Arthrogryposis Multiplex Congenita 

Arthrogryposis Multiplex Congenita – Introduction

•  congenital syndrome with symmetrical reduction in muscle size (often replaced with fibrofatty tissue) and joint deformities⁽¹⁾
•  multiple contractures of joints of ≥ 2 anatomical regions at birth (Ortop Traumatol Rehabil 2006 Feb 28;8(1):69, Med Pregl 2006 Jul-Aug;59(7-8):375)
•  also described as “not a disease but a term describing multiple congenital contractures” involving ≥ 2 joints with ankylosis (Med Pregl 2006 Jul-Aug;59(7-8):375 [Serbian])

Synonyms

•  AMC
•  congenital multiple arthrogryposis
•  fibrous ankylosis of multiple joints
•  multiple congenital contractures

Types

• Type I⁽¹⁾
  •  “loose” type with little involvement
  •  good functional prognosis
  •  clinically correctable
  •  minor walking difficulty
  •  spinal muscles not involved
  •  shape of extremities appears normal
  •  secondary operations not usually necessary
• Type II⁽¹⁾
  •  “stiff” type with little pre-operative joint movement
  •  severe club foot deformity
  •  severe knee and hip joint subluxation or dislocation
  •  spinal muscle involvement
  •  few muscle fibers found intra-operatively
  •  joint capsules thick and contracted
  •  intra-articular adhesions
  •  severe rigidity of joints results in abnormally shaped joints

Epidemiology

Who Is Most Affected

•  present at birth⁽¹⁾
•  all races⁽¹⁾
•  equally in males and females⁽¹⁾

Incidence/Prevalence

• incidence 6.2 per 100,000 live births
  •  however true incidence cannot be established because many cases result in spontaneous miscarriages or stillbirth
  •  > 90% of cases associated with birth defects
  •  Reference – Med Pregl 2006 Jul-Aug;59(7-8):375 [Serbian]

Associated Conditions

•  > 90% of cases associated with birth defects (Med Pregl 2006 Jul-Aug;59(7-8):375 [Serbian])
•  congenital abnormalities as part of syndrome with or without central nervous system involvement (J Pediatr Orthop B 1997 Jul;6(3):159)
•  cholestatic jaundice and renal involvement described in case series of 2 brothers (Turk J Pediatr 2005 Jan-Mar;47(1):67)
•  atlantoaxial subluxation in woman aged 27 years described in case report (J Neurosurg 2000 Jul;93(1 Suppl):130)
•  congenital ophthalmoplegia and juvenile glaucoma described in case report (J Pediatr Ophthalmol Strabismus 1989 Jul-Aug;26(4):204)
• severe otolaryngologic manifestations described in case report
  •  expressionless face
  •  micrognathia (small jaw)
  •  poor suck reflex
  •  high arched palate
  •  omega-shaped epiglottis
  •  airway compromise
  •  achalasia (constriction of esophagus)
  •  aspiration pneumonitis
  •  poor nutrition
  •  Reference – Ann Otol Rhinol Laryngol 1990 Feb;99(2 Pt 1):94

Etiology and Pathogenesis

Causes

•  congenital, but not genetically inherited⁽¹⁾
•  unknown (Med Pregl 2006 Jul-Aug;59(7-8):375 [Serbian])
• viral or toxic etiology in utero affecting anterior horn cells of spinal cord suspected in most cases⁽¹⁾
  •  viral infections, for example, herpes simplex
  •  increase in intrauterine temperature due to maternal infection
  •  placental insufficiency

History and Physical

History

Chief Concern (CC)

•  abnormal appearance due to joint contractures⁽¹⁾

History of Present Illness (HPI)

•  multiple contractures of joints of ≥ 2 anatomical regions at birth (Ortop Traumatol Rehabil 2006 Feb 28;8(1):69, Med Pregl 2006 Jul-Aug;59(7-8):375 [Serbian])

Physical

General Physical

• multiple joints and muscles involved, typically symmetrical involvement⁽¹⁾
  •  muscles are fewer, smaller and often replaced by fibrous or fatty tissue
• type 2⁽¹⁾
  •  “stiff” with little pre-operative joint movement
  •  spinal muscle involvement

