Arthrogryposis

Introduction

Arthrogryposis is a term used to describe the presence of multiple contractures of joints in more than one area that are present at birth. The extended term, arthrogryposis multiplex congenita (AMC), has also been used historically to describe multiple congenital contractures (arthro=joint; gryp=curved; multiplex=multiple; congenita=present at birth). Such contractures are usually nonprogressive and may respond to physical therapy and orthopedic procedures. Arthrogryposis has been recognized for centuries in folklore, art, and medical reports. In the past, the term arthrogryposis was used as a diagnosis for any child born with multiple congenital contractures; however, over the years it has become apparent that there are many different types of conditions with multiple congenital contractures. Thus, the term has come to be used as a clinical sign or as a general category of disorders. For the purposes of this chapter, the term arthrogryposis is used as a generic term that encompasses many different conditions with varied causes. The common pathway to congenital contractures appears to be decreased fetal movement, which may occur for many different reasons. The challenge is to determine the specific cause of decreased fetal movement and then to be able to predict natural history, recurrence risk, and best therapies for a specific case. This chapter attempts to present a functional approach.

Historical Background

The first medical report of arthrogryposis was by Adolph Wilhelm Otto in 1841. In the 1930s, 1940s, and 1950s, orthopedists gathered together cases to report the effects of surgery. In the 1950s and 1960s, specific recognizable disorders began to emerge. In 1983, Moessinger proposed the unifying theory, based on animal studies, that lack of fetal movement leads to a whole set of secondary deformations including congenital contractures. Also in the 1980s, Hall and coworkers developed a clinical approach to congenital contractures. Many specific types of arthrogryposis began to be enumerated. In the 1990s, specific genes responsible for inherited forms of arthrogryposis began to be mapped and defined; in addition, multiple mechanisms leading to decreased fetal movement began to be elucidated.

Epidemiology

Approximately 1 in 100 children is born with some type of congenital contracture (clubfoot: 1/300; dislocated hip: 1/200; camptodactyly: 1/200; and so forth), but arthrogryposis implies more generalized involvement. The incidence of newborns with multiple congenital contractures from epidemiological studies is about 1 in 3000 live births. The most common specific condition is Amyoplasia, or “classical arthrogryposis,” which occurs in about 1 in 10,000 births and, as noted later, has a relatively good prognosis.

Some data suggest multiple congenital contractures are common among miscarriages and stillbirths; thus, the in utero frequency may be higher than at birth. Evaluation of fetal movement is not routinely a part of fetal ultrasound. However, affected babies often come to attention when clubfoot or an unusual positioning of a limb is noted during routine prenatal ultrasonography and further real-time investigations indicate a more generalized limitation of a joint movement in utero .

Difficult births occur in many cases of arthrogryposis. Abnormal positioning, such as breech and transverse lies, often requires cesarean section. Fracture of long bones during vaginal deliveries of infants with arthrogryposis is common both because of the abnormal, inflexible positioning of the limbs and the decreased ossification often seen related to decreased in utero fetal movement. Environmental events, including trauma to mother, maternal viral illnesses, bleeding, and medications taken by mother, have now been implicated as causative agents for some cases of arthrogryposis. Uterine abnormalities and oligohydramnios are rare findings, and even more rarely causative.

Arthrogryposis can be divided into three groups as defined by Hall in a large study of affected individuals: (1) primarily involving limbs; (2) involving limbs plus other body areas; and (3) involving central nervous system (CNS) abnormalities or leading to early death, or both. Clinically, this approach helps lead to the differential diagnosis and recognition of specific conditions.

Pathogenesis

It has become increasingly apparent, both from animal and human studies, that anything that leads to decreased fetal movement in utero may also lead to congenital contractures or fixation of the fetal joints. With decreased fetal movement, a series of abnormalities are seen to a greater or lesser extent: (1) contractures of joints; (2) polyhydramnios, apparently secondary to lack of fetal swallowing, which leads also to immature intestinal tract development with secondary feeding problems after birth; (3) pulmonary hypoplasia secondary to lack of fetal breathing with failure of maturation of alveolae and surfactin; (4) short umbilical cord; (5) intrauterine growth restriction; (6) osteoporosis of bones; and (7) craniofacial abnormalities including micrognathia, cleft palate (both hard and soft palate), underdeveloped maxilla, prominent bridge of the nose, and depressed tip of the nose. In its most severe form, this combination is called the fetal akinesia deformation sequence. Because it was first described phenotypically by Pena and Shokeir, when defining a specific familial syndrome, it is also sometimes called the Pena-Shokeir phenotype. However, the combination of morphological and pathological features can be seen with generalized decreased movement from many causes and is present in many other specific conditions.

