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Last updated: 11/12/2024
Years published: 1986, 1988, 1990, 1991, 1997, 1999, 2010, 2013, 2016, 2019, 2023, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Judith G. Hall, OC, MD, FCAHS, FRSC, Professor Emerita of Pediatrics and Medical Genetics, University of British Columbia & Childrenโs and Womenโs Health Centre of British Columbia, Department of Pediatrics, BCโs Childrenโs Hospital, for assistance in the preparation of this report.
Summary
Arthrogryposis multiplex congenita (AMC) is a term used to describe a group of congenital (present at birth) conditions characterized by joint contractures in two or more joints of the body. Therefore, AMC is a descriptive term for over 400 different conditions rather than a single diagnosis.
The causes of AMC include genetic and environmental factors, as well as abnormalities that occur during fetal development while the baby is developing inside the womb (uterus).
People with AMC have contractures with limited joint movement, with or without muscle weakness, in the body areas involved. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, restricting the movement of the affected joint.
The localization and the severity of the contractures vary and do not progress to previously unaffected joints but may change over time due to growth and treatment. The limbs, spine and jaw can be affected. The contractures in AMC are present at birth; however, they develop throughout pregnancy and can be detected in prenatal exams. Spinal deformities may be present at birth or may develop throughout childhood and adolescence.
Depending on the underlying diagnosis, other body systems such as the central nervous system (brain and spinal cord), respiratory, gastrointestinal, and genital and urinary systems may be affected. Intellectual ability is usually normal unless the brain is involved, but sensation remains intact.
When congenital contractures occur only in one body area, it is not referred to as arthrogryposis but rather an isolated congenital contracture, such as clubfoot.
Different systems exist to classify AMC based on whether the central nervous system is involved, the genetic causes, or the specific symptoms. The most common classification divides AMC into amyoplasia, distal arthrogryposis and cases involving the central nervous system.
Introduction
Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles but the terminology used has been inconsistent in clinical and research communities. The updated definition of arthrogryposis multiplex congenita (AMC) was developed in 2019.
The term arthrogryposis is Greek, from arthron (joint) + gryp (curved) + osis (condition). Multiplex is Latin for multiple and congenita, also Latin, is from the word congenitus meaning present at birth. Thus, AMC is a term for multiple curved joints that are present at birth. AMC, arthrogryposis and multiple congenital contractures are all terms that are been used interchangeably.
The most common universal symptom is limited or absent movement around small and large joints (contractures).
Arthrogryposis multiplex congenita (AMC) is a group of congenital conditions in which people have joint stiffness, or contractures, in two or more areas of the body. These contractures, present at birth, cause limited movement around affected joints, which may be bent or straightened. Affected muscles can be underdeveloped (hypoplastic), leading to limbs that appear tube-shaped with a soft, doughy feel, sometimes accompanied by soft tissue webbing over the joints.
In addition to joint abnormalities, some people with AMC may have thin and fragile long bones in their arms and legs, and around one-third may have central nervous system issues. Other features may include cleft palate (an opening in the roof of the mouth) and in males, undescended testes (cryptorchidism). Intellectual abilities may vary based on the involvement of the central nervous system (brain and spinal cord).
The specific symptoms, their severity, and additional features vary widely based on the underlying cause of AMC. The two main forms of AMC are amyoplasia and distal arthrogryposis (DA), each presenting distinct symptoms:
AMC can also be associated with severe low muscle tone (hypotonia).
Central and peripheral nervous system disorders that are associated with AMC include:
For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Most types of distal arthrogryposis have associated known gene variants.
Orphanet, the European rare disease database has information on many of the arthrogryposis syndrome subtypes.
The cause of AMC depends on the specific type. For many types, the cause is not fully understood. Arthrogryposis or AMC is not a specific diagnosis, but a physical finding that can be associated with numerous disorders and conditions. AMC is thought to be related to decreased movement in utero, which can have multiple causes. Neurologic and muscle problems may well be the most common causes of decreased fetal movement, but connective tissue disorders, maternal illness and limited space are also common causes.
