Arthrogryposis 

Updated: Jan 03, 2019
Author: Mithilesh K Lal, MD, MBBS, MRCP, FRCPCH, MRCPCH(UK); Chief Editor: Maria Descartes, MD 

Overview

Background

The term arthrogryposis, or arthrogryposis multiplex congenita (AMC), refers to a group of nonprogressive conditions characterized by multiple joint contractures found throughout the body at birth.[1]  The designation is currently used in connection with a very heterogeneous series of disorders that all include the common feature of multiple congenital joint contractures.[2]

Pathophysiology

The major cause of arthrogryposis is fetal akinesia (ie, decreased fetal movements) due to fetal abnormalities (eg, neurogenic, muscle, or connective tissue abnormalities; mechanical limitations to movement) or maternal disorders (eg, infection, drugs, trauma, other maternal illnesses). Generalized fetal akinesia can also lead to polyhydramnios, pulmonary hypoplasia, micrognathia, ocular hypertelorism, and short umbilical cord.

During early embryogenesis, joint development is almost always normal. Motion is essential for the normal development of joints and their contiguous structures; lack of fetal movement causes extra connective tissue to develop around the joint. This results in fixation of the joint, limiting movement and further aggravating the joint contracture. Contractures secondary to fetal akinesia are more severe in patients in whom the diagnosis is made early in pregnancy and in those who experience akinesia for longer periods of time during gestation.

Epidemiology

Frequency

United States

The frequency is about 1 in 3000 live births.[3, 4]

International

Arthrogryposis multiplex congenita is more common in isolated populations such as Finland and the Bedouin community in Israel.[5]

Mortality/Morbidity

The life span of affected individuals depends on the disease severity and associated malformations but is usually normal. About 50% of patients with limb involvement and central nervous system (CNS) dysfunction die in the first year of life.

Scoliosis may compromise respiratory function. A retrospective study by Li et al indicated that arthrogryposis patients with concomitant scoliosis have worse pulmonary function than do individuals with adolescent idiopathic scoliosis. In study patients with arthrogryposis/secondary scoliosis, mean values for forced vital capacity (%FVC), forced expiratory volume in 1 second (%FEV1), and the ratio of FEV1 to FVC (%FEV1/FVC) were 48.8, 45.3, and 92.1, respectively, compared with 70.3, 69.7, and 96.9, respectively, for subjects with adolescent idiopathic scoliosis.[6]

Race

No racial predilection has been described.

Sex

Males are primarily affected in X-linked recessive disorders; otherwise, males and females are equally affected.

Age

Arthrogryposis is detectable at birth or in utero using ultrasonography.

 

Presentation

History

Family history

Review the history of children with arthrogryposis and other affected family members. Look for the presence of hyperextensibility, dislocated joints, dislocated hips, and clubfeet in other family members. Inquire about increased incidence of congenital contractures in second-degree and third-degree relatives.

Consanguinity increases the chance that both parents carry the same disease gene. Consanguinity is more common in families with rare recessive diseases than in those with common recessive diseases.

Some chromosomal abnormalities dramatically increase with maternal age, and single-gene dominant mutations can increase with paternal age.

Look for marked intrafamilial variability; the parent may be very mildly affected or may have had contractures early in infancy. Review previous miscarriages or stillbirths.

Pregnancy history

Infants born to mothers affected with myotonic dystrophy, myasthenia gravis, or multiple sclerosis are at risk. A mother with congenital myotonic dystrophy may have a child who inherits the gene and is severely affected with resistant contractures. A mother with myasthenia gravis or multiple sclerosis can have children with congenital contractures.

Maternal infections (rubella, rubeola, coxsackievirus, enterovirus, Akabane) can lead to CNS or peripheral nerve destruction with secondary congenital contractures. Protracted or severe nausea may suggest maternal viral infection or encephalitis.

Maternal fever of more than 39°C for an extended period or maternal hyperthermia can cause contractures due to abnormal nerve growth or migration. This can be caused by prolonged soaking in hot tubs or hot baths.

Exposure to teratogens, such as drugs, alcohol, curare, methocarbamol, and phenytoin, may lead to decreased fetal movement.

Oligohydramnios or chronic amniotic fluid leakage may cause fetal constraint and secondary deformational contractures. Polyhydramnios may suggest fetal compromise (ie, defect in swallowing) and is a poor prognostic sign if associated with fetal hydrops.

Ask about uterine abnormalities such as bicornuate uterus with a septum or uterine fibroid.

Ask if the mother had large fibroids or other tumors, severe hypotension at a critical time, or severe hypoxia (eg, carbon monoxide poisoning) during pregnancy.

Review abnormal fetal movements such as decreased fetal movements, fetal kicking in one place, and decreased rolling.

Other complications that may be related to contractures include bleeding, abnormal fetal lies, threatened abortion, attempted termination, and trauma, such as a blow to the abdomen. An abnormal fetal lie may be a clue to intrauterine joint contractures.

Delivery history

Delivery history is usually atypical because of abnormal fetal presentation or difficulty due to the fixed fetal joints.

Breech or transverse fetal position is relatively common. Length of gestation is usually normal, but induction of labor is often prolonged. A limb is fractured during traumatic delivery in about 5-10% of cases.

Check for abnormal placenta, membranes, or cord insertion in cases that involve amniotic bands or vascular compromise. The umbilical cord may be shortened or wrapped around a limb, leading to compression.

Arthrogryposis epidemics have been reported, but whether these are due to chance occurrence, environmental factors, or infectious agents is unclear. Any clustering of children born with congenital contractures should be investigated.

In multiple births or twins, lack of movement due to uterine crowding can cause contractures. The death of one twin may lead to vascular compromise in the remaining twin.

