The universal finding in patients with Arthrogryposis multiplex congenita are contractures, occurring mainly in a symmetric fashion. Depending on the type of AMC, larger joints may be affected, such as the shoulder, elbow, hip, and knee in amyoplasia, while smaller joints, such as those of hand and feet are targeted in distal arthrogryposis [7]. The shoulders are internally rotated and adducted, while an extension of elbows, ulnar deviation, and flexion of wrists, knee extension, and finger stiffness are common findings in these patients. The feet are often in equinovarus position. All of these findings significantly contribute to poor gait and movement [8].

In addition to findings related to the joints, proximal muscles wasting and soft-tissue webbing over the affected joints are also frequently observed.

Skeletal symptoms, such as micrognathia, development of abnormally slender and long bones of the upper extremities, and scoliosis are often identified, while other organs may be affected as well.

Hypoplasia of the lungs, growth retardation, abdominal hernias, gastroschisis, congenital heart defects, cleft palate, cryptorchidism, as well as ocular abnormalities are rare but are encountered in patients with AMC [9].

Neurological impairment may or may not be present, depending on the etiology of AMC, but in some forms, intellectual disability may be present.

• Seizure

  SHPK Isolated Sedoheptulokinase Deficiency – 99.96 2 of 2 SLC18A3 Congenital Myasthenic Syndrome, Fetal Akinesia Deformation Sequence AR 99.97 5 of 5 SLC25A1 Congenital Myasthenic Syndrome AR 90 23 of 25 SLC35A3 Arthrogryposis, Mental Retardation, And Seizures [igenomix.es]

AMC is most commonly diagnosed during the prenatal period, using ultrasound techniques. Reduced fetal movement in utero during the second or third trimester is usually highly suggestive of AMC, and signs include abnormal positioning during routine scanning or prolonged lack of mobility. Fixed joints, micrognathia, limb deformities, growth retardation, are some of the findings that can be observed and should be thoroughly investigated.

The diagnosis in neonates and infants is made during clinical examination, when symmetric joint involvement is discovered, together with accompanying findings. In patients in whom myopathies and neuropathies are underlying causes, the diagnosis can be made through electromyography testing [10], as well as muscle biopsy.

Radiographic findings may include gracile bones, defects in the carpal and tarsal bones, scoliosis, an absence of the patella, ankylosis, and skeletal dysplasia [11].

Whenever suspicion toward AMC is evidence-based, genetic testing should be performed, especially if other congenital abnormalities are present. Karyotyping of both parents and the fetus or child should be performed, as well as another genetic testing, depending on the clinical presentation.

Treatment of arthrogryposis multiplex congenita is currently directed at rehabilitation, supportive therapy, and management of joint mobility. It is imperative to identify this condition as early as possible, to prevent a development of severe contractures that may be difficult to treat.

Initiation of physical activity to improve joint motion in both passive and active way, but also to induce muscle development is one of the key steps in the early stages of therapy, and it is shown to be effective in patients with amyoplasia. Manipulation of affected limbs right after birth has been associated with more effective treatment outcomes, particularly in patients with distal arthrogryposes.

Orthotic management has been recommended, for correction of joint mobility, and for prevention of further deformities, through casting or bracing, and has shown a good result when initiated during the first few months of life. It is important to note that despite good results with physical therapy, recurrence of joint deformities may occur.

In addition to physical therapy and orthotic management, surgical procedures may be necessary to correct numerous deformities caused by contractures [12]. Surgery may be indicated in patients that require severe corrections, with a goal of correcting a passive range of motion. Muscle and tendon transfers have been performed, and although they have improved functions in numerous patients, several complications may occur when applying the surgical treatment, including the development of new contractures and functional deterioration. There may be challenging intubation during surgical intervention since the majority of patients have micrognathia and trismus.

AMC is, in most cases, a non-progressive disease, and with prompt and proper management that can result in significant motor improvement, survival rates until the late adulthood are very high. In patients with central nervous system involvement, the disease can be quite debilitating. The prognosis significantly varies depending on the etiology, but if AMC can be managed, and the motor status of the patients can be improved with long-term therapy, this ensures significant improvement in the quality of life.

The etiology of AMC significantly varies between different forms of the disease. The principal etiological component is reduced or absent fetal mobility - fetal akinesia which can be caused by numerous factors:

• Maternal diseases, such as myasthenia gravis, diabetes, multiple sclerosis, vascular malformations, can contribute to fetal akinesia through different pathways.
• A physical limitation of the fetal mobility can result in AMC, which can be observed in maternal uterine malformations, multiple gestations, oligohydramnios, and other diseases that prevent fetal movements.
• Diseases of the muscular system, including muscular dystrophy, congenital myopathies, intrauterine myositis, as well as mitochondrial diseases.
• Diseases involving connective tissue, including synostosis, dystrophic dysplasia, but also different syndromes such as Larsen syndrome, may result in AMC.
• Neurological abnormalities in mother or fetus, including motor neuron disease, microcephaly, hydranencephaly, atrophy of spinal nerves, maternal myasthenia gravis.

In addition to numerous factors that influence fetal development and in utero mobility, the genetic basis of the disease is established in up to 30% of cases [3]. Several patterns of inheritance have been associated with the development of this disorder:

• Distal arthrogryposis is a group of disorders transmitted by autosomal dominant pattern, with more than 10 distinct forms have been recognized, characterized by different genetic and clinical details.
• Chromosomal deletions and aberrations have been associated with the development of AMC.
• Both X-linked and autosomal recessive patterns of inheritance have been observed in genetic diseases, such as infantile spinal muscular atrophy and anterior horn diseases, in which arthrogryposis develops.

