Pediatric Annals

Special Issue Article 

Arthrogryposis Multiplex Congenita

Seth Langston, MD; Alison Chu, MD

Abstract

Arthrogryposis multiplex congenita (AMC) is a complex, etiologically diverse, clinical descriptor identified in a variety of diagnoses characterized by multiple congenital joint contractures. The root cause of AMC is decreased fetal movement in-utero, whether resulting from maternal or pregnancy influences, nervous system pathology, or an underlying genetic abnormality. Prenatal diagnosis via ultrasonography can be challenging and may require additional imaging techniques or studies. After birth, these infants may require assistance breathing and feeding depending on the underlying diagnosis. Physical therapy and surgical intervention of the contractures are the mainstays of therapy, and outcomes can be good when intervention is provided in a timely manner. Those infants with syndromic causes of arthrogryposis are more likely to have poor outcomes; therefore, determining the underlying etiology for AMC is important as this can influence counseling regarding individual prognosis as well as future pregnancies. [Pediatr Ann. 2020;49(7):e299–e304.]

Abstract

Arthrogryposis multiplex congenita (AMC) is a complex, etiologically diverse, clinical descriptor identified in a variety of diagnoses characterized by multiple congenital joint contractures. The root cause of AMC is decreased fetal movement in-utero, whether resulting from maternal or pregnancy influences, nervous system pathology, or an underlying genetic abnormality. Prenatal diagnosis via ultrasonography can be challenging and may require additional imaging techniques or studies. After birth, these infants may require assistance breathing and feeding depending on the underlying diagnosis. Physical therapy and surgical intervention of the contractures are the mainstays of therapy, and outcomes can be good when intervention is provided in a timely manner. Those infants with syndromic causes of arthrogryposis are more likely to have poor outcomes; therefore, determining the underlying etiology for AMC is important as this can influence counseling regarding individual prognosis as well as future pregnancies. [Pediatr Ann. 2020;49(7):e299–e304.]

Joint development is an intricate process normally occurring around the fifth or sixth week of gestation, as mesenchymal cells covered by ectoderm bud from the main embryo body trunk.1 Fetal movement is subsequently able to be visualized by 8 to 9 weeks. This complex embryologic process involving osseous and cartilaginous development is impaired by any factor prohibiting or limiting fetal movement, resulting in contractures. Contractures develop when normally elastic structures such as ligaments, tendons, or muscles become inelastic, causing limitations in the full range of motion of the joint.

Arthrogryposis is used to describe the physical examination findings of congenital nonprogressive contractures affecting at least two or more separate body sites. This term is used interchangably with arthrogryposis multiplex congenita (AMC), an umbrella term that encompasses the vast number of diagnoses with congenital contractures involving at least two or more body sites.2 More than 400 conditions have been described that present with arthrogryposis.3 The common mechanism fundamental to development of these contractures is decreased mobility in-utero. These congenital contractures are characterized by hypoplastic muscle with deposition of fatty and fibrous tissue around the joint. Limbs may appear tubular and slender, with a “doughy” sensation upon palpation. Affected limbs may differ depending on the underlying diagnosis and can include, but are not limited to, the shoulders, knees, hips, and ankles (Figure 1).

Representative images of potential clinical findings in arthrogryposis. (A) A 1-week-old full-term neonate with examination notable for bilateral club feet, contractures of the upper and lower extremities, and small chest. Note, that the right lower extremity is positioned at a 90° angle to the trunk. (B) Chest and abdominal radiograph of the same neonate in panel A. The radiograph demonstrates bilateral upper extremities contracted at the elbows and wrists. Again, the lower extremities can be observed to be flexed at the hip. (C) A 1-day-old full-term infant with suspected distal arthrogryposis, with examination notable for micrognathia, low-set ears with crinkled helices, overlapping digits on bilateral hands, tapered fingers that are splayed and hypermobile with lack of flexion creases on the palms, and bilateral club feet (not shown).

Figure 1.

Representative images of potential clinical findings in arthrogryposis. (A) A 1-week-old full-term neonate with examination notable for bilateral club feet, contractures of the upper and lower extremities, and small chest. Note, that the right lower extremity is positioned at a 90° angle to the trunk. (B) Chest and abdominal radiograph of the same neonate in panel A. The radiograph demonstrates bilateral upper extremities contracted at the elbows and wrists. Again, the lower extremities can be observed to be flexed at the hip. (C) A 1-day-old full-term infant with suspected distal arthrogryposis, with examination notable for micrognathia, low-set ears with crinkled helices, overlapping digits on bilateral hands, tapered fingers that are splayed and hypermobile with lack of flexion creases on the palms, and bilateral club feet (not shown).