Physical

Although joint contractures and associated clinical manifestations vary from case to case, several characteristics are common, including the following:

  • Involved extremities are fusiform or cylindrical in shape, with thin subcutaneous tissue and absent skin creases

  • Deformities are usually symmetric, and severity increases distally, with the hands and feet typically the most deformed

  • Joint rigidity may be present

  • The patient may have joint dislocation, especially the hips and, occasionally, the knees

  • Atrophy may be present, and muscles or muscle groups may be absent

  • Sensation is usually intact, although deep tendon reflexes may be diminished or absent

Contractures

Points to consider include the following (see the images below):

  • Distal joints are affected more frequently than proximal joints

  • Observe flexion versus extension, limitation of movement (fixed vs passive vs active), and characteristic position at rest; note the severity of all limitations. Distinguish between complete fusion or ankylosis and soft-tissue contracture

  • Range of motion in the jaw is frequently limited

  • Intrinsically derived contractures are frequently associated with polyhydramnios; the contractures are symmetrical and accompanied by taut skin, pterygia across joints, and a lack of flexion creases; recurrence risk and prognosis depend on etiology

  • Extrinsically derived contractures are associated with positional limb anomalies, large ears, loose skin, and normal or exaggerated flexion creases; patients have an excellent prognosis and a low recurrence risk

The hands of a patient with contractural arachnoda The hands of a patient with contractural arachnodactyly (Beals syndrome). Note the long, thin fingers with interphalangeal joint contractures.
A girl with an autosomal recessive type of multipl A girl with an autosomal recessive type of multiple pterygium syndrome. Note the multiple joint contractures at the knees with marked pterygia, including intercrural webbing, affecting her stance and ambulation.

Deformities

Limb deformities include pterygium, shortening, webs, compression (eg, due to cord wrapping), absent patella, dislocated radial heads, and dimples.

Facies deformities include asymmetry, flat nasal bridge, and hemangioma. Jaw deformities include micrognathia and trismus. See the image below.

A mother and child both affected with trismus pseu A mother and child both affected with trismus pseudocamptodactyly. Note the small mouth (with limited ability to open) and flexion contractures of fingers on dorsiflexion.

Other deformities include scoliosis, genital deformities (cryptorchidism, lack of labia, microphallus), and hernia (inguinal, umbilical).

Other features of the fetal akinesia sequence include intrauterine growth retardation, pulmonary hypoplasia, and craniofacial anomalies such as hypertelorism, cleft palate, depressed nasal tip, high nasal bridge, functional short gut with feeding problems, and short umbilical cord.

Absent or distorted crease abnormalities are a result of aberrant form or function in early hand or foot development. See the image below.

An infant with distal arthrogryposis type I. Note An infant with distal arthrogryposis type I. Note medially overlapping fingers, tightly clenched fists, and positional foot contractures.

Malformations

Craniofacial malformations may involve the CNS (structural malformations, seizures, mental retardation [MR]), skull (craniosynostosis, asymmetry, microencephaly), eyes (small and malformed eyes, corneal opacities, ptosis, strabismus), and palate (high, cleft, submucous cleft).

Respiratory problems include tracheal and laryngeal clefts and stenosis. Hypoplasia, weak muscles, or hypoplastic diaphragm may affect lung function.

Limb malformations include deletion anomalies, radioulnar synostosis, syndactyly, and shortened digits.

Skin vasculature abnormalities may cause hemangiomas and cutis marmorata; distal limbs may be blue and cold.

Cardiac problems include congenital anomalies and cardiomyopathy. The kidneys, ureters, and bladder may have structural anomalies.

Nervous system problems include loss of vigor; lethargy; sluggish, brisk, or absent deep tendon reflexes; and sensory deficits.

Muscle malformations include decreased muscle mass, soft muscle texture, fibrous bands, abnormal tendon attachments, and muscle changes over time.

Connective tissue abnormalities

Skin webs (pterygia) across joints, with limitation of movement, are common. Skin dimples are common over joints where movement is limited.

Skin may be soft, doughy, thick, or extensible. Subcutaneous fat is decreased or increased. Inguinal, umbilical, or diaphragmatic hernias may be present. Thickness in joints, symphalangism, and abnormalities in tendon attachment and length may also be present.

Associated skin defects include scalp defects, amniotic bands on limbs, and nail defects.

Pretibial linear skin indentation may be a sign of autosomal recessive inheritance or at least a sign for an increased risk of recurrence.

Causes

Arthrogryposis is presumed to be multifactorial in etiology.[7] In most cases, arthrogryposis multiplex congenita (AMC) is not a genetic condition. However, in approximately 30% of cases, a genetic cause can be identified.[8]

Arthrogryposis is a physical sign in many specific medical conditions. It can be a component of numerous conditions caused by environmental agents, single gene defects (autosomal dominant, autosomal recessive, X-linked recessive), chromosomal abnormalities, known syndromes, or unknown conditions. The principal cause is persistently decreased fetal movements (fetal akinesia) due to either fetal or maternal abnormalities.

The molecular basis of most genetic causes is not yet determined. However, the following 5 genetic loci associated with autosomal recessive arthrogryposis multiplex congenita have been described to date using a linkage analysis approach[9, 10] :

  • Lethal congenital contracture syndrome (OMIM 253310) (9q34) - This is characterized by early fetal hydrops and akinesia, Pena-Shokeir phenotype, multiple pterygia and fractures, and a specific neuropathology in the spinal cord

  • Neurogenic type of arthrogryposis multiplex congenita (OMIM 208100) (5q35) - This is a nonprogressive, nonlethal, multiple joint contracture described in a large Israeli-Arab inbred kindred

  • Arthrogryposis-renal dysfunction-cholestasis syndrome (OMIM 208085) (15q26.1) - This is a neurogenic arthrogryposis multiplex congenita with renal tubular dysfunction and neonatal cholestasis, with bile duct hypoplasia and low gamma glumyl transpeptidase activity, leading to death within the first year of life

  • Lethal congenital contracture syndrome (LCCS) type 2 (OMIM 607598) (12q13) - This is a lethal arthrogryposis multiplex congenita characterized by multiple joint contractures and micrognathia, normal duration of pregnancy, markedly distended urinary bladder, and lack of hydrops, pterygia, and fractures; it is prevalent in a large inbred Israeli-Bedouin kindred

  • A novel autosomal recessive LCCS type 3 - This is similar to LCCS2 but lacks the urogenic bladder defect; the genetic defect leading to this syndrome was mapped to 3.4 Mb on chromosome 19p13, and it was shown that LCCS3 results from a mutation in PIP5K1C (GenBank accession number NM_012398)

Neuropathic abnormalities are the most common cause of arthrogryposis. They may include malformations or malfunctions of the central and peripheral nervous systems. Abnormalities include meningomyelocele, anencephaly, hydranencephaly, holoprosencephaly, spinal muscular atrophy, cerebrooculofacial-skeletal syndrome, and Marden-Walker syndrome.

