Arthrogryposis

Disease/Disorder

Definition

Arthrogryposis is the presence of nonprogressive, usually symmetric, congenital contractures of at least two joint levels and in multiple body areas. Arthrogryposis or arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders with well over 400 known conditions. Affected individuals commonly have decreased fetal movement (fetal akinesia).¹

Etiology

Fetal akinesia in-utero with normally developing joints and limbs is hypothesized to be the cause of AMC. The lack of movement around the joint leads to development of extra connective tissue formation around the joint.² fixing the joint in place and eventually to contractures. Maternal causes of fetal akinesia include uterine structure anomalies, fetal crowding, infection, maternal illness, or toxins. Fetal causes include connective tissue or skeletal defects, vascular compromise, muscle defects, and peripheral or central nervous system (PNS, CNS) pathology. AMC can be genetically inherited through autosomal dominant (AD), autosomal recessive (AR), de novo, X-linked, or mitochondrial mechanisms. More than 400 genes are associated with AMC.¹ The most frequent genetic cause of AMC is a primary involvement of skeletal muscle, followed by brain involvement with or without spinal cord defect.³

Epidemiology including risk factors and primary prevention

AMC occurs from 1/3000 to 1/5000 live births, affecting males and females equally^2,3 Muscle disorders, muscular dystrophies, mitochondrial disorders, neural tube defects, or other PNS and CNS disorders are at an increased risk for AMC. Neurogenic factors are the most common cause of fetal akinesia presented in 70-80% of AMC patients.⁴

Other risk factors include maternal illnesses, such as multiple sclerosis, diabetes mellitus, myasthenia gravis, and maternal hyperthermia in the first trimester. Severe bleeding during pregnancy or after a failed pregnancy termination, metabolic disease such as phosphofructokinase deficiency and drugs taken during pregnancy (e.g., muscle relaxants, misoprostol, cocaine, alcohol) are also associated with arthrogryposis.⁵ Additionally, maternal Zika virus infection is the most frequent viral infection causing AMC and CNS anomalies.⁶

Regular prenatal care assists with early diagnosis of decreased fetal movement but does not decrease incidence or improve outcome.

Patho-anatomy/physiology

The pathophysiology is related to the specific type of AMC. Exact mechanisms are not well understood in some subtypes. In general, fetal akinesia leads to collagen overgrowth, where extra connective tissue forms around the joint leading to the thickening of joint capsules. Restricted movement results in less pliable tendon, bone flattening, and possibly decreased limb growth, further increasing the contracture.

In AMC amyoplasia type, the anterior horn cells in the spinal cord are affected at about 8 to 10 weeks in-utero, resulting in muscle weakness and contractures that are so prevalent in affected newborns.

In distal arthrogryposis (DA), genetic anomalies are thought to cause altered sarcomere integrity and muscle contractility resulting in contractures. In vitro and in situ studies have demonstrated the role of mutations in genes encoding troponin T, troponin I, and beta tropomyosin. These mutations increase ATPase and may alter calcium sensitivity, leading to increased contractility of developing fast twitch muscles, and progressing to contractures.³ Over 400 different DA cases showed the association of MYBPC2 mutation with DA. MYBPC2 mutations affect the binding site of myosin S2 which is crucial for the regulation of thick and thin filament.⁷ Genes related to neuronal function have also been found to be related in cases of DA.³

In central etiologies, there may be decreased corticospinal tract activation of spinal cord motor neurons or spinal cord motor neurons may be directly injured.

In congenital myopathies, there may be alterations in genes that encode mysosin light chains in skeletal muscles. Genetic alterations have also been observed in congenital myopathy and muscular dystrophy, which can affect A-type lamins and glycosylation, which then impairs contractility.

In mothers with myasthenia gravis, maternal antibodies may block the acetylcholine receptors in the fetus, causing decreased fetal movement and thus contractures⁸

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

	Amyoplasia	Distal Arthrogryposis (DA)	Diastrophic Dysplasia
Inheritance	Sporadic	AD/AR	AR
Extremities affected	Legs and arms	Hands and feet	Arms, legs, spine
Other deformities	Equinovarus feet Extended elbows Midfacial hemangioma Dislocated hips Scoliosis common	Camptodactyly Overlapping fingers Ulnar deviation Foot deformities	Short stature/dwarfism Elbow, finger, and hip contractures Cystic external ear mass Cleft palate
Comments	Symmetric involvement Most common form (1/3) of AMC	10 subtypes based on hierarchy of phenotypes Type 2B (Sheldon Hall) syndrome most common	High infant mortality rate; if survive beyond infancy–normal lifespan

