Arthrogryposis is also known as distal arthrogryposis, pterygium syndrome is a general or descriptive term for the development of nonprogressive contractures affecting one or more areas of the body before birth (congenitally). A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. When congenital contractures occur only in one body area, it is not referred to as arthrogryposis but rather an isolated congenital contracture. The most common form of isolated congenital contracture is clubfoot. When arthrogryposis affects two or more different areas of the body, it may be referred to as arthrogryposis multiplex congenital (AMC). The most common form of AMC is amyoplasia. Arthrogryposis and arthrogryposis multiplex congenital are sometimes used interchangeably.
The symptoms of AMC are present at birth (congenital). However, specific symptoms and physical findings can differ greatly in range and severity from one person to another, even within a family. In most cases, affected infants have contractures of various joints. The joints of the legs and arms are usually affected; the legs are affected more often than the arms. The joints of the shoulders, elbows, knees, wrists, ankles, fingers, toes, and/or hips are also commonly affected. In addition, the jaws and back may also be affected in individuals with AMC. In most cases, AMC occurs randomly, for no apparent reason (sporadic). More than 400 different conditions can cause isolated or multiple contractures and the causes, genetics, specific symptoms, and severity of these disorders vary dramatically. Mutations in over 400 genes have been identified as responsible for different types of arthrogryposis. These can be grouped by tissue, affected part of a cell involved, and function.
Classification
Some of the different types of AMC include:
- Arthrogryposis multiplex due to muscular dystrophy.
- Arthrogryposis ectodermal dysplasia is another anomaly, also known as Cote Adamopoulos Pantelakis syndrome, Trichooculodermovertebral syndrome, TODV syndrome, and Alves syndrome.
- Arthrogryposis epileptic seizures migrational brain disorder.[rx]
- Arthrogryposis IUGR thoracic dystrophy, also known as Van Bervliet syndrome.
- Arthrogryposis-like disorder, also known as Kuskokwim disease.[rx]
- Arthrogryposis-like hand anomaly and sensorineural deafness.
- Arthrogryposis multiplex congenital CNS calcification.[rx]
- Arthrogryposis multiplex congenital distal (AMCD), also known as X-linked spinal muscular atrophy type 2.
- Gordon syndrome, also known as distal arthrogryposis type 3.[rx]
- Arthrogryposis multiplex congenital, distal type 2A, also known as Freeman–Sheldon syndrome.[rx]
- Arthrogryposis multiplex congenital, distal type 2B, also known as Sheldon–Hall syndrome.[rx]
- Arthrogryposis multiplex congenital neurogenic type (AMCN).[rx] This particular type of AMC has been linked to the AMCN gene on locus 5q35.
- Arthrogryposis multiplex congenital pulmonary hypoplasia, also with a large number of synonyms.
- Arthrogryposis multiplex congenital whistling face, also known as Illum syndrome.
- Arthrogryposis multiplex congenital, distal type 1 (AMCD1).[rx]
- Arthrogryposis ophthalmoplegia retinopathy, also known as Oculomelic amyoplasia.
- Arthrogryposis renal dysfunction cholestasis syndrome, also known as ARC Syndrome.
Another form has been related to mutations in the leucine-rich glioma-inactivated 4 (LGI4) gene.[rx]
Symptoms
The most common universal symptom of AMC is limited or absent movement around small and large joints (contractures). The contractures are present at birth (congenital). The muscles of the affected limbs may be underdeveloped (hypoplastic), resulting in a tube-shaped limb with a soft, doughy feeling. Soft tissue webbing may develop over the affected joints.
In addition to joint abnormalities, other findings occur with greater frequency in individuals with AMC. These include abnormally slender and fragile long bones of the arms and legs and cleft palate, a condition in which the roof of the mouth fails to fuse leaving a groove across the top of the mouth. In males, the testes may fail to descend into the scrotum (cryptorchidism). Intelligence may or may not be affected. Approximately one-third of individuals with AMC may have structural or functional abnormalities of the central nervous system.
Additional symptoms associated with AMC are related to the underlying disorder that causes the condition in each individual. The specific symptoms and their severity can vary dramatically based upon the underlying cause. Two of the most common forms of AMC are amyoplasia and a group of genetic disorders called the distal arthrogryposes.