Muscle abnormalities (malformations or malfunctions) are relatively rare causes of arthrogryposis. Some associated diseases include congenital muscular dystrophies, congenital myopathies, intrauterine myositis, and mitochondrial disorders.

A French study, by Wallach et al, of 42 children with arthrogryposis found that in 19.1% of patients, the condition had a neurologic etiology, mainly involving polymicrogyria, while in 9.5% of the group, the disease arose myopathically.[11]

Connective tissue abnormalities in tendon, bone, joint, or joint lining may develop in such a way that restricts fetal movements, resulting in congenital contractures. Examples include synostosis, lack of joint development, aberrant fixation of joints (as in diastrophic dysplasia and metatropic dwarfism), aberrant laxity of joints with dislocations (as in Larsen syndrome), and aberrant soft tissue fixations (as in popliteal pterygium syndrome). In some forms of distal arthrogryposis, the tendon develops normally but fails to attach to the appropriate place around the joint or bone. This results in abnormal lack of movement of the joints with secondary contractures at birth.

Limited space for fetal movement inside the uterus may contribute to the development of contractures. Examples include multiple births, uterine structural abnormalities, oligohydramnios in renal agenesis, and early persistent leakage of amniotic fluid.

Intrauterine vascular compromise may result in a loss of function in nerve and muscle with development of fetal akinesia and secondary joint contractures. Examples include severe maternal bleeding during pregnancy and failed attempts at termination of pregnancy.

 

DDx

Diagnostic Considerations

Disorders characterized mainly by limb involvement[12]

Amyoplasia (classic arthrogryposis)[7, 13]

This is characterized as follows:

  • The most common type of arthrogryposis seen in clinical practice and constitutes about one third of cases

  • The incidence is about 1 in 10,000 live births

  • Amyoplasia is a sporadic condition and has not been observed in siblings or offspring

  • The pathogenesis is thought to involve impaired blood circulation to the fetus early in pregnancy; hypotension and hypoxia damage the anterior horn cells, resulting in a lack or underdevelopment of muscle tissue, with fatty or connective tissue replacement

  • Symmetrical limb involvement is noted

  • The distinct positioning of the body includes internally rotated and adducted shoulders; fixed, extended elbows; pronated forearms; and flexed wrists and fingers

  • A severe talipes equinovarus deformity with either flexed or extended knees may be present

  • Hips may be flexed and externally rotated or extended and subluxated or dislocated

  • Characteristic midline facial hemangioma is often noted

  • Intelligence is normal

The natural history of untreated amyoplasia is largely undocumented and unknown. However, a study documented a 94% rate of survival for individuals with amyoplasia at 20 years.[4] Without treatment, the ambulatory and functional potential of afflicted individuals is poor.

Distal arthrogryposes

These involve the distal joints and include the following types and subtypes (all have autosomal dominant inheritance with reduced penetrance and variable expressivity)[14] :

  • Type I (Distotarlar dysmorphism) - Adducted thumbs, ulnar deviation of metacarpophalangeal (MP) joints, normal facies

  • Type IIA (Freeman-Sheldon syndrome, whistling face syndrome, craniocarpal tarsal dystrophy, windmill hand) - Distinctive facies, flexion and ulnar deviation of the fingers

  • Type IIB - Distinctive facies, flexion and ulnar deviation of the fingers, vertical talus

  • Type III (Gordon syndrome) - Cleft palate, finger contractures, clubfoot

  • Type IV - Scoliosis, finger contractures

  • Type V - Limited ocular motility, ptosis, finger contractures

  • Type VI - Sensorineural hearing loss, finger contractures

  • Type VII (trismus-pseudocamptylodactyly syndrome, Hecht syndrome) - Inability to fully open mouth, facultative camptodactyly

  • Type VIII (Dominant pterygium syndrome) - Multiple pterygium, finger contractures

  • Type IX (congenital contractual arachnodactyly, Beals syndrome) - Ear deformity, finger contractures

Bony fusion

This is likely to be confused with arthrogryposis but includes symphalangism (ie, fusion of phalanges), coalition (ie, fusion of the carpals and tarsal bones), and synostosis (ie, fusion of long bones).

Contractural arachnodactyly (Beals syndrome; OMIM 121050)

This is an autosomal dominant disorder. It is characterized by joint contractures; a long, thin body build; and crumpling ears. It usually lacks the cardiovascular and ocular abnormalities of Marfan syndrome.

Other

Other associated syndromes and conditions include absence of dermal ridges, absence of distal interphalangeal joint (DIP) creases, amniotic bands, antecubital webbing, camptodactyly, coalition, humeroradial synostosis, familial impaired pronation and supination of forearm, Liebenberg syndrome, nail-patella syndrome, Nievergelt-Pearlman syndrome, Poland anomaly, radioulnar synostosis, symphalangism, symphalangism-brachydactyly, Tel-Hashomer camptodactyly, and trismus pseudocamptodactyly.

Disorders that involve the limbs and other body parts[12]

Multiple pterygium syndrome

Multiple pterygium syndrome is heterogeneous (OMIM 265000, autosomal recessive; OMIM 178100, autosomal dominant).[15, 16] It is characterized as follows:

  • The autosomal recessive type is characterized by multiple joint contractures with marked pterygia, dysmorphic facies (flat, sad, motionless facial appearance), and cervical vertebral anomalies

  • The autosomal dominant type is characterized by multiple pterygia with or without MR

  • Multiple pterygium syndrome, characterized by pterygia with flexion contractures, scoliosis, and cleft palate, has been reported in several families and is associated with malignant hyperthermia

  • Multiple pterygium syndrome, Escobar type is characterized by webbing of the neck that increases with age, webbing of the knees and elbows that develops before adolescence, multiple joint contractures, and lumbar lordosis[17]

Lethal multiple pterygium syndrome (OMIM 253290)[18]

This is an autosomal recessive disorder characterized by early death, hydrops, cystic hygroma, dysmorphic facies (eg, hypertelorism, markedly flattened nasal bridge with hypoplastic nasal alae, cleft palate, micrognathia, low-set ears), marked webbing and flexion contractures of multiple joints, short neck, small chest, and hypoplastic lungs.