The primary underlying mechanism that leads to congenital contractures is believed to be decreased fetal movement during pregnancy. The joints begin to develop in a fetus around five or six weeks into pregnancy. Motion is essential for the proper development of fetal joints. A lack of fetal movement allows for excess connective tissue to form around the joints, which can result in the joint becoming fixed and/or limiting the movement of a joint. In theory, any factor that diminishes or restricts fetal movement can cause congenital contractures. Such factors can include fetal crowding (in which there is not enough room for the fetus to move around) such as when there are multiple births or uterine structural abnormalities. Restricted fetal movement can also occur secondary to maternal disorders including viral infections, drug use, trauma or other maternal illnesses. Low levels of amniotic fluid around the fetus (oligohydramnios) has also been linked to decreased fetal movement.
Abnormalities affecting the development of connective tissue can cause AMC as well. Connective tissue is the material between the cells of the body that gives tissues form and strength. The abnormal development of connective tissue in the joints can restrict fetal movements, potentially causing multiple contractures. A lack of joint development or the abnormal fusion of bones (synostosis) that are normally separate have also been associated with multiple congenital contractures. Several disorders which are associated with abnormalities of connective tissue development have been associated with multiple congenital contractures including diastrophic dysplasia, metatropic dwarfism, popliteal pterygium syndrome and Larsen syndrome.
In many patients with AMC, the exact underlying cause of the contractures cannot be identified.
Some cases of AMC occur as part of rare genetic disorders that are inherited. Some cases of AMC are related to multiple factors including genetic and environmental ones (multifactorial inheritance).
AMC may occur as part of certain single-gene disorders that can be inherited in an autosomal recessive, autosomal dominant or X-linked pattern. AMC may also occur as part of chromosomal disorders (e.g., trisomy 18, many microdeletions and microduplications). AMC can also occur as part of certain connective tissue disorders. In addition, some cases of AMC may occur due to abnormalities or disorders associated with improper development of the central nervous system or the peripheral nervous system or as part of intrinsic muscle disorders. These disorders may be genetic or may occur due to environmental factors.
Amyoplasia, the most common form of AMC, occurs randomly (sporadically). The distal arthrogryposes, another common form of AMC, are usually inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Most of the central and peripheral nervous system disorders that are associated with AMC develop due to multiple factors including genetic and environmental ones (multifactorial inheritance).
Less often, AMC may be associated with certain muscle disorders including muscular dystrophies, certain mitochondrial disorders and a variety of genetic muscle disorders that are present at birth (congenital myopathies). Such disorders are usually inherited.
In many patients with AMC, the exact underlying cause of the contractures cannot be identified.
The number of males and females affected by AMC is approximately equal. The condition has been reported in individuals of Asian, African and European descent. Isolated congenital contractures affect approximately 1 in 500 individuals in the general population. AMC affects approximately 1 in 3,000 individuals.
A diagnosis of AMC is made based upon identification of characteristic symptoms (e.g., multiple congenital contractures), a detailed patient history and a thorough clinical evaluation. Certain tests may be necessary to determine the underlying cause of AMC including nerve conduction, electromyography and muscle biopsy, which can help diagnose neuropathic or myopathic disorders. A nerve conduction study measures how rapidly nerves carry an electrical impulse. Electromyography is a test that records electrical activity in skeletal voluntary muscles at rest and during muscle contraction. A biopsy is a procedure in which a small amount of affected tissue (e.g., muscle) is removed and studied under a microscopic to detect characteristic changes or findings that can aid in obtaining a diagnosis. Imaging studies of the central nervous system (CNS) and genetic tests including comparative genomic hybridization (CGH) array, microarray and exome studies may also be useful studies in making a diagnosis. Because variants in many genes can lead to arthrogryposis, whole genome sequencing is often required (preferably in both parents for comparison as well) to make a diagnosis.
Treatment
The treatment of AMC is directed toward the specific findings that are apparent in each individual. A multidisciplinary approach is best. Standard physical therapy, which can improve joint motion and avoid muscle atrophy in the newborn period is beneficial. Gentle joint manipulation and stretching exercises may also be beneficial. Removable splints for the knees and feet that permit regular muscle movement and exercise are also recommended. Serial casting to mobilize stiff joints is helpful.
In some patients, surgery may be necessary to achieve better positioning and increase the range of motion in certain joints, especially the ankles, knees, hips, elbows or wrists. Rarely, tendon transfers have been performed to improve muscle function. Tendons are the tissue by which muscle is attached to bone. A multidisciplinary approach is desirable for best long-term results, including pediatrician, neurologist, orthopedist, rehabilitation physician and therapist and medical geneticist.
