Arthrogryposis (multiple congenital contractures): Diagnostic approach to etiology, classification, genetics, and general principles

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Abstract

Arthrogryposis has been the term used to describe multiple congenital contractures for over a century. It is a descriptive term and present in over 400 specific conditions. Responsible gene abnormalities have been found for more than 150 specific types of arthrogryposis. Decreased fetal movement is present in all affected individuals which leads to a variety of secondary deformations. Decreased fetal movement (fetal akinesia) is associated with increased connective tissue around the immobilized joint, skin dimpling overlying the immobilized joint, disuse atrophy of the muscles that mobilize the joint and abnormal surface of the joint depending on the immobilized position. Other frequently observed features include: micrognathia, mildly shortened limbs, intrauterine growth restriction, pulmonary hypoplasia and short and/or immature gut. Primary etiologies include neuropathic processes; myopathic processes; end-plate abnormalities; maternal illness, trauma and drugs; limitation of fetal space; vascular compromise; and metabolic disorders to the developing embryo/fetus.

Introduction

The descriptive terms arthrogryposis (arthro = joint; gryp = curved) and arthrogryposis multiplex congenita (multiplex = multiple, congenital = present at birth) have been used for the last century to describe conditions with multiple congenital contractures [Hall, 2013b]. All three terms are now used interchangeably. Arthrogryposis is a sign rather than a diagnosis. It implies contractures in multiple body areas (e.g., more than just club feet or dislocated hips), usually involving the limbs, but may also include limitation of full range of movement of the jaw, neck, and spine at birth. The contractures are usually non-progressive and improve over time with early physiotherapy and appropriate orthopedic care. Two-thirds of affected individuals are able to live independent and productive lives. The term arthrogryposis is used to describe a very heterogeneous group of affected individuals who are recognized in the newborn period to have multiple congenital contractures. Over 400 specific conditions (including gene mutations and chromosomal abnormalities, deletions, and duplications) have been described as having multiple congenital joint contractures. A responsible gene alteration has been found in more than 150 of these conditions [Hall, 2013b]. The challenge, of course, is to identify the primary etiology of a specific type of arthrogryposis.

Although arthrogryposis has been thought of as a rare condition, in fact, it occurs in between one in 3000 and one in 5000 live births [Lowry et al., 2010]. However, each specific type is relatively rare. The most common type of arthrogryposis is the sporadic condition, Amyoplasia, which has a frequency of one in 10,000 [Hall, 2014].

In the past, the literature concerning arthrogryposis was very confusing because reports lumped multiple different conditions together, frequently related to reporting the responses to various therapies. However, over the last 30 years, great progress has been made in distinguishing specific types of arthrogryposis, recognizing responsible genes, and understanding the multiple pathways that may lead to involvement. Arthrogryposis is particularly interesting because it is a window into embryonic and fetal movement and all the elements that must be present for the normal in utero movement to develop—movement is, after all, a characteristic of all living beings. This article will attempt to discuss general etiologic categories and the commonalities seen with decrease fetal movement (fetal akinesia), to present a diagnostic approach, and to discuss prenatal diagnosis and potential therapies.

Section snippets

General etiologic categories

All forms of arthrogryposis are associated with decreased fetal movement (fetal akinesia). There is a direct relationship between the early onset of fetal akinesia and the severity of contractures. The earlier and the longer the duration of decreased movements, the more severe the contractures will be at birth. In most forms of arthrogryposis, joint development is normal during embryogenesis. However, the decreased movement is associated with: 1) an increase of connective tissue around the

Myopathic processes

Abnormalities of muscle formation structure and/or function are known to lead to secondarily decreased fetal movement. Abnormalities of fast twitch muscles are seen in many types of distal arthrogryposis [Bamshad et al., 1996] (Table 4). Severe myopathic and dystrophic processes (including nemaline myopathy, central core/nuclear myopathies, reducing body myopathy, etc.) have also been observed to have multiple congenital contracutres at birth. Recently, genes involved in mechanical transduction

Neuropathic processes

Neuropathic processes leading to arthrogryposis include abnormalities in nerve formation, structure and/or function. These may involve the central nervous system (brain and spinal cord) and/or peripheral nerves. Thus, if nerves fail to form, migrate normally, mature, maintain maturation, or myelinate, they can lead to decreased in utero movement and/or hypotonia; either of which may then lead to the secondary joint and muscle changes seen in arthrogryposis. Thus, congenital neuropathies of many

Neuromuscular end-plate

Recently, the neuromuscular end-plate has been implicated in producing arthrogryposis, often because of mutations in the genes for the various components of the end-plate [Michalk et al., 2008]. Several forms of pterygium syndrome have been found to be related to failure of formation and maturation of the embryonic/fetal end-plate. When pterygia or webs are found across a joint they reflect early and sustained lack movement during in utero development (as well as after birth). It appears that