All arthrogryposis types

• Cognition/behavior: Cognition is typically normal if there is no underlying neurologic, chromosomal or developmental disorder.
• Ambulation: Walking is often delayed until to 2-5 years old.
• Scoliosis: Can be rapidly progressive if detected before 1 year of age.
• Adults: The majority of adults are ambulatory, can live normal lifespan, less than half become completely independent, others continue to require assistance. Pain related to spine and foot/ankle is a common concern of adult.²

Specific secondary or associated conditions and complications

Associated conditions and complications include

• Anesthesia risk: Increased spinal cord injury risk because of underdeveloped first and second vertebrae (caution with anesthesia for surgery).
• Malignant hyperthermia.
• Increased risk for aspiration.
• Scoliosis/kyphoscoliosis.
• Arthritis.
• Fractures of long bones.
• Constipation.
• Feeding difficulties are common in early infancy and may persist through childhood.
• Obesity: although usually thin body habitus, overfeeding, and limited energy expenditure with severe contractures can increase the risk of obesity in infants, children, and adults.

Essentials of Assessment

History

Obstetric history

• Maternal illness such as diabetes, infections (including zika virus), myasthenia gravis, exposure to toxins, drugs, alcohol, and maternal fevers or bleeding.
• Prenatal ultrasound history: fetal movement, limb deformities, and amniotic fluid levels.
• Prenatal genetic testing: amniocentesis, cell free DNA.⁹
• History of uterine abnormalities such as myoma/fibroma or bicornate uterus, gestational age, multiple birth, placental abnormalities, and breech presentation.
• History of abortions, miscarriages, and stillbirths.

Family history neurologic or genetic disorders and consanguinity.

Physical examination

Physical findings may vary and include:

Limbs

• At least 2 or more joint contractures in multiple body areas.
• Hip and knee flexion, shoulder adduction, elbow extension, wrist and finger flexion contractures are common.⁸ Joint fusion-synostosis or soft tissue contractures may also be present.
• Pterygium: skin webs in between joints.
• Muscle atrophy.
• Equinovarus or clubfoot deformities are most common. Congenital vertical talus, isolated equinus deformity, congenital metatarsus adductus, pes equinovalgus, or pes calcaneovalgus are occasionally seen as well.⁴
• Deep grooves, tight bands, dimples (especially over joints with decreased movement).
• Hirsutism: areas with low activity.
• Shortened digits or underdeveloped ends of digits.
• Syndactyly: webbing of digits.

Trunk/spine/genitalia

• Scoliosis (23% of patients).¹⁰
• Cryptorchidism.
• Hernia.
• Hydrocele.
• Underdeveloped labia.

Head/neck

• Webbed neck.
• Abnormal head shape (craniosynostosis, microcephaly).
• Scalp defects, abnormal hair pattern.
• Midline facial hemangioma or birthmarks: especially in amyoplasia.
• Micrognathia, high arched or cleft palate, trismus.
• Flat bridge of nose, asymmetric faces.
• Abnormal ear shape and folding.

Neurologic

• Abnormal reflexes: absent, diminished, or brisk.
• Hypotonia may or may not be present.
• Oculomotor apraxia or ptosis.
• Sensation generally intact.
• Cognition: typically normal. 25% of individuals have intellectual disability/CNS involvement.^5,6

Functional assessment

Functional history should include

• Developmental milestones.
• Trunk/head control.
• Activities of daily of living.
• Gross and fine motor difficulties.
• Bracing, equipment, and home adaptations.
• Speech and swallowing difficulties, including feeding
• Pain

Functional assessment

• Range of motion.
• Transfers, mobility, and gait.
• Use of upper extremities for various tasks.
• Gross and fine motor skill assessment.

Laboratory studies

Genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability, developmental delay or multiple congenital anomalies associated with AMC should be preferred as first tier investigation over electromyography/nerve conduction studies (EMG/NCS) and muscle biopsy.^3,9

Distal arthrogryposis genetic tests: TNNI2, TPM2, MYBPC1, MYBPC2, PIEZO2, TTN, TNNT3, MYH8, and MYH3.^3,7

Targeted molecular analysis should be carried out in AMC patient with severe hypotonia to rule out myotonic dystrophies, spinal muscular atrophy and congenital myopathies.¹

Creatine phosphokinase: test in generalized or progressive muscular weakness.