Amyoplasia is the most common form of AMC. Amyoplasia is a disorder characterized by multiple contractures of the joints. The shoulders may be internally rotated and drawn inward (adducted), the elbows are usually extended, and the wrists are usually flexed. In most affected individuals, the fingers are flexed and stiff. Although in most reports, the distal joints (i.e., those joints furthest away from the center of the body) are usually more severely affected, the shoulders and hips (which are proximal joints) often have significant contractures. Affected individuals usually have severe clubfoot. Some affected individuals may have dislocated hips. In some cases, a birthmark (a splotchy reddish birthmark also called a “stork mark”) may be found at birth on the face. Individuals with amyoplasia usually have normal intelligence, no significant craniofacial abnormalities, and no other serious abnormalities of internal organs (visceral abnormalities). However, about 10% of individuals with amyoplasia have abdominal abnormalities such as gastroschisis (a condition in which a hole is present in the wall of the abdomen allowing the intestines to intrude out of the abdominal space) or intestinal atresia (blockage of the intestine). Another 10% have squashed or missing distal fingers or toes. Amyoplasia is common in one monozygotic twin. Amyoplasia appears to be sporadic and does not recur in families. The diagnosis of amyoplasia is clinical at this time.
The distal arthrogryposes are a specific subgroup of AMC. This subgroup is characterized by multiple congenital contractures. Common symptoms include contractures of two or more areas of the body, less involvement of the proximal joints (those joints closest to the center of the body), and highly variable expressivity, which means that specific symptoms vary greatly even among individuals with the same disorder and even in the same family. At least 10 different forms of distal arthrogryposis have been identified including Freeman-Sheldon syndrome, Gordon syndrome, trismus-pseudocamptodactyly syndrome, multiple pterygium syndrome, and Sheldon-Hall syndrome. (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 with known gene mutations.
Causes
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. 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 as autosomal recessive, autosomal dominant, or X-linked traits. 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.
The primary underlying mechanism that leads to congenital contractures is believed to be decreased fetal movement during development. 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 would 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 illness. Low levels of amniotic fluid around the fetus (oligohydramnios) have also been linked to decreased fetal movement.
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 an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) only in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
Central and peripheral nervous system disorders that are associated with AMC include a condition in which the brain and spinal cord do not close before birth (meningomyelocele), the spinal muscular atrophies, and disorders in which there is an incomplete development of certain portions of the brain (e.g., anencephaly, hydranencephaly or holoprosencephaly). Most of these disorders 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.
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 has 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 dystrophic dysplasia, metabotropic dwarfism, popliteal pterygium syndrome, and Larsen syndrome. AMC can also be seen associated with severe hypotonia (lax muscles with little strength). In many cases of AMC, the exact underlying cause of the contractures cannot be identified.
Research on arthrogryposis has shown that anything that inhibits normal joint movement before birth can result in joint contractures.[rx] Arthrogryposis could be caused by genetic and environmental factors. In principle: any factor that curtails fetal movement can result in congenital contractures.[rx] The exact causes of arthrogryposis are unknown.
Extrinsic factors
The malformations of arthrogryposis can be secondary to environmental factors such as decreased intrauterine movement, oligohydramnios (low volume or abnormal distribution of intrauterine fluid), and defects in the fetal blood supply. Other causes could be hyperthermia, limb immobilization, and viral infections. A specific virus that may cause arthrogryposis is a contraction of the Zika virus during pregnancy. Congenital Zika syndrome (CZS), may occur when there is vertical transmission of the Zika virus to the fetus.[rx] Myasthenia gravis of the mother leads also in rare cases to arthrogryposis. The major cause in humans is fetal akinesia, however, this is disputed lately.[rx]
Intrinsic factors
Arthrogryposis could also be caused by intrinsic factors. This includes molecular, muscle- and connective tissue development disorders or neurological abnormalities.
Molecular basis
Research has shown that there are more than 35 specific genetic disorders associated with arthrogryposis. Most of those mutations are missense, which means the mutation results in different amino acids. Other mutations that could cause arthrogryposis are single gene defects (X-linked recessive, autosomal recessive, and autosomal dominant), mitochondrial defects, and chromosomal disorders (for example trisomy 18).[rx] This is mostly seen in distal arthrogryposis. Mutations in at least five genes (TNN12, TNNT3, TPM2, MYH3, and MYH8) could cause distal arthrogryposis.[rx] There could be also connective tissue, neurological, or muscle development disorders.[rx]
Muscle and connective tissue development disorders
Loss of muscle mass with an imbalance of muscle power at the joint can lead to connective tissue abnormality.[rx] This leads to joint fixation and reduced fetal movement.[rx] Also muscle abnormalities could lead to a reduction in fetal movement. Those could be dystrophy, myopathy, and mitochondrial disorders. This is mostly the result of abnormal function of the dystrophin-glycoprotein-associated complex in the sarcolemma of skeletal muscles.[rx]
Neurological abnormalities
Seventy to eighty percent of cases of the most severe forms of arthrogryposis are caused by neurological abnormalities, which can be either genetic or environmental.[rx]
The underlying etiology and pathogenesis of congenital contractures, particularly arthrogryposis, and the mechanism of the mutations remains an active area of investigation because identifying these factors could help to develop treatment and congenital finding of arthrogryposis.[rx][rx]
Diagnosis
A diagnosis of AMC is made based upon the 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. An 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 microscope to detect characteristic changes or findings that can aid in obtaining a diagnosis. Imaging studies of the central nervous system (CNS) and comparative genomic hybridization (CGH) array, microarray, and exome studies may also be useful studies in making diagnoses. Because of the many mutations that can lead to arthrogryposis, whole-genome sequencing is often required (preferable 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.
