or examiner to achieve maximal adduction [Loeys et al 2010].
- 3.
Clinical diagnosis: on bending forward, a vertical difference of ≥1.5 cm between the ribs of the left and right hemithorax is observed [Loeys et al 2010].
- 4.
Radiographic: a Cobb's angle (angle between a line drawn along the superior-end plate of the superior-end vertebra and a second line drawn along the inferior-end plate of the inferior-end vertebra of the scoliosis measured on anterior-posterior view of the spine) of ≥20° is seen [Loeys et al 2010].
Clinical Characteristics
Clinical Description
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Phenotypic expression is variable within and between families. 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, prominent anterior crus of the antihelix, and/or mild contractures without impairment. 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. Only one child with the severe form of CCA has been confirmed to have an FBN2 pathogenic variant [Wang et al 1996], but it remains unclear if additional variants affecting other genes could account for this phenotype.
Classic CCA
Table 3.
Selected Clinical Features in Classic Congenital Contractural Arachnodactyly by Frequency
| Clinical Feature | Frequency 1, 2 |
|---|---|
| Arachnodactyly | 98% |
| Small-joint contractures | 92% |
| Large-joint contractures | 88% |
| Crumpled ears | 78% |
| Kyphosis/scoliosis | 62% |
| Muscle hypoplasia | 55% |
| Dolichostenomelia | 50% |
| Pectus deformity | 41% |
| Highly arched palate | 67% |
| Micrognathia | 34% |
- 1.
Features are ordered by frequency.
- 2.
%s are based on individuals with a confirmed (likely) FBN2 pathogenic variant [Meerschaut et al 2019].
Features seen in individuals with CCA
- Arachnodactyly (long slender fingers and toes) caused by overgrowth of the phalanges (Figure 1)
- Joint contractures
- Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
- Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults. - "Crumpled" ears. Hearing is normal in individuals with CCA.
- Kyphosis/scoliosis. Scoliosis can be congenital or develop/worsen during periods of fast growth (6 months – 2 years, pubertal growth spurt), and may cause significant morbidity in CCA.
- Muscle hypoplasia. A thin body habitus with relative underdevelopment of the muscular reliefs with reference to age, activity level, and nutritional status. Of note, muscular hypoplasia was more frequently reported in patients suspected with CCA without a (likely) pathogenic FBN2 variant (65%) [Meerschaut et al 2019]. However, this feature is likely underreported (Figure 1).
- Dolichostenomelia. A tall and slender habitus with long-bone overgrowth evoking a marfanoid habitus
- Pectus deformity (most frequently pectus excavatum). Due to overgrowth of the ribs, the sternum and anterior thoracic wall are pushed in (pectus excavatum) or out (pectus carinatum).
- Craniofacial abnormalities
- Dolichocephaly (long, narrow skull)
- Enophthalmia and mildly downslanting palpebral fissures (rare)
- Flat midface
- Highly arched palate
- Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic FBN2 variant [Meerschaut et al 2019], it may be underassessed.
Figure 1.
Features of CCA A. Facial characteristics in a child age two years: midface hypoplasia and micrognathia
Other features, not routinely assessed in case reports of CCA
- Aortic root dilatation had been documented in individuals with CCA with a confirmed FBN2 pathogenic variant [Park et al 1998, Carmical et al 1999, Gupta et al 2002, Snape et al 2006, Callewaert et al 2009, Takeda et al 2015, Meerschaut et al 2019] and may be present in up to 10%-15% of individuals with CCA harboring a (likely) pathogenic FBN2 variant. Progression of aortic dilatation and aortic dissection was reported in one family [Takeda et al 2015] and in one nine-month-old child with CCA [Siddiqui & Panesar 2019]. Therefore, the presence of progressive aortic root dilatation does not eliminate the possibility of CCA, but clinicians should also consider other diagnoses that could account for this rare finding in CCA (see Differential Diagnosis).
- Ocular features. Myopia is frequently reported, but unlikely to be more common than in the general population. Keratoconus has been noted in two individuals [Callewaert et al 2009]. Of note, ectopia lentis has never been reported in persons with a confirmed (likely) pathogenic FBN2 variant.
- Bowed long bones. Incidental reports, but rarely assessed as it requires radiographs
- Recurrent patellar dislocations can be disabling [Callewaert et al 2009].
- Congenital diaphragmatic hernia. Reported in one individual [Meerschaut et al 2019]
- Cervical anomalies including a narrowed foramen magnum and C2-C3 fusion have been reported in one individual with a clinical, but not molecular, diagnosis of CCA [Meena et al 2015].