The causes of AMC can be categorized as caused by factors that are extrinsic or intrinsic to the fetus (Figure 2). Extrinsic factors include maternal or gestational influences, such as viral infections or multiple gestation, respectively. Intrinsic factors consist of innate pathology of the fetus.

Diagnostic differential of arthrogryposis.

Figure 2.

Diagnostic differential of arthrogryposis.

It is essential that the practitioner be mindful of the numerous conditions that may present with AMC and approach the affected infant with a broad differential as the scope of treatment may differ depending on the underlying etiology. This review characterizes the clinical characteristics of a child with suspected AMC and describes the diagnosis, management, and outcomes of these children.

Epidemiology

AMC has an incidence of 1 in 3,000 to 5,000 live births, with males and females being equally affected.4,5 More than 400 syndromes and 300 genes have been identified to be associated with AMC.6 The clinical findings of AMC are seen in a number of conditions that result from either intrinsic or extrinsic problems of the fetus that cause decreased fetal movement (fetal akinesia) and include neurologic diseases, connective tissue defects, maternal diseases, or obstruction to fetal growth. Disorders exclusively affecting the limbs and those of nervous system origin appear to be the most common conditions resulting in AMC.6,7 Genetic mutations are estimated to be responsible for approximately 30% to 50% of conditions presenting with AMC, with new causal genes still being identified.8 The inheritance pattern is varied and may be autosomal dominant, autosomal recessive, X-linked, or mitochondrial-dependent.4

Etiologies

Exclusive Limb Involvement

The most common diagnoses to manifest with AMC appear to be amyoplasia and distal arthrogryposis. Amyoplasia accounts for about one-third of all arthrogryposis cases and is considered to be sporadic.4 It is secondary to underdevelopment of the muscle, possibly due to decreased perfusion or hypoxia in-utero, with the proximal joints most commonly affected in a symmetric fashion.9 Mental development appears to be normal. Distal arthrogryposis (DA) (Figure 1C) includes 10 autosomal dominant disorders that affect the distal part of the limbs (ie, the hands and feet).9 No concurrent neurologic disease or primary myopathy is present in DA. Commonly associated genes affected in DA encode for components of fast-twitch myofibers. Each DA type is characterized by which specific lower extremity joints are affected, and at least two or more major diagnostic criteria that describe the joint deformity must be met to make the diagnosis of DA.10 Like amyoplasia, mental development is expected to be intact.

Other conditions to present with AMC and normal neurologic status include impairment of the fetus' growth as caused by fetal crowding from multiple gestation, oligohydramnios, or uterine abnormalities. Osteochondrodysplasias, resulting in abnormal bone and cartilage development with subsequent variations of dwarfism, may also be responsible for AMC.11 Multiple pterygium syndrome is characterized by webbing of the skin, known as pterygium, resulting in multiple musculoskeletal abnormalities such as joint contractures. There is a mild phenotype, known as Escobar syndrome, and a lethal variant referred to as lethal multiple pterygium syndrome.11

Abnormal Neurologic Function

Abnormalities within the nervous system are responsible for a significant number of AMC cases (Table 1). If neurologic abnormalities are identified on examination, defects in the central nervous system (CNS), peripheral nervous system, and the neuromuscular junction should be considered. A genetic etiology is most likely in these situations. Symptoms that specifically point toward CNS involvement include presence of hypotonia, encephalopathy, seizures, and developmental delay. There are a host of disorders outside the scope of this review that present with aberrant neurologic function. These can be considered in the following domains: structural brain anomalies, cerebellar and/or brain stem anomalies, syndromes such as peroxisomal disorders, or chromosomal abnormalities. Trisomy 18 is the aneuploidy most commonly reported in association with AMC.6

Nervous Systems Causes of Arthrogryposis Multiplex Congenita

Table 1:

Nervous Systems Causes of Arthrogryposis Multiplex Congenita

Neuromuscular disorders are typically problematic in the peripheral nervous system and muscles, but they may present with perturbations in the CNS. Commonly observed signs and symptoms include muscle weakness and atrophy leading to hypotonia, reduced or absent deep tendon reflexes, and distal sensory loss. Disorders such as the congenital muscular dystrophies, which are particularly rare, can clinically present with a variety of phenotypes and are a result of abnormal protein development that leads to erroneous muscle development and function.12 For example, congenital myotonic dystrophy secondary to an inherited trinucleotide repeat of CTG, which is the most common neuromuscular disease to present in the neonatal period, should be considered in a hypotonic baby requiring respiratory assistance.12 The family history may be notable for myotonic dystrophy, particularly if the mother exhibits the classic facial features of bilateral temporal wasting and ptosis. Spinal muscular atrophy, due to degradation of the anterior horn cell of the spinal cord, is also an important diagnosis to consider when investigating AMC, as fetal presentation may reflect a more severe process.13

Peripheral neuropathies due to an arrest of peripheral myelination may present with severe intellectual disability and seizures in the setting of AMC.14 Syndromic forms of arthrogryposis, involving both the CNS and additional organ systems, can be severe and commonly result in neonatal or infantile death.6,15

Maternal Exposures

Maternal exposures have also been associated with AMC. Neonatal myasthenia gravis affects 10% to 20% of fetuses born to mothers with myasthenia gravis and is due to transplacental passage of maternal anti-acetylcholine receptor antibodies, which leads to neuromuscular junction receptor loss in the fetus, causing muscle weakness and AMC.16 Recently, maternal zika virus infection has been identified as a causative agent of AMC due to central nervous system anomalies likely due to microcephaly and aberrant cerebral development. A recent case series investigating infants in Brazil exposed to zika virus identified arthrogryposis in six of the seven infants with abnormal brain imaging on magnetic resonance imaging (MRI).17 Other maternal infections that may result in arthrogryposis include coxsackie viruses, rubella, toxoplasmosis, and varicella. Additionally, toxic exposures to alcohol, phenytoin, and cocaine will also increase the risk of AMC.11

Diagnosis

Although fetal movement is present by 8 weeks gestational age, the majority of affected fetuses are not identified until the second trimester. Even then, approximately 75% of infants found to be affected by AMC postnatally were missed by prenatal ultrasound.18 The identification of joint contractures on fetal ultrasound depends on the position of the fetus, as well as factors such as maternal habitus and amniotic fluid volume. Tjon et al.,19 however, prospectively studied a cohort of fetuses identified to have contractures at the 20-week structural anomaly scan and reported that with use of advanced ultrasound examination and serial motor assessments, a more definitive diagnosis could be made. When joint contractures are visualized, a fetal MRI in the second or third trimester may be warranted if there is concern for CNS etiologies or to delineate severity of lung hypoplasia, if present, to help assess for potential postnatal medical requirements.3 After birth, the approach to diagnosis is dependent on the practitioners' leading concerns. A thorough review of the pregnancy and family history is required to investigate if either may have contributed to the affected infant. A comprehensive physical examination should be performed assessing for any dysmorphic features, neurologic abnormalities, or additional congenital anomalies that might suggest a syndromic cause of the AMC. Taking note of the distribution and gross appearance of the joint contractures is essential as these findings may be helpful in narrowing the differential diagnosis.

Biochemical evaluation should be performed to assess for the presence of multi-organ involvement. Injury to the muscle generally causes an elevated serum creatine kinase (CK) level. Although increased serum CK levels may indicate a neuromuscular etiology, it is not uncommon for CK levels to also be slightly elevated in other conditions presenting with arthrogryposis, limiting its utility in targeting a specific diagnosis.20,21 A formal consultation with genetic specialists is essential to the care of these infants. Genetic investigation should include a chromosomal microarray, especially when an infant with multiple anomalies is evaluated. If a microarray does not yield a satisfactory explanation, clinical whole exome sequencing (WES) should be obtained, bearing in mind that this test may result with variants of unknown clinical significance. About 60% of genetic causes for AMC should be detected with WES.20 Targeted gene testing for common and uncommon causes of AMC may be recommended in the form of gene panels that provide robust sequencing sensitivity.

Postnatal MRIs should be performed to evaluate for CNS etiologies, with attention to the cerebral hemispheres, cerebellum, and brainstem.