Skin

•  skin smooth over joints – folds reduced or absent⁽¹⁾
•  skin dimples at large joints⁽¹⁾

Extremities

• upper limb joints⁽¹⁾
  •  shoulder joints held in adduction
  •  elbow joints held in extension (less frequently in flexion)
  •  wrists flexed
  •  thumbs adducted
  •  fingers flexed in varying degrees
• lower limb joints⁽¹⁾
  •  hip subluxation or dislocation
  •  knee hyperextended
  •  feet in talipes equinovarus (club feet)
• type I⁽¹⁾
  •  “loose” with little involvement
  •  minor walking difficulty
  •  shape of extremities appears normal
• type II⁽¹⁾
  •  “stiff” with little pre-operative joint movement
  •  severe club foot deformity
  •  severe knee and hip joint subluxation or dislocation
  •  severe rigidity of joints resulting in abnormally shaped joints

Neuro

•  normal intellect⁽¹⁾
•  normal sensation⁽¹⁾

Diagnosis

Making the Diagnosis

• typical characteristics⁽¹⁾
  •  present at birth
  •  multiple joints and muscles involved
  •  presentation usually symmetric
  •  no systemic involvement
  •  normal intellect
  •  not genetically inherited
  •  not due to embryologic malformation
  •  muscles decreased in bulk and may be replaced by fibrous tissue
  •  normal sensation
  •  no progression after birth

Differential Diagnosis

•  15 cases of arthrogryposis reported associated with maternal use of misoprostol at 8-12 weeks gestation (Am J Med Genet 2000 Dec 11;95(4):297)
• nervous system disorders⁽¹⁾
  •  focal anterior horn cell deficiency
  •  generalized anterior horn cell deficiency
  •  structural brain disorder/damage
  •  congenital spinal muscular atrophy
• abnormalities of joints and contiguous tissue⁽¹⁾
  •  congenital contractural arachnodactyly
  •  Freeman Sheldon syndrome
  •  laxity or hypertonicity with intrauterine dislocation and contractures
• distal arthrogryposis syndromes⁽¹⁾
  •  type 1 dominant distal
  •  type 2a dominant distal (Gordon syndrome)
  •  type 2e distal
  •  digitotalar dysmorphism
  •  trismus pseudocamptodactyly
  •  distal distribution, type not specified
  •  Larsen syndrome
  •  spondylo-epi-metaphyseal dysplasia with joint laxity
  •  trisomy 18, extended breech position with bilateral hip dislocations
  •  siblings with bifid humeri, hypertelorism and hip and knee joint dislocations
• pterygium syndromes⁽¹⁾
  •  multiple pterygium syndrome
  •  lethal multiple pterygium syndrome
  •  popliteal pterygium syndrome
  •  ptosis, scoliosis, pterygia
  •  antecubital webbing syndrome (Liebenberg)
• skeletal disorders⁽¹⁾
  •  diastrophic dysplasia
  •  parastremmatic dysplasia
  •  Kniest dysplasia
  •  metatropic dysplasia
  •  camptomelic dysplasia
  •  Schwartz syndrome
  • fetal alcohol syndrome with synostoses
  • osteogenesis imperfecta with bowing/contractures
• myopathies⁽¹⁾
  •  Emery-Dreifuss muscular dystrophy
  •  hypotonia, myopathy, mild contractures
• intrauterine/maternal factors⁽¹⁾
  • fetal alcohol syndrome with contractures
  •  infections
  •  untreated maternal systemic lupus erythematosus (SLE)
  •  intrauterine fetal constraint
  •  deformity (pressure)
  •  amniotic fluid leakage
  •  multiple pregnancies
  •  intrauterine tumors
  •  disruption (bands)
• miscellaneous⁽¹⁾
  •  pseudotrisomy 18 with contractures
  •  Roberts pseudothalidomide syndrome
  •  deafness with distal contractures
  •  VACTERL association
  •  multiple abnormalities and contractures not otherwise specified

