AUTHOR INFORMATION

Section 1 of 12

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	James Bowman, MD

eMedicine Journal, February 13 2006, VOLUME 7, Number 2

INTRODUCTION

Section 2 of 12

Background: Arthrogryposis, or arthrogryposis multiplex congenita, comprises nonprogressive conditions characterized by multiple joint contractures found throughout the body at birth. The term currently is used in connection with a very heterogeneous group of disorders having the common feature of multiple congenital joint contractures.

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 also can 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 who are diagnosed early in pregnancy and in those who experience akinesia for longer periods of time during gestation.

Frequency:

• In the US: Frequency is about 1 in 3,000 live births.

Mortality/Morbidity:

• Life span is usually normal, but it may be related to the disease severity and associated malformations.

• In disorders with limb involvement and CNS dysfunction, about 50% of patients die in the first year of life.

• Scoliosis may compromise respiratory function.

Race: No racial predilection is described.

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

Age: Arthrogryposis is detectable at birth or in utero by ultrasound examination.

CLINICAL

Section 3 of 12

History:

• Family history


• • Review history of affected children 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 the parents will both carry the same disease gene. Consanguinity is seen more frequently in families with rare recessive diseases than in those with common recessive diseases.
  
  
  
  • Some chromosomal abnormalities increase dramatically with maternal age, and single-gene dominant mutations can increase with paternal age.
  
  
  
  • Look for marked intrafamilial variability; the parent may be affected very mildly 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. In congenital myotonic dystrophy, a mother with the disease 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 born 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 above 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 can indicate fetal compromise (ie, defect in swallowing), but it 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 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. Fracture of a limb occurs during traumatic delivery in about 5-10% of cases.
  
  
  
  • Check for abnormal placenta, membranes, or cord insertion in case of 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, there are several common characteristics, 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 hands and feet typically being 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


• • 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 severity of all limitations. Distinguish between complete fusion or ankylosis and soft-tissue contracture.

  • Range of motion in the jaw frequently is limited.

  • Intrinsically derived contractures frequently are associated with polyhydramnios; the contractures are symmetric and accompanied by taut skin, pterygia across joints, and lack of flexion creases. Recurrence risk and prognosis are dependent 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.
  
  
  
• Deformities


• • Deformities in the limbs 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.
  
  
  
  • 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.
  
  
  
• 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; slow, fast, 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 with time.
  
  
  
• Connective tissue abnormalities


• • Skin webs (pterygia) across joints, with limitation of movement, are common. Skin dimples are observed frequently over joints where movement is limited.
  
  
  
  • Skin may be soft, doughy, thick, or extensible. There is decreased or increased subcutaneous fat; inguinal, umbilical, or diaphragmatic hernias; thickness in joints; symphalangism; and abnormalities in tendon attachment and length.

  • 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 a physical sign observed in many specific medical conditions. It can be a component of a number of 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.



• Neuropathic abnormalities are the most common cause of arthrogryposis. They may be 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.



• 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 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.

DIFFERENTIALS

Section 4 of 12

Other Problems to be Considered:

Disorders with mainly limb involvement

Amyoplasia is the most common type of arthrogryposis seen in clinical practice and constitutes about one third of cases. Incidence is about 1 in 10,000 live births. Amyoplasia is a sporadic condition and has not been observed in siblings or offspring. 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 may be present. Muscles are hypoplastic and usually are replaced by fibrous and fatty tissue. Intelligence is normal.

Distal arthrogryposes involve the distal joints and include 7 subtypes described as follows:

• Type I (OMIM 108120) is characterized by medially overlapping fingers, tightly clenched fists at birth, ulnar deviation of fingers and camptodactyly in adults, and positional foot contractures. Intelligence is usually normal, and the condition is inherited as an autosomal dominant trait.
  
  
• Type II is characterized by a heterogeneous group of congenital distal joint contractures associated with various combinations of manifestations.
  
  
• Type IIA, also known as Gordon syndrome, is characterized by short stature (90%), cleft palate, bifid uvula, epicanthal folds, congenital ptosis, short neck, and camptodactyly.
  
  
• Type IIB is characterized by distal contractures; short stature; short neck; congenital ptosis; ophthalmoplegia; decreased range of ocular motion; a somewhat immobile face; hard and woody muscles; smooth, shiny, tapering fingers; and absent palmar creases. Muscle biopsy in one case revealed the presence of red-ragged fibers, suggesting a mitochondrial disorder.
  
  
• Type IIC is characterized by distal contractures notably affecting the feet with equinovarus deformity, cleft lip or palate, and lack of short stature.
  
  
• Type IID is characterized by congenital contractures with scoliosis, lack of short stature, cerebral palsy, congenital ptosis, epicanthal folds, keratoconus, immobile face, and cleft lip.
  
