Arthrogryposis multiplex congenita

Definition

Arthrogryposis multiplex congenita (AMC) is a term used to describe the presence of two or more (multiplex) joint contractures (arthrogryposis) present at birth (congenita). A joint contracture is a limitation of the normal range of motion of a joint.

Description

There are at least 21 recognized forms of AMC. Ten of these fall into a category called the distal arthrogryposes. Four of these are syndromes that include AMC as a set of symptoms. Each involves at least two joint contractures evident from birth. None of the AMC disorders are progressive, meaning the symptoms do not worsen with age.

Distal arthrogryposis (DAs) are all characterized by contractures of the fingers and toes. Each type can be distinguished by specific characteristics:

• Type 1a DA: club feet that point inward and down (talipes equinovarus).
• Type 2 DA: down slanting of the opening between the upper and lower eyelids (palpebral fissures), a small mouth with pursed lips and malformations of the nose that cause a whistling appearance upon breathing, a curvature of the spine (scoliosis ), and some instances of mild developmental retardation. Type 2b DA, is characterized by those characteristics of type 2 DA accompanied by earlobes that are attached to the skin of the face and a permanent bending (flexion) of one or more fingers (camptodactyly).
• Type 3 DA: talipes equinovarus, camptodactyly, short stature, and vertebral abnormalities.
• Type 4 DA: short stature, an abnormally short neck, immobile facial expressions, camptodactyly, and the lack of the normal prominent creases (flexion creases) on the palms of the hands.
• Type 5 DA: contractures of the arms and legs, limited eye movement, deep set eyes, and abnormal coloring of the retina of the eye.
• Type 6 DA: camptodactyly, an abnormally small head (microcephaly), and hearing loss caused by an abnormality of the auditory nerve (sensorineural hearing loss).
• Type 7 DA: camptodactyly when an affected individual attempts to open the hand, short stature, abnormally short muscles in the legs, and an inability to open the mouth completely (trismus).
• Type 8 DA: contractures of the wrist and/or ankles, short stature, and scoliosis.
• Type 9 DA: lack of muscle tone and development, abnormally low shoulder-to-shoulder width to body height ratio (marfanoid habitus), severe outward curvature of the spine in the neck and upper back (kyphoscoliosis), and contractures of the hips and shoulders.

The most serious forms of DA are types 6 and 9.

Signs and symptoms

The four syndromes that include arthrogryposis as a set of symptoms are cerebrooculofacioskeletal syndrome, adducted thumb-clubfoot syndrome, Saethre-Chotzen syndrome , and arthropathy-camptodactylypericarditis syndrome. Cerebrooculofacioskeletal (COFS) syndrome is characterized by an abnormally small head (microcephaly), a lack of muscle tone (hypotonia), eye defects, abnormally large ears and nose, a receding chin (micrognathia), and kyphoscoliosis. Adducted thumb-clubfoot syndrome is characterized by clubfoot (equinovarus talipes), clasped (adducted) thumbs, abnormally long fingers and toes (arachnodactyly), a prominent forehead, and psychomotor delay. Saethre-Chotzen syndrome is characterized by flattened facial features, wide set eyes (hypertelorism), abnormalities of the skull (craniosynostosis ), abnormalities of the eyes, partially fused fingers or toes (syndactyly), congenital heart defects, and contractures of the elbows and knees. Arthropathy-camptodactyly-pericarditis syndrome is characterized by contractures of the elbows, wrists, and fingers; an abnormally elevated generalized stiffness upon waking; arthritis of the hips, shoulders, elbows, and knees; and, inflammation of the membranous sac that protects the heart (pericarditis).

The other forms of AMC include three relatively common forms: X-linked arthrogryposis, neurogenic arthrogryposis, amyoplasia ; and four extremely rare forms that may or may not represent distinct disorders: spondylospinal thoracic dysostosis, Jarcho-Levin syndrome, prenatal growth retardation with pelvic hypolasia and arthrogryposis in the lower limbs, and lethal congenital contracture syndrome.