Passive enhancement
There are several passive devices for enhancing limb movement, intended to be worn to aid movement and encourage muscular development. For example, the Wilmington Robotic Exoskeleton is a potential assistive device built on a back brace, shadowing the upper arm and forearm. It can be difficult to fit and heavy and awkward to wear.[rx][rx][rx]
Researchers at the University of Delaware are developing a light and unobtrusive therapeutic garment, suitable for babies and children, called the Playskin Lift. The garment looks like normal clothing but contains bundled steel wires under the arms, which help to push the arms toward a lifted position while allowing the wearer to move freely from that position.[rx][rx][rx][rx]
Wrist surgery
Children with the amyoplasia type of arthrogryposis usually have flexion and ulnar deviation of the wrists.[rx] Dorsal carpal wedge osteotomy is indicated for wrists with excessive flexion contracture deformity when non-surgical interventions such as occupational therapy and splinting have failed to improve function. On the dorsal side, at the level of the mid corpus, a wedge osteotomy is made. Sufficient bone is resected to at least be able to put the wrist in a neutral position. If the wrist also has ulnar deviation, more bone can be taken from the radial side to correct this abnormality. This position is held into place with two cross K-wires. In addition, a tendon transfer of the extensor carpi ulnaris to the extensor carpi radialis brevis may be performed to correct ulnar deviation or wrist extension weakness, or both. This tendon transfer is only used if the extensor carpi ulnaris appears to be functional enough.[51]
Thumb surgery
The soft tissue envelope in congenital contractual conditions such as clasped or arthrogrypotic thumbs is often deficient in two planes, the thumb-index web and the flexor aspect of the thumb. There is often an appearance of increased skin at the base of the index finger that is part of the deformity. This tissue can be used to resurface the thumb-index web after a comprehensive release of all the tight structures to allow for a larger range of motion of the thumb. This technique is called the index rotation flap.
The flap is taken from the radial side of the index finger. It is proximally based at the distal edge of the thumb-index web. The flap is made as wide as possible, but still small enough to close with the excessive skin on the palmar side of the index finger. The flap is rotated around the tightest part of the thumb to the metacarpophalangeal joint of the thumb, allowing for a larger range of motion.[rx]
Foot surgeries
Generally, foot surgery is usually reserved for patients with a walking or ambulatory potential. Foot surgery may also be indicated to assist brace and orthosis fitting and hence promote supported standing. The most common foot deformity in arthrogryposis is club feet or talipes equinovarus. In the early years of life, serial casting according to the Ponseti method usually yields good results. The Ponseti method can also be used as a first-line treatment in older and more resistant cases.[rx] In such severe and neglected cases bony surgery in the form of foot osteotomies and arthrodesis is usually indicated. It is usually accompanied by soft tissue surgery in the form of the release of contracted tendon and capsular structures. In older patients near skeletal maturity, joint fusion or arthrodesis may be indicated as well.[rx] Less frequent patients with arthrogryposis may develop congenital vertical talus also known as a rocker-bottom foot. Similarly, congenital vertical talus is classically managed by serial casting according to the reversed Ponseti method. Resistant or recurrent cases may be offered an extensive soft tissue release. However, this is fraught with the risk of foot stiffness and pain in the long term. Talectomy or excision of the talus to give room for the creation of plantigrade foot has been practiced. Naviculectomy or midtarsal resection arthroplasty represents a less invasive option with satisfactory short-term results.[rx]
In some cases, 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. In rare cases, tendon transfers have been performed to improve muscle function. Tendons are the tissue by which muscle is attached to the bone. A multidisciplinary approach is desirable for the best long-term results, including pediatricians, neurologists, orthopedists, rehabilitation physicians and therapists, and medical geneticists. Genetic counseling may be recommended for affected individuals and their families. Another treatment is symptomatic and supportive.
References