Classification by Hall[18, 19] and Entezami et al[20, 21] is as follows:

  • Type I (Gillin-Pryse-Davis syndrome): Multiple pterygia, pulmonary hypoplasia, genital anomalies, and marked flexed extremities with a reduced muscle mass

  • Type II (Chen syndrome)[22] : Multiple pterygia, hygroma colli, facial anomalies, undermodeled long bones, cartilaginous fusion of joints and bony fusion of the spinous processes of the vertebrae, polyhydramnios, hypoplastic lungs and heart, and diaphragmatic hernia

  • Type III (van Regemorter syndrome): Multiple pterygia, pulmonary hypoplasia, facial anomalies, thin extremities with reduced muscle mass, and fusions of the long tubular bones

  • Type IV (Herva syndrome): Multiple pterygia, degeneration of the anterior horn cells of the spinal cord, and observed particularly in Finland

Popliteal pterygium syndrome (OMIM 119500)

This is an autosomal dominant disorder characterized by popliteal webs, cleft lip or palate, webs in the mouth, and unusual nails.

Lethal popliteal pterygium syndrome (OMIM 263650)

This is also known as Bartsocas-Papas syndrome and is an autosomal recessive disorder characterized by severe webs across the knee. In the newborn period, it is associated with facial clefting and fused digits (synostosis of the hand and foot bones). It is usually lethal.

Freeman-Sheldon syndrome (OMIM 193700)

This is also known as whistling face syndrome and is an autosomal dominant disorder. It is characterized by a masklike face with a small mouth, giving a whistling face appearance; deep-set eyes; small nose with a broad nasal bridge; epicanthal folds; strabismus; high arched palate; small tongue; an H-shaped cutaneous dimpling on the chin; flexion of fingers; equinovarus feet with contracted toes; kyphosis; scoliosis; and other anomalies.[23]

Osteochondrodysplasias

This is known to have associated congenital contractures, including metatropic dysplasia, perinatal lethal osteogenesis imperfecta, parastremmatic dysplasia, Jansen metaphyseal dysplasia, Saul-Wilson syndrome, geleophysic syndrome, synspondylism, spondyloepiphyseal dysplasia congenita, and otospondylomegaepiphyseal dysplasia.

Other

Other associated syndromes and conditions include focal femoral dysplasia, hand-muscle wasting and sensorineural deafness, Holt-Oram syndrome, Kuskokwim syndrome, Larsen dysplasia, leprechaunism, megalocornea with multiple skeletal anomalies, Möbius syndrome, nemaline myopathy, oculodentodigital syndrome, ophthalmomandibulomelic dysplasia, orocraniodigital syndrome, otopalatodigital syndrome, Pfeiffer syndrome, Prader-Willi habitus/osteoporosis/hand contractures, pseudothalidomide syndrome, Puretic-Murray syndrome, sacral agenesis, Schwartz-Jampel syndrome, tuberous sclerosis, VATER (vertebral [defects], [imperforate] anus, tracheoesophageal [fistula], radial and renal [dysplasia]) complex, Weaver syndrome, Winchester syndrome, and X-trapezoidocephaly with midfacial hypoplasia and cartilage abnormalities.

Disorders with limb involvement and CNS dysfunction[12]

These include the following:

  • Associated chromosome abnormalities include 45,X; 47,XXY; 48,XXXY; 49,XXXXX; 49,XXXXY; trisomies (4p, 8, 8 mosaicism, 9, 9q, 10p, 10q, 11q, 13, 14, 15, 18, 21); and many others

  • Cerebrooculofacioskeletal syndrome (OMIM 214150) is a common lethal condition characterized by contractures, brain anomalies, dysmyelination, microphthalmia, cataracts, renal anomalies, and other visceral anomalies

  • Neu-Laxova syndrome (OMIM 256520) is a lethal autosomal recessive disorder characterized by dramatic contractures, intrauterine growth retardation, microcephaly, open eyes, tight ichthyotic skin, and severe CNS anomalies

  • Restrictive dermopathy (OMIM 275210) is a lethal autosomal recessive disorder characterized by contractures and failure of fetal skin to grow normally; this restricts fetal movement, leading to secondary contractures

  • Pena-Shokeir phenotype (OMIM 208150) is characterized by pulmonary hypoplasia, intrauterine growth retardation, polyhydramnios, short umbilical cord, unusual craniofacies, and short, fixed limbs; phenotype is caused by fetal akinesia rather than a specific syndrome[24, 25, 21, 26]

Other associated syndromes and conditions

These include the following:

  • Adducted thumbs

  • Bowen-Conradi syndrome

  • C syndrome

  • Syndrome of cloudy cornea, diaphragmatic defects, and distal limb deformities

  • Syndrome of craniofacial and brain anomalies and intrauterine growth retardation

  • Syndrome of cryptorchidism, chest deformity, and contractures

  • Fetal alcohol syndrome

  • Faciocardiomelic syndrome

  • FG syndrome

  • Maternal multiple sclerosis

  • Maternal autoantibodies

  • Marden-Walker syndrome

  • Meckel syndrome

  • Meningomyelocele

  • Mietens syndrome

  • Miller-Dieker syndrome

  • Neurofibromatosis

  • Congenital myotonic dystrophy

  • Congenital myasthenia gravis

  • Popliteal pterygium with facial clefts

  • Pseudotrisomy 18

  • Spinal muscular atrophy

  • Sturge-Weber syndrome

  • Toriello-Bauserman syndrome

  • X-linked lethal arthrogryposis

  • Zellweger syndrome

 

Workup

Laboratory Studies

See the list below:

  • In general, laboratory tests are not extremely useful in arthrogryposis.

  • Obtain creatine phosphokinase (CPK) levels when the following conditions are present:

    • Generalized weakness

    • Doughy or decreased muscle mass

    • Progressive worsening

  • Viral cultures may reveal an infectious process.

  • Immunoglobulin M levels and specific viral titers (eg, coxsackievirus, enterovirus, Akabane virus) in the newborn may reveal intrauterine infection.

  • Maternal antibodies to neurotransmitters in the infant may indicate myasthenia gravis.

  • Cytogenetic study is indicated in the following situations:

    • Multiple organ or system involvement

    • Presence of CNS abnormalities, such as microcephaly, MR, lethargy, degenerative changes, or eye anomalies

  • Consider performing a fibroblast chromosome study if lymphocyte chromosome levels are normal and the patient has mental retardation (MR) without diagnosis.