In some cases, the cause of AMC may remain unknown despite all diagnostic procedures.

Incidence rates of AMC vary from 1 in 3,000 to 1 in 5,100 live births [4], and it is often established as a constituent of other underlying diseases. Gender predilection is evident in X-linked forms of the disease, and the vast majority of cases are evident at birth or even it may be observed during fetal development.

The pathogenesis of arthrogryposis multiplex congenita principally includes fetal akinesia, which may occur due to numerous causes, including genetic aberrations and uterine anatomical malformations. As a result of reduced or completely absent fetal mobility for a prolonged period of time (it is established that reduced mobility for > 3 weeks can result in AMC), bone, muscle and tendon development is suppressed. Normal muscle and tendon stretching is affected, compliance of joint capsules and ligaments are reduced, all leading to contractures and fibrosis of the joints.

Fetal mobility usually appears after eight weeks, and it is established that restriction of motility in early fetal development will result in more severe forms of the disease.

Development of neurological abnormalities, such as microcephaly and hydranencephaly, from either genetic or other causes, can result in severe forms of AMC. Genetic components have been identified in a range of diseases in which AMC occurs, and several loci have been identified in the autosomal recessive forms of this disorder [5], including defects in the phosphatidylinositol pathway, which leads to impaired endocytosis of synaptic vesicles, thus impeding the activity of the neuromuscular junction [6].

Prevention of underlying causes is highly unlikely, but early recognition of arthrogryposis multiplex congenita can significantly aid in reducing the severity of illness. Timely management and prompt implementation of physical therapy may provide very good outcomes in patients and significantly improve the quality of life. Early diagnosis can facilitate genetic counseling and optimize perinatal care, but also provide parents with vital information [13].

Arthrogryposis multiplex congenita (AMC) comprises a group of numerous congenital conditions that cause reduced joint mobility, usually affecting multiple joints in a symmetric fashion [1]. There are two distinct forms of AMC: amyoplasia (also known as the classic form), in which multiple symmetric contractures of larger joints in the limbs are observed; and distal arthrogryposis, in which contractures develop on smaller joints, such as those of the hands and feet while sparing the larger joints. The cause of these congenital conditions is primarily linked to illnesses or events that lead to reduced mobility during fetal development, including multiple gestations, oligohydramnios, uterine malformations, and many other illnesses, while a genetic component has been confirmed in the case of distal arthrogryposis, i.e. autosomal dominant pattern of inheritance has been observed, but autosomal recessive, X-linked, as well as sporadic patterns, have been documented in various diseases [2]. The incidence of AMC ranges between 1 in 3,000 to 1 in 5,100 live births. Clinical manifestations are present at birth, vary depending on the affected joints and include internal rotation of the shoulder, extension and pronation of the elbow, persistent knee flexion or extension, clubfoot, external rotation and abduction of the hip, jaw immobility, while neurological impairment may be observed, depending on the etiology, and may include intellectual disability and other functional abnormalities. When AMC is identified early, proper rehabilitation and supportive therapy considerably improve the patients' status. Survival rates are very high, with the majority of patients reaching late adulthood unless a serious central nervous system involvement is present. The diagnosis is made by clinical examination, imaging studies, and electromyography, while muscle biopsy is done in cases that involve neuropathy and myopathy as underlying causes. Treatment principles involve improving joint mobility, through casting, orthoses, and rehabilitation by strengthening the overall musculature, while surgical treatment is reserved for larger deformities.

Arthrogryposis multiplex congenita is a term that describes the development of non-progressive joint rigidity and impaired development of surrounding muscles and tendons. This disorder appears in numerous conditions that may be of genetic, environmental, or sometimes unknown cause, while maternal factors may also result in the development of this disease. Some of the causes include abnormalities in the development of the muscles, the brain, and other parts of the nervous system. Important causes include insufficient room for the development of the fetus due to anatomical abnormalities of the uterus, presence of maternal diseases such as myasthenia gravis, multiple gestations, and many other. Specific forms of the disease may include neurological abnormalities, which can result in a significant burden for the patient and the parents.

Regardless of the cause, this disease occurs as a result of reduced fetal mobility, and it is estimated that three weeks of reduced or no fetal mobility can result in arthrogryposis multiplex congenita. Because the fetus is not moving, there is inadequate development and maturation of muscles, bones, tendons, and joints, which leads to stiffening and limited movement of limbs, as a result of hardening of the tissues surrounding the affected joint.

This disorder usually occurs in about 1 in 3,000 live births, with equal gender predilection, while some patients may develop this syndrome in diseases that are transferred through the X chromosome, which means that is can occur in boys more frequently.

The disease manifestations are present at birth, and this illness target joints in a symmetric fashion, i.e. both elbows or shoulders are affected. There are two distinct forms of this disease - amyoplasia, which targets larger joints, such as shoulders, hips, elbows, and knees; and distal arthrogryposis, which targets the smaller joints, such as those of the hands and feet. Findings include abnormally positioned, stiff joints and extremities, with the extremities appearing "featureless" as a result of underdeveloped muscles and tendons. In addition to findings on the limbs, this disorder can affect the spine as well, and severe cases may present with a great disability. Forms of this disorder that include neurological impairment present with intellectual disability, as well as with other manifestations regarding the nervous system.

The diagnosis of this disease can be made through fetal ultrasonography, clinical examination, electromyography, biopsy of the muscle, genetic testing, but other diagnostic tools may also be useful. Early treatment may provide significantly better outcomes, especially if started during the first few months of life, and consists of physical therapy with or without the use or orthotics, and surgical therapy. The prognosis, which could be very good, depends on the seriousness of the disease, timing of the treatment and its results.

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