Connective tissue abnormalities

The tendons, bones, joints, as well as joint lining and fluid may develop in a way that restricts fetal movement, resulting in congenital contractures. Many of the chondrodysplasias are associated with limitation of joint movement because of abnormal bone or cartilage formation. These conditions can be quite resistant to mobilization therapy because the bone structure is the basis of limited joint movement. Abnormalities in tendon formation and placement may lead to limitation of the range of

Space limitation

Limitation of space within the uterus may restrict fetal movement leading secondarily to congenital contractures usually occurring during the second half of pregnancy). This may be seen with structural anomalies of the uterus (as in bicornuate uterus) [Hall, 2012a], with multiple births (as in triplets, quadruplets, etc), in the presence of amniotic bands, with decreased amniotic fluid (as with chronic amniotic fluid leakage) [Hall, 2013a], and with uterine tumors such as fibroids. When

Maternal illness

Many maternal disorders have been associated with arthrogryposis. These may be related to specific maternal illnesses or exposures such as: multiple sclerosis, maternal diabetes, myasthenia gravis, myotonic dystrophy, and the development of matneral antibodies against paternally inherited fetal neurotransmitter receptors. Maternal infections such as rubella, rubeola, coxsakie, and encephalitis, have also been reported to have fetal effects, including multiple congenital contractures. In

Maternal exposures

Maternal exposures to medications, drugs, and environmental factors have also been associated with multiple congenital contractures in the newborn [Hall, 2013b, Hall and Reed, 1982]. Medications such as muscle relaxants (Robaxin), chemical abortifacients (Misoprostol), and antiepileptics (Phenobarbital, Dilantin) which cross the placenta have been implicated in the past in producing arthrogryposis. Excessive alcohol and addictive drugs (such as cocaine) have also been reported to be associated

Intrauterine vascular compromise

The circulating blood of the placenta normally nourishes the developing fetus enabling nerves, muscles and bones to grow and function in utero. When the vascular supply is cut off or limited, these developing structures are easily damaged, and may miss important developmental steps; and thereby, may lead to secondary and tertiary effects. Even transient loss of functional neurons or muscle may result in sufficient fetal akinesia to develop mild joint contractures which may worsen over time, in

Metabolic disturbances

Several metabolic disorders, manifesting in utero, result in the affected infants being born with arthrogryposis. See Table 5. Maternal acidosis (or maternal illness causing maternal acidosis) is also thought to have negative effects on the developing fetal nervous system. Thus, preventing or treating maternal metabolic imbalances and treating the inherited metabolic disorder in utero or at birth may result in more favorable outcomes. Children with arthrogryposis, particularly those with a

Epigenetic disorders

The control of gene expression is just beginning to be understood. It seems quite likely that alternative physiologic pathways during development and transgenerational effects will play some role in the complex development of fetal movement. Potential pathways for in utero therapy (to increase movement) and non-surgical therapies (such as medical treatment in order to decrease the excessive connective tissue around joints), as well as the engagement of mechanical transduction developmental

Diagnostic approach

Since there are so many conditions with multiple congenital contractures, careful evaluation is needed to make a specific diagnosis (See Table 1). The evaluation includes careful history of the pregnancy and delivery, a full 3-generation family history, a detailed physical examination with documentation of which parts of the body are involved, the degree of flexion or extension of various joints, photographs at different ages and detailed measurements (including the range of motion of various

Three useful sub-categories

A useful approach to finding a specific diagnosis in arthrogryposis is to classify the affected individual into subgroups: a) Involvement of limbs only, b) Limbs plus other system abnormalities, and c) Neuromuscular involvement plus central nervous system dysfunction or intellectual disability [Hall, 2013b].

Table 7 lists some of the common disorders in these three categories (for an extensive differential diagnosis refer to Chapter 161 in Emery and Rimoin [Hall, 2013b]. This approach seems

Prenatal diagnosis

75% of arthrogryposis is not diagnosed prior to delivery in spite of numerous prenatal ultrasound studies, because fetal movement is not routinely studied prenatally [Filges and Hall, 2013]. When suspicion arises (maternal concern about lack of fetal movement, clubfoot observed, etc.) up to 45 min by an experienced ultrasound technician may be needed to examine fetal movement of each limb area. In familial situations of high risk, ultrasound studies to evaluate fetal movement should be done at

Therapy

Therapy is beyond the scope of this article; however, early physical therapy (before leaving the nursery) has been found to mobilize joints and save muscle from disuse atrophy. Care should be taken with the physical therapy to avoid iatrogenic fractures of long bones since the long bones are most often osteoporotic. Most affected infants will need orthopedic and multidisciplinary care. Casting should be delayed a few months in order to mobilize joint tissues if possible.

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