  • Nuclear DNA mutation analysis is used to identify certain disorders, such as spinal muscular dystrophy.

  • Mitochondrial mutation analysis is used to identify certain disorders, such as mitochondrial myopathy.

Imaging Studies

Use photography to document the extent of deformities (range of motion and position of arthrogryposis) and to assess progress during treatment.

Use radiography to evaluate the following skeletal and joint abnormalities:

  • Bony abnormalities (eg, gracile bones, fusions, extra or missing carpals and tarsals)

  • Disproportionately short stature (ie, skeletal dysplasias)

  • Scoliosis

  • Ankylosis

  • Absence of patella

  • Humeroradial synostosis

Ultrasonography can help in evaluating the CNS and other viscera for anomalies. Ultrasonography also establishes potential muscle tissue.

A study by Dicke et al of the efficacy of obstetric ultrasonography in detecting fetal limb abnormalities indicated that the modality had an 81.3% sensitivity for the prenatal diagnosis of arthrogryposis. The investigators examined cases of arthrogryposis, polydactyly, limb reduction defects, and abnormal hand position, that underwent obstetric ultrasonographic scanning at their institution over a 20-year period.[27]

CT scanning can be used to evaluate the CNS and the muscle mass. MRI can be used to evaluate muscle mass obscured by contractures.

Prenatal assessment of a fetus with arthrogryposis is as follows[28] :

  • Pregnancy history

  • Family history

  • Imaging studies of multiple contractures with ultrasound: For mechanisms extrinsic to the fetus, investigations include serial ultrasound assessment, parental examination, fetal MRI, and delivery planning. For mechanisms intrinsic to the fetus, investigations include karyotype and/or DNA testing, serial ultrasound assessment, parental examination, fetal MRI, referral to other specialties, and delivery planning. Other conditions may include primary CNS disease, primary muscular disease including amyoplasia, connective-tissue disorder, skeletal dysplasia, vascular disruption, and Pena-Shokeir phenotype.

First trimester prenatal ultrasound findings are as follows[29] :

  • Total fetal immobility: Suspect lethal arthrogryposis.[30]

  • Talipes and bilateral fixed flexion deformities of the hands, wrists, elbows, and knees: Suspect lethal arthrogryposis.[31]

  • Abnormal flexion of the hips and extension of the knees: Suspect Pena-Shokeir phenotype (lethal).[32]

  • Increased nuchal translucency: This is a useful marker, especially when there is a syndrome present, and is correlated with lethal arthrogryposis multiplex congenita.

  • Cystic hygroma associated with multiple contractures: Suspect lethal multiple pterygium syndrome when other characteristic findings such as ocular hypertelorism, hypoplastic lungs, cleft palate, and hydramnios are present.[33]

Second trimester prenatal ultrasound findings are as follows[29] :

  • Joint contracture of all the extremities with clinched hands, clubfeet, and, essentially absent fetal movements, often associated with polyhydramnios and pulmonary hypoplasia: Suspect lethal types of arthrogryposis.

  • Cystic hygroma associated with pleural effusion: This is a common early second trimester finding in both lethal and nonlethal types of arthrogryposis multiplex congenita.

  • Fetal hydrops: Possibly suspect lethal types of arthrogryposis.

  • Arthrogryposis and decreased fetal mobility associated with multiple congenital anomalies: Suspect a possible syndrome.

Third trimester prenatal ultrasound findings are as follows[29] :

  • Multiple joint contractures and other deformities such as talipes: This may not become apparent until the third trimester.

  • Decreased fetal movement, micrognathia, polyhydramnios, hypoechogenicity, and hypomineralization of the long bones[34] ; pleural effusions; ventriculomegaly; hydronephrosis; and collapsed stomach: These may be common sonographic findings in the third trimester.

Other Tests

See the list below:

  • Perform an ophthalmologic evaluation for opacity and retinal degeneration.

Procedures

See the list below:

  • Skin biopsy should be performed for culture of fibroblasts to be used for chromosome analysis.

  • Muscle biopsy

    • Muscle biopsy is probably the most important diagnostic procedure. It should be included in all autopsies and at time of surgery.

    • Distinguish myopathic from neuropathic conditions by obtaining muscle specimens from normal and affected areas.

    • Special histopathologic and electron micrographic studies are used to evaluate fatty and connective tissue replacement of muscle fibers and variations in fiber size, such as decreased fiber diameter. All are nonspecific signs of muscle atrophy.

  • Electromyography (EMG) of normal and affected areas is useful in differentiating neurogenic and myopathic causes.

  • Nerve conduction tests measure conduction velocities in motor and sensory nerves; these should be performed when a peripheral neuropathy is suspected.

  • An autopsy should be performed to discover more about the following:

    • CNS (ie, brain neuropathology)

    • Spinal cord (number and size of anterior horn cells, presence or absence of tracts at various levels)

    • Ganglia and peripheral nerves

    • Eye (ie, neuropathology)

    • Muscle tissue from different muscle groups (ie, electron microscopy and special stains)

    • Fibrous bands replacing muscle

    • Tendon attachments

    • Other visceral anomalies, malformations, deformations, and disruptions

Histologic Findings

Neurogenic types of arthrogryposis multiplex congenita

See the list below:

  • Muscle fiber type predominance or disproportion is the most common neurogenic abnormality in arthrogryposis (26%). These are nonspecific alterations. Dysgenesis of the motor nuclei of the spinal cord and brainstem involves the replacement of fasciculi of muscle fibers by small muscle fibers and adipose tissue. Examples include Pierre-Robin syndrome and Möbius syndrome.

  • Dysgenesis of the CNS is the second most common neurogenic abnormality in arthrogryposis (23%), with disorganization of neurons and a decrease in neurons of the cortex and motor nuclei of the brainstem and spinal cord. Clinical syndromes associated with this abnormality include trisomy 18, partial deletion of the long arm of chromosome 18 syndrome, and Zellweger syndrome.

  • Dysgenesis of the anterior horn, another common neurogenic abnormality in arthrogryposis, is the cause of Meckel-Gruber syndrome and anencephaly.

  • Spinal muscular atrophy (eg, Werdnig-Hoffmann disease) is another neurogenic abnormality in arthrogryposis.