Although myopathies are a cause of AMC, muscle biopsies are not routinely required for diagnosis of myopathy in an era of enhanced genetic diagnosis.20 In general, nerve conduction studies, electromyography, and muscle biopsies have low sensitivity and specificity. However, if there is uncertainty in the etiology of the arthrogryposis with high suspicion for a potential neuromuscular disorder, an evaluation utilizing combined muscle biopsy and nerve conduction studies/electromyography improves diagnostic value.22

Management

Prenatal management includes consideration for cesarean delivery on a case-bycase basis, as the maldeveloped extremities may place the infant at increased risk of fractures.23 Prenatal evaluation, such as genetic testing, should be offered based upon clinical suspicion if the discovery of prenatal findings for arthrogryposis is early enough. Prenatal counseling of the family regarding fetuses found to have severe, life-limiting disease should be offered. Postnatally, early evaluation and intervention in infancy is essential to optimize long-term outcomes. Care should be provided at a tertiary referral center to ensure multidisciplinary team management is delivered. Monitoring of the infant's respiratory status will be important, as the infant may present with respiratory insufficiency if the infant is hypotonic or has contractures inhibiting respiratory effort. Consultation with physical therapy is essential to initiate splinting of the affected joints soon after delivery. Orthopedics will need to be involved to plan potential surgery throughout infancy and beyond. Occupational therapy is also important as affected infants may present with difficulties feeding due to hypotonia or micrognathia. Care should be taken to monitor for seizure activity, and an electroencephalogram should be obtained if any concerns arise; antiepileptic therapy should be initiated if warranted.

Outcomes

Infants with AMC are affected to variable degrees depending on the underlying diagnosis resulting in contractures. Nervous system disorders have worse outcomes due to the higher complexity of disease involvement. Those infants with exclusive limb involvement seem to respond more favorably to noninvasive interventions such as physical therapy; however, surgical fixation is still needed in a number of conditions.24,25

Obeidat et al.26 identified that children who undergo multiple surgical procedures at an early age will have improved outcomes such as independently walking and performing activities of daily living. Measurement tools such as the Pediatric Outcome Data Collection Instrument have been created to assess people affected by arthrogryposis. In a study completed by Amor et al.,27 people affected exclusively by amyoplasia demonstrated improved upper extremity function and global functioning skills over a 3-year period after receiving recommended therapies and procedures.27

Conclusion

AMC describes a diverse spectrum of clinical conditions based on the presence of joint contractures in two or more body sites. It is a challenging finding because a single diagnosis must be carefully extracted from a thorough medical evaluation. Genetic evaluation is usually warranted, as a vast number of conditions presenting with AMC are genetic in origin. The complexity of medical issues affecting children with AMC requires a multidisciplinary team approach for diagnosis and for long-term management. This includes assistance from neurologists, orthopedic surgeons, occupational and physical therapists, and geneticists. Although the overall outcome is dependent on the underlying disease process, those patients only affected in the limbs typically have a good prognosis. The general clinician should be diligent in following these patients and ensuring all specialty care is provided as needed.

References

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  27. Amor CJ, Spaeth MC, Chafey DH, Gogola GR. Use of the Pediatric Outcomes Data Collection Instrument to evaluate functional outcomes in arthrogryposis. J Pediatr Orthop. 2011;31(3):293–296. doi:10.1097/BPO.0b013e31820cad93 [CrossRef] PMID:21415689

Nervous Systems Causes of Arthrogryposis Multiplex Congenita

Structural brain anomalies
  Cerebral atrophy
  Pontocerebellar hypoplasia
  Abnormal cortical development
  Microcephaly
Neuromuscular disorders
  Congenital muscular dystrophy
  Spinal muscular atrophy
  Channelopathies
  Congenital demyelinating neuropathies
  Myasthenia gravis
Syndromic
  Trisomy 13, 18, 21
  Microdeletion 5q23
  Peroxisomal disorders
  Prader-Willi syndrome
  Pena-Shokeir syndrome
  X-linked arthrogryposis syndromes
Authors

Seth Langston, MD, is a Senior Neonatology Fellow. Alison Chu, MD, is an Assistant Professor-in-Residence. Both authors are affiliated with the Division of Neonatology, Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles (UCLA).

Address correspondence to Alison Chu, MD, Division of Neonatology, Department of Pediatrics, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, MDCC B2-411, Los Angeles, CA 90095; email: alisonchu@mednet.ucla.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20200624-01

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