Congenital Contractural Arachnodactyly

Disease Overview

Congenital contractural arachnodactyly (CCA) is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or differently shaped ears resulting in a “crumpled” appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are differently positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); a short neck. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited in an autosomal dominant pattern.

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Synonyms

• CCA
• Beals syndrome
• Beals-Hecht syndrome
• arthrogryposis, distal, type 9

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Signs & Symptoms

CCA encompasses a broad range of symptoms. The specific symptoms that develop in each individual case and the severity of symptoms often vary. Most individuals have permanent fixation of certain joints in a flexed position (contractures) that is present a birth (congenital). The joints of the fingers, elbows, knees and hips are most often affected. In most cases, contractures improve with age.

Some affected infants have differently shaped ears giving them a “crumpled” appearance. Additional common symptoms include long, slender fingers and toes (arachnodactyly), permanently flexed fingers (camptodactyly), underdevelopment of certain muscles (muscular hypoplasia), and front-to-back and side-to-side curvature of the spine (kyphoscoliosis). Kyphoscoliosis is usually progressive and severe, often necessitating surgery.

Some children have a specific heart defect known as mitral valve prolapse (MVP). The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. MVP occurs when one or both flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation). In some patients, no associated symptoms are apparent (asymptomatic). However, in other people, MVP can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness and/or other symptoms and signs.

Less common symptoms may occur in some children. Additional differences of the head and face (craniofacial) region include a small jaw (micrognathia), a prominent forehead (frontal bossing), a highly arched palate, a long narrow head (dolichocephaly or scaphocephaly), or a wide head (brachycephaly). Nearsightedness (myopia) affecting the eyes may also occur.

Some individuals may have a short neck. Some affected individuals have a clubbed foot, inwardly clasped (adducted thumbs) and bowed long bones of the arms and leg.

Rarely, individuals with CCA may develop a severe form of the disorder associated with life-threatening complications. This severe form of CCA is associated with various heart and intestinal abnormalities including atrial and ventricular septal defects; improper development of the aorta resulting in blockage of blood flow (interrupted aortic arch); a single umbilical artery; a condition in which the tube (esophagus) that normally carries food from the mouth to the stomach narrows to a thin cord or ends in a pouch rather than providing passage to the stomach (esophageal atresia); abnormal closure or blockage of the first part of the small intestine (duodenal atresia); and obstruction of the intestines due to malformation of part of the intestines (intestinal malrotation).

Rarer still, CCA may be associated with aortic root dilatation, a condition characterized by widening (dilatation) of the opening where the aorta and the heart chamber connect (aortic root).

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Causes

CCA occurs due to changes (variants or mutations) to the fibrillin-2 (FBN2) gene.

CCA is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of gene variant is necessary to cause a particular disease. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the gene variant from an affected parent to children is 50% for each pregnancy. The risk is the same for males and females.

Interestingly, studies of a largely Ashkenazi Jewish population have shown that deletions of exons 1-8 in the FBN2 gene are not associated with any pathology and is considered a benign variant.

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Affected populations

CCA affects males and females in equal numbers. The prevalence of CCA is unknown. For years, researchers speculated that the Marfan syndrome (another rare connective tissue disorder) and CCA may be the same disorder because of the overlap of clinical symptoms. However, investigators have determined these disorders are caused by variants in different genes confirming that CCA is a distinct disorder.

Because of the similarities with the more recognized Marfan syndrome, it is difficult to determine the true incidence of CCA in the general population. However, molecular genetic testing can confirm a diagnosis of CCA and should allow researchers to obtain a more accurate idea of its incidence in the future.

The recent identification of another condition with overlapping symptoms, Loeys-Dietz syndrome has led to additional misdiagnosis (see below).

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of CCA. Comparisons may be useful for a differential diagnosis:

Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Symptoms of this disorder may be a fixed range of motion of joints; shoulders that are bent inward and internally rotated; wrists and fingers that are bent and muscles that are underdeveloped. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)

Marfan syndrome is an inherited disorder of the connective tissue. It is characterized by unusually thin, long, limbs, feet and fingers, an unusual limberness of the joints, a relaxation of the muscles, a progressive curvature of the spine, a protruding or indented breastbone and flat feet. Enlargement and degeneration of the aorta, mitral valve prolapse and the possibility of an aortic aneurysm are serious consequences of Marfan syndrome. (For more information on this disorder, choose “Marfan syndrome” as your search term in the Rare Disease Database.)