Maternal antibody for myasthenia gravis

Imaging

Prenatal ultrasound detecting AMC is important both for parental counseling and safe delivery.⁶

Radiologic studies: x-rays, including pelvis x-rays in infants to evaluate hip joint, foot x-rays to determine vertical talus (in infants), and scoliosis x-rays, which can be done at any age, and may need to be obtained every 6 months to 1 year depending on severity and progression.

Magnetic resonance imaging (MRI) of the brain and spinal cord help to rule out central or spinal cord anomalies. Whole body muscle MRI may be of value given that specific muscle patterns on MRI have been shown to be associated with specific phenotypes.¹¹

Supplemental assessment tools

Muscle biopsy and EMG/NCS are often used to examine for neuromuscular etiologies.  However, muscle biopsies have little impact on the diagnosis in AMC, unless there is a clinical suspicion of an underlying congenital myopathy or a peripheral neuropathy or motoneuron disease.⁹

Environmental

Environmental barrier assessment should include: the number of stairs around the home; accessibility of home, school, and community; and transportation needs.

Social role and social support system

Social history should include: the number of people in the home; primary and secondary caregivers; friends, hobbies, interests, and extracurricular activities; support/coping resources (patient, family, school, and community); and transition to adulthood needs and financial needs.

Professional issues

Family planning: genetic counseling should be offered to parents to help them understand recurrence risks after having their first child with AMC of genetic etiology.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Published treatment guidelines do not exist, but good practice suggests emphasis on the following areas.

Early intervention

• Active and passive range of motion to decrease severity of contractures.
• Strengthening any functional muscles.¹²
• Bracing and splinting.
• Adaptive equipment and mobility devices.
• Conservative management is the priority when treating patients with arthrogryposis. Treatment with serial casting using the Ponseti technique shows the best improvement in function and mobility for patients with arthrogrypotic clubfeet.^2,13

Surgical interventions in first year if possible.

Repeat surgeries throughout childhood and adolescence to improve function

• Hand, wrist, and finger deformity corrections. For elbow extension contractures, performing the triceps tendon release before 2 years of age possibly improves the overall passive total arc of elbow motion, compared with children 2–3 years old, and older. Although shoulder surgery is rarely needed, a distal humerus derotational osteotomy can be beneficial for severe internal rotation contractures.²
• Scoliosis surgery.
• Soft tissue releases, tenotomies, and tendon transfers. Osteotomies are used for the severe case of equinus.² The recurrence rate of foot deformities after primary surgery of the equinovarus foot may approach 75–100%.⁴
• Hip and knee flexion contracture release-community walkers found to have less than 20-degree contractures of knees and hips.¹¹

At different disease stages

Infant stage (0-18 months)

• Range of motion: passive and active in all affected joint, daily home stretching program.
• Bracing/splinting: thermoplastic splints and serial casting; dynamic splints occasionally for elbow flexion.
• Facilitating transitioning movements (rolling, sitting and standing); enabling a child to explore and interact with environment. Standing devices are recommended for motor impaired children.¹²
• Correction of foot deformities: 4 weeks. Ponseti castinging, and surgery with the goal of plantigrade and braceable feet to allow full weight bearing.
• Correction of hips-6-8 months.
• Upper extremity surgeries ideally are performed between 3-12 months for optimal outcomes.¹¹

Toddler (18 months-4 years of age)

Rehabilitation goals should focus on balance, mobility and fine motor activities to maximize independence.

• Ongoing range of motion and strengthening exercises.
• Use of orthotics such as a Hip –knee- ankle orthosis (HKAFO) to stabilize the hips during walking, a knee ankle orthosis (KAFO) or ankle foot orthosis (AFOs)s to stabilize the knee or ankle joint. 
• Use of assistive devices including a stander or gait trainer to prevent contractures and aid in ADLs.  Posterior walker may be necessary to prevent falls and conserve energy. Hands free gait trainer will permit exploration with peers.
• Overhead slings or upper extremity exoskeletons may be helpful to allow child to use arms and promote fine motor skills.¹²
• Explorative play with toys is integral for fine motor including self feeding development.

Childhood /adolescent (5 years and up)

For school age patients, focus on self-care and ADLs is of utmost importance.