Myopathic types of arthrogryposis multiplex congenita

See the list below:

  • Central core disease is a form of arthrogryposis in which the central portion of each muscle fiber contains a zone in which oxidative enzyme activity is absent.

  • Nemaline myopathy is indicated by abnormal threadlike structures in muscle cells. In type I nemaline myopathy, nemaline rods are present. In type II, the number of fibers with central nuclei is increased.

  • Congenital muscular dystrophy is indicated by muscle fibers that demonstrate a rounded configuration and conspicuous variation in diameter. Perimysial and endomysial connective tissues are markedly increased.

  • Mitochondrial cytopathy is indicated by numerous ragged-red fibers on muscle biopsy samples. It is associated with CNS abnormalities consistent with mitochondrial disease.

  • Myoneural junction abnormality (eg, congenital myasthenia gravis) is another myopathic type of arthrogryposis.

 

Treatment

Medical Care

See the list below:

  • No completely successful approach to treat arthrogryposis has been found. Goals include lower-limb alignment and establishment of stability for ambulation and upper-limb function for self-care. Early gentle manipulation soon after birth improves passive and active range of motion. This is especially true in the case of the inherited distal arthrogryposes, in which prolonged immobilization associated with casting may be undesirable. Late manipulation is of little value.

  • Early vigorous physical therapy to stretch contractures is very important in improving joint motion and avoiding muscle atrophy. Patients with amyoplasia or distal arthrogryposis respond well to physical therapy with excellent functional outcome. However, physical therapy may actually be harmful in patients with diastrophic dysplasia, because it may lead to joint ankylosis. Recurrence of deformities following stretching is common, and surgery is often indicated.

  • Splinting combined with physical therapy appears preferable to continuous casting. Night splinting after surgical procedures is indicated to maintain increased range of motion.

  • Feeding assistance and intubation is needed in patients with severe trismus.

  • See Deterrence/Prevention for information on recurrence risk.

Surgical Care

The perioperative management of the arthrogrypotic patient can be difficult and is managed by an experienced anesthesia and medical team.[35, 36, 7] The following issues are noted:

  • Difficult in venous access

  • Prone to develop intraoperative hyperthermia

  • Certain drugs influenced by decreased muscle mass

  • Postoperatively, increased difficulty with atelectasis and stridor with an increased risk of aspiration

  • Vertebral instability secondary to decreased muscle mass and high cervical hypoplasia

If surgery is contemplated, early (age 3-12 mo) one-stage (bone and tendon transfer) surgery should be performed. Fine-tuning procedures, such as opponensplasty, may improve function at a later stage.

Specific joint problems should be addressed with regard to treatment of other joints and the goals for the patient. Soft-tissue surgery should be performed early, with osteotomies performed when growth is completed. In soft-tissue release procedures, tenotomies should be accompanied by capsulotomies. Long-term bracing and assistive devices are usually needed.

  • Feet

    • The most common deformity is a rigid talipes equinovarus deformity. The goal of treatment is a plantigrade, braceable foot.

    • Casting in the first 3 months and attempting to stretch the skin often fail to correct the deformity. The patient eventually needs an extensive medial and lateral release, followed by prolonged casting and bracing.

    • Recurrence is common as the child grows, and the patient may need eventual treatment with bony procedures, such as lateral column shortenings (Lichtblau procedures) or talectomy.

    • In a skeletally mature deformed foot, triple arthrodesis often gives a satisfactory plantigrade foot. In an older child with no previous treatment, a combination of soft-tissue releases and bony procedures may be indicated.

  • Knees

    • The goal of treatment is an extended knee for ambulation. This is more easily accomplished in an extension or hyperextension deformity than in a flexion deformity.

    • Flexion knee deformities are more common than fixed knee deformities and are more resistant to treatment.

    • A mild contracture (< 20°) does not interfere with functional ambulation and can be treated with passive stretching and splinting.

    • Moderate contractures (20-60°) need soft-tissue releases, including posterior capsulotomy of the knee joint, followed by long-term bracing.

    • Severe contractures (>60°) may need femoral shortening, in addition to soft-tissue releases, to decrease tension on neurovascular structures behind the knee. In an older child with severe flexion deformity, a knee disarticulation may be indicated.

    • Extension deformities often present as recurvatum or even anterior dislocation, but they respond better to physical therapy than flexion deformities. Initial treatment for recurvatum is passive stretching and splinting. If unsuccessful, quadricepsplasty should be performed when the patient is younger than 6 months. The deformity should be corrected before treating a dislocated hip to facilitate hip reduction.

  • Hips

    • Hip surgery should follow foot and knee surgery, especially in the presence of knee extension deformities. Hip surgery should be performed when the patient is younger than 1 year to facilitate ambulation. In some patients with bilateral hip dislocations and extremely mobile hips, open reduction may be attempted.

    • Hip flexion contractures are more difficult to treat than dislocations. Mild hip flexion contracture is acceptable for ambulation. A flexion contracture greater than 35° requires soft-tissue releases.

    • A bilateral hip dislocation greater than 35° with flexion contracture should be treated with stretching and soft-tissue releases but not with reduction.

    • Unilateral hip dislocation requires reduction to avoid pelvic obliquity and scoliosis.

  • Upper extremities

    • Treatment involves development of self-help skills (eg, feeding and toileting) and mobility skills (eg, pushing out of chair and using crutches). In evaluating the upper extremities, overall function of the entire extremity should be considered rather than function of the individual joints.

    • Upper-extremity surgery should not be considered until the patient is older than 5-6 years. Shoulder function is usually satisfactory without a rotational osteotomy unless the shoulder is severely internally rotated.

  • Elbows

    • The goal of treatment is an elbow with passive or active flexion capability (feeding arm) and extension capability (toilet arm). Extension is corrected with either capsulotomy (ie, to allow passive flexion) or capsulotomy plus provision of a motor power, provided by a Steindler flexorplasty, a triceps transfer, or a pectoralis major transfer.

    • Because the elbow is crucial to hand function, the elbow must be mobile before a wrist deformity is corrected.

  • Wrists

    • The major wrist deformity is flexion with ulnar deviation. Treatment should begin with stretching and splinting.

    • A severe deformity requires proximal row carpectomy with or without fusion.

    • A trapezoid wedge excision improves dorsiflexion.