Severe CCA with Cardiovascular and/or Gastrointestinal Anomalies
In addition to the typical skeletal findings in CCA, a few infants with multiple cardiovascular and/or gastrointestinal anomalies requiring surgical correction as early as the first week of life have been reported [Lipson et al 1974, Currarino & Friedman 1986, Macnab et al 1991, Wang et al 1996]. The most common cardiovascular anomalies include interrupted aortic arch and atrial or ventricular septal defects. Gastrointestinal anomalies include esophageal or duodenal atresia and/or intestinal malrotation.
The age of death has ranged from eight days to 11.5 months. Respiratory complications including tracheomalacia and respiratory infections have been the cause of death in most.
Somatic Mosaicism
Somatic mosaicism has been reported in the following instances:
- A mother with somatic mosaicism for an FBN2 variant had features of classic CCA. Her daughter, who inherited the FBN2 pathogenic variant, had severe CCA with cardiovascular and gastrointestinal anomalies [Wang et al 1996].
- A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [Lavillaureix et al 2017].
- Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [Putnam et al 1997].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been documented to date.
Some case reports claim a more severe phenotype for deletions [Lavillaureix et al 2017] or splice site variants in the central region of the gene (exons 24-35) (this remains unconfirmed) [Wang et al 1996]. In addition, phenotypic variability between and within families is wide, independent of the variant type (splice site or missense) [Callewaert et al 2009].
Meerschaut et al [2019] state that individuals with a confirmed FBN2 (likely) pathogenic variant have a higher clinical score (Table 2) than those without an FBN2 (likely) pathogenic variant (P<0.001). Nevertheless, persons without an FBN2 (likely) pathogenic variant but with a clinical score as high as 19 have been reported, making it impossible to clinically differentiate between individuals with and without an FBN2 (likely) pathogenic variant.
Penetrance
The penetrance for CCA is likely up to 100%, but some disease manifestations, including the ear and joint manifestations, may become less obvious with age. Nevertheless, upon careful examination, less than 1.2% of the variability of the clinical score (Table 2) could be attributed to age [Meerschaut et al 2019]. Indeed, a previous report indicates that the diagnosis was often retrospectively made in one parent of a proband due to mild features still evident in adulthood (mild contractures without any functional impairment and/or prominent helical crus and anterior antihelical crus ["tram track" ears]) [Callewaert et al 2009]. In addition, long-bone overgrowth and scoliosis may become more prominent with age.
Clinical manifestations are the same in males and females.
Nomenclature
Congenital contractural arachnodactyly (CCA) has been referred to as distal arthrogryposis type 9 (OMIM 121050). This term should be avoided as it puts too much emphasis on the distal contractures while minimizing the significance of other manifestations, including marfanoid habitus, proximal contractures, and aortic and ocular involvement.
Prevalence
The prevalence is not known. To date about 70 probands with CCA have been described. Most described individuals are white, but this likely represents an ascertainment bias [Author, personal observation]. There is no reason to assume that CCA shows any specific geographic or ethnic predilection. Indeed, affected individuals from China [Chen et al 2009, Liu et al 2015, Guo et al 2016], Japan [Takeda et al 2015], India, and the Middle East [Callewaert et al 2009, Mehar et al 2014, Meerschaut et al 2019] have been described.
Differential Diagnosis
Disorders with features that overlap with those of congenital contractural arachnodactyly (CCA) are summarized in Table 4.
Table 4.
Disorders to Consider in the Differential Diagnosis of Congenital Contractural Arachnodactyly (CCA)
| Differential Diagnosis Disorder | Gene | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/CCA | Distinguishing from CCA | |||
| Marfan syndrome | FBN1 | AD |
|
|
| Loeys-Dietz syndrome | SMAD2 SMAD3 TGFB2 TGFB3 TGFBR1 TGFBR2 | AD |
|
|
| Stickler syndrome | COL2A1 COL9A1 COL9A2 COL9A3 COL11A1 COL11A2 | AD AR 4 | Marfanoid body habitus (in some affected individuals), but usually secondary to a shortened trunk, rather than long-bone overgrowth |
|
| Homocystinuria | CBS | AR |
|
|
| Distal arthrogryposes (DA) (OMIM PS108120) | ECEL1 MYBPC1 MYH3 MYH8 PIEZO2 TNNI2 TNNT3 TPM2 | AD AR 5 |
|
|
| Bethlem myopathy (see Collagen Type VI-Related Disorders & OMIM 616471) | COL6A1 COL6A2 COL6A3 COL12A1 | AD AR |
| Absence of marfanoid habitus, arachnodactyly, & crumpled ears |
| Van den Ende - Gupta syndrome (OMIM 600920) | SCARF2 | AR |
|
|