  
• Type IIE is characterized by trismus and an unusual contracture of the hand in which the wrist is flexed and the metacarpophalangeal joint extended.

WORKUP

Section 5 of 12

Lab Studies:

• In general, laboratory tests are not extremely useful.



• 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 fibroblast chromosome study if lymphocyte chromosomes are normal and the patient has MR without diagnosis.



• Nuclear DNA mutation analysis will identify certain disorders, such as spinal muscular dystrophy.



• Mitochondrial mutation analysis will identify certain disorders, such as mitochondrial myopathy.

Imaging Studies:

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



• Use radiographs 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 to evaluate the CNS and other viscera for anomalies. Ultrasonography also establishes potential muscle tissue.



• CT scanning can evaluate the CNS and the muscle mass.



• MRI can evaluate muscle mass obscured by contractures.



• Prenatal ultrasonography can be used to discover the following:


• • Decreased fetal movement
  
  
  
  • Abnormal fetal lie
  
  
  
  • Polyhydramnios or oligohydramnios
  
  
  

Other Tests:

• Obtain an ophthalmologic evaluation for opacity and retinal degeneration.

Procedures:

• Skin biopsy should be done 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) in 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 done 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
  
  
  

Neurogenic types of arthrogryposis multiplex congenita

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 and decrease in neurons of the cortex and motor nuclei of the brainstem and spinal cord. Clinical syndromes 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

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 increased markedly. Mitochondrial cytopathy is indicated by numerous ragged-red fibers on muscle biopsy. It is associated with CNS abnormalities consistent with mitochondrial disease. Myoneural junction abnormality (eg, congenital myasthenia gravis) is another myopathic type of arthrogryposis.

TREATMENT

Section 6 of 12

Medical Care:

• There is no completely successful approach to treatment. Goals are 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 to 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 actually may be harmful in diastrophic dysplasia, because it may lead to joint ankylosis. Recurrence of deformities following stretching is common, and surgery often is 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:

• 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, at a later stage may improve function.

• 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 at the time growth is completed. In soft-tissue release procedures, tenotomies should be accompanied by capsulotomies. Long-term bracing and assistive devices usually are 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 will need 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 accomplished more easily in an extension or hyperextension deformity than in a flexion deformity.

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

  • A mild contracture (<20°) will 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° will need soft-tissue releases.

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

Consultations:

• Clinical geneticist



• Orthopedic surgeon



• Plastic surgeon



• Radiologist



• Neurologist



• Developmental pediatrician

• Pathologist

• Psychologist

• Physical and occupational therapists

• Social worker

• Educator

• Orthotist

• Rehabilitation engineer

Diet: No special diet is required.

Activity:

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



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



• Patients with more severe joint involvement are dependent on help from other people to a higher degree than those with less severe joint involvement.

MEDICATION

Section 7 of 12

Drug therapy currently is not a component of the standard of care for this condition. See Treatment.

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Admit the patient for surgical intervention.

Further Outpatient Care:

• Carefully monitor the patient, watching for postoperative complications.

Transfer:

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

Deterrence/Prevention:

• Recurrence risk depends on whether the contractures are extrinsically or intrinsically derived. Extrinsically derived contractures have a low recurrence risk, while 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:


• • 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 will be carriers. Their sons will have a 50% chance of being affected, and their daughters will 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 those 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, is from 3-5%.

Complications:

• Anesthesia can be difficult because vascular access often is restricted.



• Intubation may pose problems for patients with a small underdeveloped jaw, limited movement of the temporomandibular joint, or a narrow airway.



• 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 carries 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.



• Skeletal changes secondary to the original deformities are observed in some patients; 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 often are abnormal (eg, cryptorchidism, absent labia majora) because of abnormal hip position.



• Prognosis depends on whether defects are intrinsically or extrinsically derived. Extrinsically derived contractures have an excellent prognosis, while intrinsically derived contractures have a prognosis dependent on 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
  
  
  
• Despite severe handicaps, prognosis for most children with normal intelligence may be good enough to live 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.

Patient Education:

• 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 also may be concerned about additional unrecognized malformations, risk of 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, E-mail: 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, E-mail: 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
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Anesthesia should be undertaken carefully, since patients who have a rare form of arthrogryposis are prone to having malignant hyperthermia.



• Physical therapy in diastrophic dysplasia may lead to joint ankylosis.



• Refer the patient to clinical geneticists and physicians (especially orthopedists) who are experienced in treating arthrogryposis to ensure that the patient receives proper diagnosis, genetic counseling, and management of contractures.

Special Concerns:

• Family members should make sure the patient can perform hygienic necessities, since extension contractures of elbow joints may make this difficult.

TEST QUESTIONS

Section 10 of 12

CME Question 1: In evaluating a newborn with arthrogryposis, what should be the initial investigation?