  • Fingers

    • Minimal to moderate flexion deformities require passive stretching and splinting.

    • More severe deformities require soft-tissue releases and often require proximal interphalangeal joint fusions.

    • Thumb-in-palm deformities need to be corrected to provide opposition-improved grasp.

  • Spine

    • The spine is affected in about one third of patients. Scoliosis begins early and progresses to become a long, severe, rigid, C-shaped curve. This curve responds poorly to orthoses because it is progressive.

    • Curves greater than 35° should be treated with spinal fusion and instrumentation.

Consultations

See the list below:

  • Clinical geneticist

  • Orthopedic surgeon

  • Plastic surgeon

  • Radiologist

  • Neurologist

  • Developmental pediatrician

  • Pathologist

  • Psychologist

  • Physical and occupational therapists

  • Social worker

  • Educator

  • Orthotist

  • Rehabilitation engineer

Diet

See the list below:

  • No special diet is required.

Activity

See the list below:

  • Physical activity may be limited because of existing orthopedic problems. As a group, patients appear to cope well socially, participating in social activities that correspond to their needs.

  • Walking is more restricted in patients with flexion contractures of the lower extremities than in those with extension contractures. Flexion contractures of the hips severely impair walking ability.

  • Contracture of the elbow can cause a significant degree of disability in hand function.

  • The use of crutches can be impossible for patients with upper extremity involvement associated with severe spinal deformity.

  • Patients with more severe joint involvement depend on more help from other people than those with less severe joint involvement.

 

Medication

Medication Summary

See the list below:

  • Drug therapy is not currently a component in the standard of care for this condition.

  • See Treatment.

 

Follow-up

Further Outpatient Care

Carefully monitor the patient, watching for postoperative complications.

Further Inpatient Care

Admit the patient for surgical intervention.

Transfer

Patients may need to be transferred for further diagnostic evaluation and surgical intervention.

Deterrence/Prevention

Identifying the causes of arthrogryposis remains vital for determining the management, prognosis, predicting recurrence risks and counselling couples. Early diagnosis allows for institution of appropriate investigations and offering patients informed choice including the option of termination if indicated. Multidisciplinary work by obstetricians, geneticists, neonatologists, and pediatric pathologists optimizes the chances of achieving a diagnosis and providing parents with accurate and appropriate information to enable them make informed choices with regards to their pregnancy.[37]

Recurrence risk depends on whether the contractures are extrinsically or intrinsically derived. Extrinsically derived contractures have a low recurrence risk, whereas the recurrence risk for intrinsically derived contractures depends on etiology. Arthrogryposis may be inherited in the following ways with different recurrence risks, and the patient and parents should know this information[38] :

  • Autosomal dominant: Recurrence risk to offspring is 50% (eg, distal arthrogryposis).
  • Autosomal recessive: Recurrence risk to offspring is 25%, and both parents are obligatory carriers (eg, lethal multiple pterygium syndrome).
  • X-linked recessive: All daughters of affected males are carriers. Their sons have a 50% chance of being affected, and their daughters have a 50% chance of being carriers (eg, severe lethal, moderately severe, and resolving types of X-linked arthrogryposis).
  • Multifactorial: Combined effects of multiple genes and environmental factors cause multifactorial traits. For most multifactorial diseases, empirical risks (risks based on direct observation of data) have been derived. For example, empirical recurrence risks of neural tube defects for siblings of an affected individual range from 2-5% in most populations.
  • Mitochondrial: A small but significant number of diseases are caused by mitochondrial mutations. Because of the unique properties of mitochondria, these diseases display characteristic modes of inheritance (ie, inherited exclusively through the maternal line) and wide phenotypic variability. Only females can transmit the disease mutation to their offspring (eg, distal type IIB arthrogryposis).

Sporadic

For families in which a specific diagnosis cannot be made, the empiric recurrence risk to unaffected parents of an affected child, or to the affected individual with arthrogryposis, ranges from 3-5%.

Complications

The most common perioperative issues include difficulties with airway management, problematic intravenous access, and intraoperative hyperthermia.

Anesthesia can be difficult because vascular access is often restricted. Intubation may pose problems for patients with a small underdeveloped jaw, limited movement of the temporomandibular joint, or a narrow airway.[39]

Osseous hypoplasia, which is associated with decreased mechanical use in developing bone, is prone to fracture at multiple sites. Multiple perinatal fractures have been observed in osteopenic bones.

Prognosis

In neonates, ventilator dependence is associated with a poor prognosis. Prenatal factors that potentially predict respiratory insufficiency include decreased fetal movements, polyhydramnios, micrognathia, and thin ribs. Developmental milestones often are delayed because of limitations of movement.

Some patients develop skeletal changes secondary to the original deformities; these may include scoliosis and deformed carpal and tarsal bones, and they worsen the patient's overall condition. Limbs may undergrow after long-standing contractures. External genitalia are often abnormal (eg, cryptorchidism, absent labia majora) because of abnormal hip position.

Prognosis depends on whether defects are intrinsically or extrinsically derived. Extrinsically derived contractures carry an excellent prognosis, whereas intrinsically derived contractures carry a prognosis that depends on the etiology.

Prognosis also depends on the condition's natural history and the patient's response to therapy.

  • Natural history

    • Developmental landmarks (attainment of motor, social, and language milestones)

    • Growth of affected limbs

    • Progression of contractures

    • CNS damage (lethal, stable, improving)

    • Asymmetry of contractures (improving, worsening)

    • Changes in trunk or limbs

    • Intellectual ability

    • Socialization

  • Response to therapies

    • Spontaneous improvement

    • Response to physical therapy

    • Response to casting

    • Types of surgery at appropriate time

    • Development of motor strength proportionate to limb size[40]

Despite severe handicaps, the prognosis for most children with normal intelligence may be good enough to allow for independent, productive lives. However, many remain partially dependent on others, such as parents, relatives, and government subsidy. Dependency is related more closely to personality, education, and overall coping skills than to the degree of physical deformity.

Properly sequenced corrective surgical procedures are required to maximize musculoskeletal function.

In addition to appropriate surgical correction, good family support, a proper educational environment, and promotion of independence at an early age are required to achieve maximal function.