• Continued range of motion/therapy. Therapy should focus on speed, terrain, endurance and fall prevention for ambulatory patients, or on the ability to maneuver either a manual or power wheelchair for non-ambulatory patients.
• Ongoing reassessment of bracing needs: night splints, serial casting, and dynamic wrist splints for supervised play and for functional purposes more than stretching.
• Incorporation of adaptive equipment, mobility devices, and gait aids to achieve maximum independence and increase community participation.
• Repeat surgical interventions, if necessary.
• Regular scoliosis screening-x-rays and clinical assessment.
• Annual ophthalmology and hearing screens.
• Peer support, teacher support, coping, and counseling, if needed.
• Prepare adolescent to achieve goals for independence, career, vocation, and higher education.

Adults

Therapy focus shifts toward increasing independence, education and employment.¹²

• Home exercise program. Upper limb functions including gripping, reaching the head and face for feeding and hair care, reaching the perineal area for hygiene, and dressing, are the most important determinants of independent living for adult with arthrogyposis.¹¹
• Maintenance of functional bracing options.
• Management and prevention of obesity, hypertension, diabetes, and other conditions of adult age groups.
• Support, counseling, and family planning.

Coordination of care

Ideally, a multidisciplinary approach should be incorporated. Team members may include healthcare professionals in pediatrics, genetics, orthopedics, physiatry, neurology, physical therapy, occupational therapy, speech therapy, orthotics, social work, psychology, nutrition, and nursing. Teachers and school therapists should also receive regular communication regarding the patient.

Patient & family education

Newborn: Family education regarding the diagnosis, implications, outcomes, and expectations.

Children: When the child is old enough to start asking questions about his/her physical state, answers should be addressed appropriately. Provide parents with tools to facilitate educating their child on their diagnosis.

Adolescents/adults: Education on healthcare and community resources.

Risks and benefits of all interventions should be regularly communicated to families.

Often times physiotherapy is done remotely through telerehabilitation. As a result, it is crucial that family members are involved in care and facilitating therapies. Family involvement has been shown to plays a large role in minimizing contractures.¹⁴

Emerging/unique interventions

AMC discogram: range of motion and function of various joints are expressed as a percentage of normal and placed onto a spider web or star chart, which can track range of motion and functional improvement in relationship to various interventions.¹⁵ Pediatric Outcomes Data Collection Instrument has been found useful in amyoplasia patients.¹⁶

Cutting Edge/Emerging and Unique Concepts and Practice

Many genetic factors may lead to AMC, including sporadic gene mutations, chromosomal disorders, and mitochondrial disorders. Advances in exome/genome sequencing and genetic analysis of AMC families continue to identify possible causes of the condition, such as the ECEL1 gene causing a specific type of distal arthrogryposisand SMPD4 associated with AMC with brain malformation.^13,17,18

Patient registries are in the process of development in order to provide support for genetic and clinical studies.¹⁹

Research is being conducted in new treatment modalities such as robotic exoskeletons²⁰ and passive orthosis,²¹ as well as telerehabilitation systems for providing services to AMC patients.^14,22

Gaps in the Evidence-Based Knowledge

Current management emphasizes a collaboration of surgical and rehabilitation intervention. It is possible that exome sequencing and other techniques may not only lead to further understanding, but to new prevention and treatment strategies in the future.