Gordon syndrome is an extremely rare disorder that belongs to a group of genetic disorders known as the distal arthrogryposes. These disorders typically involve stiffness and impaired mobility of certain joints of the lower arms and legs (distal extremities) including the knees, elbows, wrists and/or ankles. These joints tend to be permanently fixed in a bent or flexed position (contractures). Gordon syndrome is characterized by the permanent fixation of several fingers in a flexed position (camptodactyly), bending inward of the foot (clubfoot or talipes), and, less frequently, incomplete closure of the roof of the mouth (cleft palate). In some patients, additional abnormalities may also be present. The range and severity of symptoms may vary from person to person. Gordon syndrome is inherited in an autosomal dominant pattern (For more information on this disorder, choose “Gordon” as your search term in the Rare Disease Database.)

Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocysteine in the urine. The condition may result from deficiency of any of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid (cysteine)–or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most patients, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase (CBS). Due to deficiency of the CBS enzyme, affected infants fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delays. By approximately age three, additional, more specific symptoms and findings may become apparent. These may include partial dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated “quivering” (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia) and other eye (ocular) abnormalities. Intelligence is normal in some affected people, but many children have progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs (“marfanoid” features). Additional skeletal abnormalities may include progressive sideways curvature of the spine (scoliosis), protrusion or depression of the breastbone (pectus carinatum or excavatum), and generalized loss of bone density (osteoporosis). In addition, in those with the disorder, blood clots may tend to develop or become lodged within certain large and small blood vessels (thromboembolisms), potentially leading to life-threatening complications. (For more information on this disorder, choose “homocystinuria” as your search term in the Rare Disease Database.)

Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body’s organ systems such as the eye, skeleton, inner ear and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor) and the ends of the bones that make up the joints of the body (epiphysis). (For more information on this disorder, choose “Stickler” as your search term in the Rare Disease Database.)

Loeys-Dietz Syndrome, first delineated in 2005, is characterized by aneurysms in cerebral, thoracic and abdominal arteries. Skeletal anomalies are similar to those seen in CCA and the Marfan syndrome and include chest wall deformities, arachnodactyly, club feet, and craniofacial features including bifid uvula, cleft palate and hypertelorism. Variants in the TGFBR1 and TGFBR2 genes are known to cause Loeys-Dietz syndrome. (For more information on this disorder, choose “Loeys-Dietz Syndrome” as your search term in the Rare Disease Database.)

The following disorders may occur along with CCA:

Keratoconus is a slowly progressive enlargement of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea). The resulting conical shape of the cornea causes blurred vision and other vision problems. Inherited forms of this disorder usually begin after puberty. Keratoconus can also occur in conjunction with a variety of other disorders.

Mitral valve prolapse syndrome is a heart disorder. The exact cause is unknown. It can be a symptom of other disorders such as connective tissue diseases or muscular dystrophy, or it may occur by itself. Major symptoms include chest pain and/or palpitations, accompanied by a heart murmur. Shortness of breath, fatigue, lightheadedness and dizzy spells, and in some people, this progresses to an inability to breathe except when sitting in an upright position. There is a characteristic click heard through a stethoscope upon physical examination. Blood may flow back through the heart valve (mitral regurgitation) causing other complications.

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Diagnosis

A diagnosis of CCA is suspected based upon a thorough clinical evaluation and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing which detects an FBN-2 gene variant in approximately 75 percent of patients.

Recently, Meerschaut et al. have proposed a scoring system for CCA to help support a diagnosis. They suggest this as a quantitative tool for research purposes and as clinical guidance in diagnosis.

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Standard Therapies

Treatment
The treatment of CCA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, orthopedists, and other health care professionals may need to plan an affect child’s treatment systematically and comprehensively.

Physical therapy, often started during childhood, may be used to treat joint contractures. Physical therapy can improve joint mobility and lessen the effects of muscular hypoplasia. In many people, joint contractures improve without treatment (spontaneously) as individuals grow older. However, for some people, surgery may be necessary to treat contractures. Kyphoscoliosis is often progressive and severe and may necessitate treatment with braces or surgery.