A: Histories of family, pregnancy, and delivery
B: CT scan to evaluate CNS or muscle mass
C: MRI to evaluate muscle mass obscured by contractures
D: Cytogenetic study to rule out chromosome anomaly
E: Muscle biopsy to distinguish myopathic from neuropathic etiologies

The correct answer is A: Although CT scan, MRI, karyotyping, and muscle biopsy may be required eventually, the initial investigation should be a detailed history about family, pregnancy, and delivery.

CME Question 2: The major cause of arthrogryposis is fetal akinesia. What is the most common etiology of fetal abnormalities that cause fetal akinesia?

A: Neurogenic syndromes
B: Myopathic syndromes
C: Connective tissue diseases
D: Space crowding in utero
E: None of the above

The correct answer is A: The most common cause of fetal abnormalities leading to fetal akinesia is neurogenic syndromes.

Pearl Question 1 (T/F): A child with multiple congenital contractures is presented for evaluation. The initial work-up should include detailed family, pregnancy, and delivery histories.

The correct answer is True: For family history, ask about affected siblings or relatives, consanguinity, parental ages, intrafamilial variability of contractures, hyperextensibility/dislocation, maternal illnesses, and miscarriages or stillbirths. For pregnancy history, ask about maternal illnesses, infections, fever, exposure to drugs or teratogens, oligohydramnios or polyhydramnios, trauma, uterine abnormalities, abnormal fetal movement, and other pregnancy complications. For delivery history, ask about abnormal fetal presentation, gestation, induction, placenta, membranes, cord, and multiple births.

Pearl Question 2 (T/F): An infant was born with multiple congenital contractures, pulmonary hypoplasia, pterygia, and other deformities. The differential diagnosis should include fetal akinesia sequence.

The correct answer is True: The characteristic features of fetal akinesia sequence include intrauterine growth retardation, multiple congenital contractures, pulmonary hypoplasia, pterygia, craniofacial anomalies (hypertelorism, cleft palate, depressed nasal tip), and other deformities.

Pearl Question 3 (T/F): Positional limb anomalies are intrinsically derived contractures with a poor prognosis and a high recurrence risk.

The correct answer is False: Intrinsically derived contractures are symmetric, with taut skin and pterygia across the joints. They frequently are associated with polyhydramnios. They lack flexion creases, and both recurrence risk and prognosis are dependent on the etiology. Extrinsically derived contractures are positional limb anomalies that frequently are associated with large ears, loose skin, and normal or exaggerated flexion creases. They carry an excellent prognosis and a low recurrence risk.

Pearl Question 4 (T/F): The major goal of surgical treatment of arthrogrypotic upper extremities involves development of self-help and mobility skills.

The correct answer is True: Surgical treatment involves development of self-help skills (eg, feeding, toileting) and mobility skills (eg, pushing out of chair, using crutches).

PICTURES

Section 11 of 12

Caption: Picture 1. Arthrogryposis. An infant with amyoplasia. Note internally rotated and adducted shoulders, fixed extended elbows, pronated forearms, flexed wrists and fingers, and severe talipes deformity.
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Caption: Picture 2. An infant with distal arthrogryposis type I. Note medially overlapping fingers, tightly clenched fists, and positional foot contractures.
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Caption: Picture 3. Arthrogryposis. The hands of a patient with contractural arachnodactyly (Beals syndrome). Note the long, thin fingers with interphalangeal joint contractures.
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Caption: Picture 4. Arthrogryposis. 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.
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Caption: Picture 5. Arthrogryposis. 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.
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Caption: Picture 6. Arthrogryposis. Twins with a lethal type of autosomal recessive multiple pterygium syndrome. Note the multiple joint contractures with marked pterygia, cardiac and lung hypoplasia, and characteristic facies.
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Caption: Picture 7. Arthrogryposis. An infant with a lethal type of multiple pterygium syndrome. Note multiple joint contractures with marked pterygia and a cystic hygroma on the posterior aspect of the head and the neck.
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Caption: Picture 8. Arthrogryposis. On the left is a photograph of an infant with fetal akinesia. Note depressed nasal bridge, micrognathia, flexion contractures of elbows, bilateral clubhands, and arthrogryposis of fingers. On the right is a radiograph of an infant with fetal akinesia. Note gracile ribs; thin, long bones with multiple fractures at mid diaphyses of the humeri, distal diaphyses of the femora, and proximal diaphyses of both tibiae and left fibula; and clubhands.
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Caption: Picture 9. Arthrogryposis. An infant with Pena-Shokeir syndrome. Note characteristic facies (ocular hypertelorism; short nose with depressed bridge; small and markedly recessed jaw; low-set, malformed ears), short neck, mild contracture at the hip, moderate contractures at elbows and knees, severe ankle contractures, and camptodactyly with ulnar deviation of the hands.
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