A study by Nouraei et al that looked at long-term outcomes with regard to function and mobility in people with arthrogryposis found that 75% of the study’s participants lived on their own or with a partner, as opposed to with family members. The respondents, which included 177 individuals from more than 15 countries, were also almost three times more likely than the general population of the United States to possess a graduate degree. However, physical function scores were lower in persons with arthrogryposis than in the general US population, although scores were similar or greater for other quality-of-life domains of the 36-Item Short Form Health Survey (SF-36).[41]

Patient Education

See the list below:

  • The birth of a child with arthrogryposis may be a catastrophic event for parents and family. They may experience anger, feelings of guilt, denial, disappointment, repulsion, or depression. Family members may have difficulty understanding or accepting the diagnosis, and they may have a tendency to look for magical answers. Family members may also be concerned about additional unrecognized malformations, risk of mental retardation (MR), and recurrence risk.

  • The following up-to-date resources should be made available to families:

AVENUES

(A National Support Group for Arthrogryposis Multiplex Congenita)

PO Box 5192 Sonora, CA 95370

Phone: 209-928-3688

email: info@avenuesforamc.com

National Organization for Rare Disorders, Inc. (NORD)

55 Kenosia Avenue

PO Box 1968

Danbury, CT 06813-1968

Phone: 800-999-6673

Fax: 203-798-2291

email: orphan@rarediseases.org

NIH/National Arthritis and Musculoskeletal and Skin Disease Information Clearinghouse

One AMS Circle

Bethesda, MD 20892-3675

Phone: 301-495-4484

Shriner's Hospital for Children

Dr. Richard McCall

3100 Samford

Shreveport, LA 71103

Phone: 318-222-5704

 

Questions & Answers

Overview

What is arthrogryposis multiplex congenita (AMC)?

What is the role of fetal akinesia in the etiology of arthrogryposis multiplex congenita (AMC)?

What is the pathophysiology of arthrogryposis multiplex congenita (AMC)?

What is the prevalence of arthrogryposis multiplex congenita (AMC) in the US?

What is the global prevalence of arthrogryposis multiplex congenita (AMC)?

What is the mortality and morbidity associated with arthrogryposis multiplex congenita (AMC)?

What are the racial predilections of arthrogryposis multiplex congenita (AMC)?

What are the sexual predilections of arthrogryposis multiplex congenita (AMC)?

How is arthrogryposis multiplex congenita (AMC) diagnosed?

Presentation

Which family history findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which pregnancy history findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which delivery history findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which physical findings are characteristic of arthrogryposis multiplex congenita (AMC)?

How are contractures characterized in arthrogryposis multiplex congenita (AMC)?

Which physical deformities are characteristic of arthrogryposis multiplex congenita (AMC)?

Which craniofacial findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which respiratory findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which limb malformation are characteristic of arthrogryposis multiplex congenita (AMC)?

Which skin findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which cardiac findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which neurological findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which muscular findings are characteristic of arthrogryposis multiplex congenita (AMC)?

Which connective tissue abnormalities are characteristic of arthrogryposis multiplex congenita (AMC)?

What causes arthrogryposis multiplex congenita (AMC)?

DDX

What is amyoplasia (classic arthrogryposis)?

What are distal arthrogryposes?

How is bony fusion differentiated from arthrogryposis multiplex congenita (AMC)?

How is contractural arachnodactyly (Beals syndrome) differentiated from arthrogryposis multiplex congenita (AMC)?

Which conditions and syndromes are associated with arthrogryposis multiplex congenita (AMC)?

Which conditions and syndromes involving multiple body parts are included in the differential diagnoses of arthrogryposis multiplex congenita (AMC)?

How is multiple pterygium syndrome differentiated from arthrogryposis multiplex congenita (AMC)?

How is lethal multiple pterygium syndrome differentiated from arthrogryposis multiplex congenita (AMC)?

How is popliteal pterygium syndrome differentiated from arthrogryposis multiplex congenita (AMC)?

How is lethal popliteal pterygium syndrome differentiated from arthrogryposis multiplex congenita (AMC)?

How is Freeman-Sheldon syndrome differentiated from arthrogryposis multiplex congenita (AMC)?

How is osteochondrodysplasias differentiated from arthrogryposis multiplex congenita (AMC)?

Which conditions with limb involvement and CNS dysfunction are included in the differential diagnoses of arthrogryposis multiplex congenita (AMC)?

Which conditions and syndromes are included in the differential diagnoses of arthrogryposis multiplex congenita (AMC)?

Workup

What is the role of lab tests in the workup of arthrogryposis multiplex congenita (AMC)?

What is the role of imaging studies in the workup of arthrogryposis multiplex congenita (AMC)?

What is the role of an ophthalmologic evaluation in the workup of arthrogryposis multiplex congenita (AMC)?

What is the role of EMG and NCS in the workup of arthrogryposis multiplex congenita (AMC)?

What are the indications for an autopsy following a death due to arthrogryposis multiplex congenita (AMC)?

What is the role of biopsy in the workup of arthrogryposis multiplex congenita (AMC)?

Which histologic findings are characteristics of neurogenic types of arthrogryposis multiplex congenita (AMC)?

Which histologic findings are characteristics of myopathic types of arthrogryposis multiplex congenita (AMC)?

Treatment

How is arthrogryposis multiplex congenita (AMC) treated?

What is the role of surgery in the treatment of arthrogryposis multiplex congenita (AMC)?

Which specialist consultations are beneficial to patients with arthrogryposis multiplex congenita (AMC)?

Which dietary modifications are used in the treatment of arthrogryposis multiplex congenita (AMC)?

Which activity modifications are used in the treatment of arthrogryposis multiplex congenita (AMC)?

Medications

What is the role of medications in the treatment of arthrogryposis multiplex congenita (AMC)?

Follow-up

When is long-term monitoring indicated in the treatment of arthrogryposis multiplex congenita (AMC)?

When is inpatient care indicated in the treatment of arthrogryposis multiplex congenita (AMC)?

When is patient transfer indicated for the diagnosis and treatment of arthrogryposis multiplex congenita (AMC)?

What are the recurrence risks for parents and patients with arthrogryposis multiplex congenita (AMC)?

What are the possible complications of arthrogryposis multiplex congenita (AMC)?

What is the prognosis of arthrogryposis multiplex congenita (AMC)?

Where are patient education resources found for arthrogryposis multiplex congenita (AMC)?