Many physicians recommend that individuals with CCA receive an echocardiogram to distinguish the disorder from Marfan syndrome and detect any heart defects that may potentially be associated with the disorder. During an echocardiogram, high-frequency sound waves are used to create a structural image of the heart and nearby tissue.

A thorough eye (ophthalmologic) examination is recommended to detect any potential eye abnormalities that are sometimes associated with CCA.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Peeters S, De Kinderen P, Meester JAN, Verstraeten A, Loeys BL. The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2. Human Mutation 2022 43:815-831.

Maya I, Kahana S, Agmon-Fishman I, et al. Based on a cohort of 52,879 microarrays, recurrent intragenic FBN2 deletion encompassing exons 1-8 does not cause Beals syndrome. European Journal of Medical Genetics. 2020 63:104008.

Meerschaut I, De Coninck S, Steyaert W, et al. A clinical scoring system for congenital contractural arachnodactyly. Genetics in Medicine 2020 22 (1):124-131.

Lavillaureix A, Heide S, Chantot-Bastaraud S, Marey I, Keren B, Grigorescu R, Jouannic JM, Gelot A, Whalen S, Héron D, Siffroi JP. Mosaic intragenic deletion of FBN2 and severe congenital contractural arachnodactyly. Clin Genet. 2017 Nov; 92(5):556-55.

Woolnough R, Dhawan A, Dow K, Walia JS. Are patients with Loeys-Dietz syndrome misdiagnosed with Beals syndrome? Pediatrics. 2017 Mar; 139(3).

Chen L, Diao Z, Xu Z, Zhou J, Wang W, Li J, Yan G, Sun H. The clinical application of preimplantation genetic diagnosis for the patient affected by congenital contractural arachnodactyly and spinal and bulbar muscular atrophy. J Assist Reprod Genet. 2016 Nov; 33(11):1459-1466.

Takeda N, Morita H, Fujita D, Inuzuka R, Taniguchi Y, Imai Y, Hirata Y, Komuro I. Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature. Am J Med Genet A. 2015 Oct; 167A (10):2382-7.

Inbar-Feigenberg M, Meirowitz N, Nanda D, Toi A, Okun N, Chitayat D. Beals syndrome (congenital contractural arachnodactyly): prenatal ultrasound findings and molecular analysis. Ultrasound Obstet Gynecol. 2014 Oct; 44(4):486-90.

Paterick TE, Humphries JA, Ammar KA, Jan MF, Loberg R, Bush M, Khandheria BK, Tajik AJ. Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management. Am J Med. 2013 Aug; 126 (8):670-8.

Paterick TE, Humphries JA, Ammar KA, et al. Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management. Am J Med 2013;126:670.

Davis MR, Summers KM. Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. Mol Genet Metab. 2012;107:635.

Callewaert BL, Loeys BL, Ficcadenti A, et al. Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations abd review of the literature. Hum Mutat 2009; 30:334.

Frédéric MY, Monino C, Marschall C, et al. The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2) and genotype-phenotype correlations. Hum Mutat 2009; 30:181.

Tuncbilek E, Alanay Y. Congenital contractural arachnodactyly (Beals syndrome). Orphanet J Rare Dis. 2006;1:20.

Gupta PA, Wallis DD, Chin TO, et al. FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly. J Med Genet. 2004;41:e56.

Gupta PA, Putnam EA, Carmical SG, et al. Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype. Hum Mutat. 2002;19:39-48.

Maslen C, Babcock D, Raghunath M, Steinmann B. A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. Am J Hum Genet. 1997;60:1389-98.

Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet. 1996;65:277-81.

Bawle RK, Hecht F. Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly. Am J Med Genet. 1992;42:19-21.

Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991;352:330-4.

Beals RK, Hecht F. Congenital contractural arachnodactyly: a heritable disorder of connective tissue. J Bone Joint Surg. 1971;53A:987-93.

INTERNET
Callewaert B. Congenital Contractural Arachnodactyly. 2001 Jan 23 [Updated 2022 Jul 14]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1386/ Accessed Aug 4, 2023.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Arthrogryposis, Distal, Type 9; DA9. Entry No: 121050. Last Edited 07/18/2023. Available at: http://omim.org/entry/121050 Accessed Aug 4, 2023.

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