X-linked arthrogryposis is generally mild and affects only the legs. Neurogenic arthrogryposis is also relatively mild and affects only the elbows and the knees. Amyoplasia is the mildest form of arthrogryposis; it is generally sporadic in appearance. Amyoplasia is characterized by contractures of the wrists, elbows, and knees; club feet, and an abnormal internal rotation of the shoulders.

Spondylospinal thoracic dysostosis is characterized by a short, curved spine; a short neck; malformations of the bones of the mouth; abnormal ribs; and congenital heart defects. Jarcho-Levin syndrome is characterized by many of the same characteristics of spondylospinal thoracic dysostosis. These two disorders differ only in the presence of a fusion of certain spinal vertebrae in spondylospinal thoracic dysostosis that has not been observed in Jarcho-Levin syndrome. Prenatal growth retardation with pelvic hypoplasia and arthrogryposis in the lower limbs has only been described in a pair of sisters and four males and one female, all of whom were siblings. It seems likely that this disorder is one of the distal arthrogryposes. Lethal congenital contracture syndrome almost inevitably leads to prenatal death prior to week 32 of gestation. It appears to be a unique variant of AMC.

Genetic profile

Various forms of arthrogryposis have been traced to a variety of gene mutations . Type 1a DA has been linked as a non-sex linked (autosomal) dominant trait caused by a mutation on the short arm of chromosome 9 at location 9p21-q21. Type 2 DA has not been localized to a particular chromosome and it is not clear how this disorder is transmitted. Type 2b DA has been linked to an autosomal dominant trait caused by a mutation on a gene localized to the short arm of chromosome 11, specifically 11p15.5. Types 3, 4, 5, 6, 7, and 8 DA have also not been localized to specific genes, but are presumed to be autosomal dominant traits. Type 8 DA may also be transmitted as a recessive or an X-linked disorder. Type 9 DA has been linked to an autosomal dominant gene on the long arm of chromosome 5, localized to 5q23-q31.

Cerebrooculofacioskeletal syndrome is an autosomal recessive trait caused by a mutation on a gene that has been localized to the long arm of chromosome 10, 10q11 specifically. Adducted thumb-clubfoot syndrome has DA that has not been localized to a particular chromosome but it is transmitted through a recessive trait. Saethre-Chotzen syndrome has been linked to an autosomal dominant trait caused by a mutation in the TWIST gene that has been localized to 7p21 on the short arm of chromosome 7. Arthropathy-camptodactyly-pericarditis syndrome has been linked to an autosomal recessive trait caused by a mutation on a gene that has been localized to the long arm of chromosome 1 at 1q25-q31.

X-linked arthrogryposis is an X-linked trait caused by a mutation on a gene that has been localized to Xp11.3-p11.2. Neurogenic arthrogryposis has been linked to both an X-linked trait and a trait caused by a gene mutation on the long arm of chromosome 5. Amyoplasia is usually sporadic and any genetic cause of this type of arthrogryposis is in doubt though vascular disruptions have been postulated. A genetic cause of spondylospinal thoracic dysostosis has not been identified. Jarcho-Levin syndrome has been linked to an autosomal recessive trait caused by a gene mutation on chromosome 19, localized to 19q13. Lethal congenital contracture syndrome has been linked to an autosomal recessive trait caused by a mutation on a gene localized to 9q34 on chromosome 9.

Demographics

Arthrogryposis occurs in approximately one in every 3,000 live births. Most cases of arthrogryposis are caused by a lack normal joint movement during fetal development. For this reason, cases of non-genetic arthrogryposis are more frequent in multiple birth pregnancies than in single birth pregnancies.

Most forms of arthrogryposis are not known to affect one subpopulation more than another. However, Jarcho-Levin syndrome has been found almost exclusively in people of Puerto Rican decent. All forms of AMC appear to affect males with approximately twice the frequency seen in females.

Diagnosis

The symptoms of AMC are primarily immobility of two or more joints. The most common joints affected are the joints of the fingers and toes. Less commonly affected joints are the knees and elbows, and rarely affected joints are the jaws, hips and shoulders.