Genetic counseling may be recommended for affected individuals and their families. Other treatments are symptomatic and supportive.
Information on current clinical trials is posted on the Internet at https://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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Hall JG. Arthrogryposes (Multiple Congenital Contractures). In: Emery and Rimoinโs Principle and Practice of Medical Genetics, 6th Ed. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds., Churchill Livingstone: New York, 2012.
Hall JG. Arthrogryposis. In: Management of Genetic Syndromes, 3rd Ed. Cassidy SB, Allanson JE eds., John Wiley & Sons: Hoboken, NJ, 2010; 81-96.
Jones KL. Ed. Smithโs Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:774-777.
Bamshad M. Arthrogryposis Multiplex Congenita. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:155.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1524-1525.
Staheli L T, Hall JG, Jaffe K M, Paholke DO. Arthrogryposis: a text atlas. Cambridge University Press; Cambridge, UK,1998.
JOURNAL ARTICLES
Dahan-Oliel N and Hall J, ed. Special Issue on Interdisciplinary Care for Arthrogryposis. AJMG 2019; 181 (3): i, 269-478.
Erratum in: Am J Med Genet 2015;167A:2866. Ogranovich, Alga [corrected to Ogranovich, Alga]; Pontรฉn, Ava [corrected to Pontรฉn, Eva].
Hall JG, Agranovich O, Pontรฉn E, van Bosse HJ. Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014. Am J Med Genet 2015;167A:1193-1195.
Hall, JG. Oligohydramnios sequence revisited in relationship to arthrogryposis, with distinctive skin changes. Am J Med Genet 2014;164A:2775-2792.
Hall JG, Aldinger KA, Tanaka, KI. Amyoplasia revisited. Am J Med Genet 2014;164:700-730.
Hall JG. Arthrogryposis (Multiple Congenital Contractures): Diagnostic Approach to Etiology, Classification, Genetics, and General Principles. Eur J Med Genet 2014;57:464-472.
Filges I, Hall JG. Failure to identify antenatal multiple congenital contractures and fetal akinesiaโproposal of guidelines to improve diagnosis. Prenat Diag 2013;33:61-74.
Hall JG. Uterine structural anomalies and arthrogryposis-death of an urban legend. Am J Med Genet 161A 2012;82-88.
Lowry RB, Sibbald B, Bedard T, Hall JG. Prevalence of multiple congenital contractures including arthrogryposis multiplex congentia in Alberta, Canada and a strategy for classification and coding. Birth Defects Res A Clin Mol Teratol 2010;88:1057-1061.
Dillon ER, Bjornson KF, Jaffe KM, Hall JG, Song K. Ambulatory activity in youth with arthrogryposis: a cohort study. J Pediatr Orthop. 2009;29:214-217.
Hall JG. Pena Shokeir Phenotype (Fetal akinesia deformation sequence) Revisited. Birth Defects Res A, 2009;85:677-694.
Bamshad M, van Heest AE, Pleasure D. Arthrogryposis: a review and update. J Bone Joint Surg Am. 2009;91:40-46.
Fassier A, Wicart P, Dubousset J, Seringe R. Arthrogryposis multiplex congenita. Long-term follow-up from birth until skeletal maturity. J Child Orthop. 2009;3:383-390.
Bevan WP, Hall JG, Bamshad M, et al. Arthrogryposis multiplex congenita (amyoplasia): an orthopaedic perspective. J Pediatr Orthop. 2007;27:594-600.
Bernstein RM. Arthrogryposis and amyoplasia. J Am Acad Orthop Surg. 2002;10:417-424.
Sells JM, Jaffe KM, Hall JG. Amyoplasia, the most common type of arthrogryposis: the potential for good outcome. Pediatrics. 1996;97:225-231.
INTERNET
Lal MK. Arthrogryposis. Medscape. Updated:July 11, 2024. Available at: https://emedicine.medscape.com/article/941917-overview Accessed Nov 12, 2024.
Genetic and Rare Disease Information Center (GARD). Arthrogryposis Multiplex Congenita (AMC). Available at: Arthrogryposis multiplex congenita โ About the Disease โ Genetic and Rare Diseases Information Center (nih.gov) Accessed Nov 12, 2024.
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