It appears that any in utero process that leads to decreased movement can secondarily lead to fetal contractures. Swinyard and Bleck described a connective tissue response to the lack of joint movement with thickening of the joint capsule and fiber deposition. The earlier such a process starts in fetal development, the more severe and immobilizing the contractures. Thus, the timing during fetal development probably plays a critical role with regard to the position of the joint (i.e. flexion versus extension) and the severity of contractures at birth. Also, when the muscles of the limbs are not used in utero they atrophy and fail to mature or may be replaced by fat and fibrous tissue. Secondary changes can occur to other organ systems as described earlier in the fetal akinesia sequence. It would appear that lack of normal joint movement, or even an unusual degree of hypotonia, that is present for more than a month during the third trimester, can produce contractures. It may take an even shorter period of time during the first and second trimesters.

The potential causes of limitation of movement in utero are numerous. At least seven categories exist: (1) muscle abnormalities, including myopathies and abnormal muscle structure or function; (2) neuropathic processes, including abnormalities in nerve structure and function, either central or peripheral, including the failure of the CNS to myelinate and/or mature; (3) abnormalities of connective tissue including skin, bone, cartilage, and joint and tendon attachments; (4) limitation of space leading to restriction of fetal movement such as a structural abnormality of the uterus, amniotic bands, chronic leakage of amniotic fluid, multiple fetuses, or uterine masses such as fibroids; (5) those related to maternal illness such as myasthenia gravis, maternal infection, compromise of uterine blood supply, prolonged maternal fever, and other maternal illnesses; (6) those related to medications, drugs, exposures, and other environmental agents or deficiencies to which mother is exposed; and (7) compromise of maternal or fetal vascular supply, which leads to hypoxia or hypotension in fetal tissues. Multiple congenital contractures can occur as a manifestation of a large number of syndromes including chromosomal abnormalities, structural abnormalities of the CNS, and metabolic disorders; the exact cause is often hard to determine.

Whether a particular type of arthrogryposis has a recurrence risk depends, of course, upon whether it has a genetic basis or an environmental basis, or has been described as sporadic. The most common form of arthrogryposis, Amyoplasia, appears to be sporadic, although it is seen with increased frequency in one of monozygotic twins. In Amyoplasia, contractures are thought to occur on the basis of placental vascular compromise leading to hypotension and oxygen deprivation at critical periods in development of nerve and muscle. This sequence could theoretically recur in a second pregnancy, although this has not been observed as yet. Autosomal dominant, autosomal recessive, X-linked recessive single gene, and even mitochondrial inheritance have all been observed, including new mutations in the affected individual. Evidence of a genetic contribution in some cases is the higher frequency than expected of clubfoot or dislocated hip in the first- and second-degree relatives of affected individuals. Environmental factors such as an abnormal uterine structure, maternal use of misoprostol, or maternal illnesses such as the development of maternal antibodies to fetal neurotransmitters (see later) can all lead to recurrence in further children even though a genetic basis is not present.

Arthrogryposis is usually not due to an abnormality in formation of structures during the embryonic stage because bones and joints almost always have formed in a normal way (the exception is some types of synostosis and chondrodysplasias). Thus, arthrogryposis is not usually a problem with embryogenesis per se , but rather a failure to develop normal movement owing to abnormal mechanical forces or dysplasias (failure of a specific tissue to mature or function), which then lead to secondary changes in the bone and joints, as well as possibly secondary changes in other organ systems.

Clinical Features

The workup of a child with multiple congenital contractures is complex because there can be so many possible causes. Box 7.1 outlines some of the important differential features. The history (including family, prenatal, pregnancy, and delivery histories) may give clues to the particular type of arthrogryposis. The newborn examination is extremely helpful in defining whether there are other problems in addition to the contractures, whether the contractures involve all four limbs, whether they are distal or proximal, and whether the positioning is characteristic (as in the case of Amyoplasia and the distal arthrogryposes).