A diagnosis of AMC is indicated by the presence of two or more joint contractures present from birth. The symptoms that are present allow the differential diagnosis between one of the forms of distal arthrogryposis, a syndromic form of arthrogryposis, and the other forms of arthrogryposis.

Treatment and management

Physical therapy has proven an effective treatment for almost all forms of AMC. Splints, braces, and removable casts are often used to improve joint positioning. In most cases, these orthopedic devices are used only at night so that proper joint mobility can be encouraged during the waking hours. Occasionally, surgery to repair foot and ankle position may be necessary, especially in the case of talipes equinovarus. Much less frequently, orthopedic surgery of the hips, kness, elbows, shoulders, and wrists is required.

Tendon replacement surgery has also been successful in individuals affected with AMC.

In an informal Internet study on AMC and aging conducted in 2000, one-third of the 100 respondents replied that they had sought alternative therapies for symptoms related to AMC. The most common of these therapies being massage therapy, hydrotherapy, and acupuncture. Massage therapy was reported as providing excellent results for some, but the lack of medical coverage for these therapies combined with their cost prevented many from continuing these treatments. When asked what helped the most in relieving symptoms of AMC, 44% of respondents named pain or anti-inflammatory drugs, both prescription and over-thecounter types. Another 20% mentioned massage, and 18% mentioned heat treatments such as saunas, hot tubs, hot packs, or hot showers and/or baths. Most survey participants noted that if they decreased their physical activity, they felt a loss of both joint mobility and stamina.

Prognosis

In cases of AMC that do not involve complications of the central nervous system, the outlook is quite good. Most individuals can achieve a sufficient range of motion in their affected joints to live healthy, complete lives. AMC is non-progressive, therefore, once a joint contracture has been repaired through physical therapy and/or surgery, it will generally not return to a state of abnormal contracture.

When AMC is complicated by involvement of the central nervous system, approximately half of affected individuals die in infancy. Among the surviving half, many have varying degrees of mental retardation.

The informal Internet survey on AMC and aging conducted in 2000 found that 50% of the 100 respondents could walk without assistance. Twenty-five percent needed braces, canes, and/or crutches, while the remaining 25% used either a scooter or wheelchair. The number of people requiring assistance to walk is expected to decline over time since many of those individuals responding to this survey did not receive medical and physical therapy treatments that are now routinely available to children affected with AMC.

Two-thirds of these survey respondents also stated that they had arthritis or arthritis-like symptoms. An informal causal relationship was also made between those who had rigorous or painful childhood physical therapy and later suffered symptoms of arthritis.

Resources

BOOKS

Stahell, L., J. Hall, K. Jaffe, and D. Paholke (eds). Arthrogryposis: A Text Atlas. London: Cambridge University Press, 1998.

PERIODICALS

Bamshad, M., L. Jorde, L., and J. Carey. "A revised and extended classification of the distal arthrogryposes." American Journal of Medical Genetics (November 1996): 227-81.

Gordon, N. "Arthrogryposis multiplex congenita." Brain & Development (October 1998): 507-11.

Hall, J., S. Reed, S., E. Driscoll "Amyoplasia: a common, sporadic condition with congenital contractures." American Journal of Medical Genetics (August 1983): 571-90.

ORGANIZATIONS

Arthrogryposis Group (TAG). 1 The Oaks, Gillingham, Dorset, SP8 4SW. UK 01-747-822655. <http://tagonline.org.uk>.

AVENUES National Support Group for Arthrogryposis Multiplex Congenita. PO Box 5192, Sonora, CA 95370. (209) 928-3688. [email protected]. <http://www.sonnet.com/avenues>.

WEBSITES

"Arthrogryposis." <http://members.aol.com/amcchat/amcinfo.htm>. (February 23, 2001).

"Entry 108120: Arthrogryposis multiplex congenita, distal, type 1; AMCD1." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=108120>. (February 23, 2001).

Paul A. Johnson