References

1. Hall JG, Kimber E, Dieterich K. Classification of arthrogryposis. Am J Med Genet C Semin Med Genet. 2019 Sep;181(3):300-303. 
2. van Bosse HJP. Orthopaedic care of the child with arthrogryposis: a 2020 overview. Curr Opin Pediatr. 2020 Feb;32(1):76-85. 
3. Laquerriere A, Jaber D, Abiusi E, et al. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita. J Med Genet. 2022 Jun;59(6):559-567.
4. Kowalczyk B, Feluś J. Arthrogryposis: an update on clinical aspects, etiology, and treatment strategies. Arch Med Sci. 2016 Feb 1;12(1):10-24.
5. Kimer E. AMC: amyoplasia and distal arthrogryposis. J Child Orthop.2015 Dec;9(6):427-32.
6. Dieterich K, Kimber E, Hall JG. Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care. Am J Med Genet C Semin Med Genet. 2019 Sep;181(3):345-353. 
7. Desai D, Stiene D, Song T, Sadayappan S. Distal Arthrogryposis and Lethal Congenital Contracture Syndrome – An Overview. Front Physiol. 2020 Jun 25;11:689.
8. Bamshad M, Van Heest AE, Pleasure D. Arthrogryposis: a review and update. J Bone Joint Surg. 2009;91(Suppl 4):40-46.
9. Dieterich K et al., The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature. 2019. Am J Med Genetics. 181 (3): 337-344.
10. Komolkin I, Ulrich EV, Agranovich OE, van Bosse HJP. Treatment of scoliosis associated with arthrogryposis multiplex congenita. J PediatrOrthoped 2017;37(Suppl 1):S24–S26.
11.  Griffet J, Dieterich K, Bourg V, Bourgeois E. Amyoplasia and distal arthrogryposis. Orthop Traumatol Surg Res. 2021 Feb;107(1S):102781. 
12. WagnerLV, Cherry JS, Sawatzky BJ, Fąfara A, Elfassy C, Eriksson M, Montpetit K, Bucci T, Donohoe M. Rehabilitation across the lifespan for individuals with arthrogryposis. Am J Med Genet C Semin Med Genet. 2019 Sep;181(3):385-392. 
13. van Bosse HJP. Challenging clubfeet: the arthrogrypotic clubfoot and the complex clubfoot. J Child Orthop. 2019 Jun 1;13(3):271-281.
14. García Aguilar CE, García-Muñoz C, Carmona-Barrientos I, Vinolo-Gil MJ, Martin-Vega FJ, Gonzalez-Medina G. Rehabilitation in Patients Diagnosed with Arthrogryposis Multiplex Congenita: A Systematic Review. Children (Basel). 2023 Apr 24;10(5):768. 
15. Mennen U. Arhtrogryposis multiplex congenita: functional classification and the AMC disc-o-gram. J Hand Surg Br. 2004;29:363-367.
16. Courtney A, Spaeth MC, Chafey DH. Use of the pediatric outcomes data instrument to evaluate functional outcomes in arthrogryposis. J Pediatr Orthop. 2011;31:293-296.
17. Nagata K., Kiryu-Seo S., Tamada, H., et al. ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis. Acta Neuropathol. 2016 Jul;132(1):111-26. 
18. Ravenscroft G, Clayton JS, Faiz F, et al. Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics. J Med Genet. 2020 Oct 15:jmedgenet-2020-106901.
19. Dahan-Oliel N, Bedard T, Darsaklis VB, Hall JG, van Bosse HJP, Hamdy RC. Development of a research platform for children with arthrogryposis multiplex congenita: study protocol for a pilot registry. BMJ Open. 2018;8(6):e021377. Published 2018 Jun 30.
20. Babik I, Kokkoni E, Cunha AB, Galloway JC, Rahman T, Lobo MA. Feasibility and Effectiveness of a Novel Exoskeleton for an Infant With Arm Movement Impairments. Pediatr Phys Ther. 2016;28(3):338-346.
21. Jensen EF, Raunsbæk J, Lund JN, Rahman T, Rasmussen J, Castro MN. Development and simulation of a passive upper extremity orthosis for amyoplasia. J Rehabil Assist Technol Eng. 2018;5:2055668318761525. Published 2018 Mar 1.
22. Gagnon M, Collins J, Elfassy C, et al. A Telerehabilitation Intervention for Youths With Arthrogryposis Multiplex Congenita: Protocol for a Pilot Study. JMIR Res Protoc. 2020;9(6):e18688. Published 2020 Jun 26.

Bibliography

Hall, J. G. (2014). Arthrogryposis (multiple congenital contractures): Diagnostic approach to etiology, classification, genetics, and general principles.European Journal of Medical Genetics, 57(8), 464–472.

Dubousset J, Guillaumat M. Long-term outcome for patients with arthrogryposis multiplex congenital. J Child Orthop. 2015;9: 449-458.

Ayadi K, Trigui M, Abid A, et al. Arthrogryposis: clinical manifestations and management. Arch Pediatr. 2015;22(8): 830-9.

Original Version of the Topic

Talia R. Collier, MD. Arthrogryposis. 8/17/2012.

Previous Revision(s) of the Topic

Yuxi Chen, MD, Kyle Menze, DO, Hana Azizi, MD. Arthrogryposis. 8/18/2016.

Yuxi Chen, MD, Nahyun Kim, MD, Michael Hagen, MD. Arthrogryposis. 6/29/2021

Author Disclosure

Yuxi Chen, MD
Nothing to Disclose

Daniella Lipnick, MD
Nothing to Disclose

Michael Hagen, MD
Nothing to Disclose