Testing Overview

•  disease gene identification reported in 61% with whole exome sequencing and 32% with targeted exome sequencing in children and fetuses with arthrogryposis multiplex congenita (AMC)
  • based on cohort study
  • 315 children and fetuses with AMC and their families were enrolled for genomic identification of candidate AMC genes
  • main genomic approaches included targeted exome sequencing (210 families), whole exome sequencing (209 families), and mapping using microarrays (15 families)
  • AMC detected during pregnancy in 80% of families and after birth in 20% of families
  • 226 families had sporadic AMC and 89 families had familial AMC, defined as ≥ 2 affected individuals
  • 67.6% of families had nonsyndromic AMC and 32.4% had syndromic AMC, defined as additional features not related to fetal akinesia sequence
  • outcomes of genomic strategies
    • 61% disease gene identification in 90 families who had whole exome sequencing
    • 32% disease gene identification in 210 families who had targeted exome sequencing
    • additional 21.6% disease gene identification in 111 families who had no gene identification from targeted exome sequencing and then had whole exome sequencing
    • 15 families had genetic mapping using microarrays
      • 100% disease gene identification in 7 families who had subsequent Sanger sequencing of candidate AMC gene
      • 100% disease gene identification in remaining 8 families who had subsequent whole exome sequencing
  • Reference – J Med Genet 2022 Jun;59(6):559full-text
•  arthrogryposis multiplex congenita (AMC) disk-o-gram provides pictorial form for reporting passive and active joint motion and function for evaluating efficacy of therapy (J Hand Surg [Br] 2004 Aug;29(4):363)

Management

Management Overview

•  physical therapy (gentle manipulation) should start soon after birth and may be adequate for Type I
•  for patients having surgery, surgery recommended between ages 3-12 months

Surgery and Procedures

• for patients having surgery, surgery recommended between ages 3-12 months⁽¹⁾
  •  offer surgery around age 6 months if physical therapy of deformed joints of elbow, wrist, thumb and fingers does not provide adequate progress
  •  after age 1 year, contractures more fixed and joint surface anatomy changes
  •  recovery more rapid and less scar tissue formation before age 1 year
• surgical approaches may include⁽¹⁾
  •  carpectomy before ossification of carpal bones
  •  soft tissue balancing
  •  elbow flexorplasty (arthrolysis and capsular release)
  •  muscle transfer from pectoralis major or latissimus dorsi
  •  triceps tendon transfer
• 2 most important surgical corrections for functional improvement are⁽¹⁾
  •  wrist surgery to improve dorsiflexion
  •  elbow surgery to improve range of motion for activities of daily living
• one-stage procedures include simultaneous surgery to⁽¹⁾
  •  bones
  •  joint
  •  soft tissue
•  osteotomy to correct deformities has little value because remodeling will reproduce deformity in 1-2 years⁽¹⁾

Other Management

•  physical therapy for upper extremity – deformed joints of elbow, wrist, thumb and fingers gently manipulated by qualified hand therapists from birth (best results achieved before 6 months of age)⁽¹⁾
• considerations for lower extremity
  •  hip treatment may not improve mobility
  •  treat knee contractures actively to improve functional ability (sit, stand and walk better)
  •  club foot and rocker-bottom foot treated conservatively and surgically
  •  Reference – Orthopade 2007 Mar;36(3):281 [German]

Complications and Prognosis

Complications

•  difficult ambulation (Orthopade 2007 Mar;36(3):281)
•  difficulty with feeding, personal hygiene and dressing (Ortop Traumatol Rehabil 2006 Feb 28;8(1):69)
• among children diagnosed with arthrogryposis multiplex congenita in 1976-2016, inability to ambulate (use of wheelchair for mobility) reported in 4% with distal arthrogryposis to 47% with amyoplasia
  •  based on retrospective cohort study
  • 114 children (53% female) diagnosed with arthrogryposis multiplex congenita in 1976-2016 in pediatric orthopedic center in Canada were assessed
    • 41.2% had amyoplasia (involvement in all 4 limbs, usually symmetric, with associated muscle abnormalities in absence of identified genetic diagnosis)
    • 43% had distal arthrogryposis (≥ 2 contractures of mostly distal extremities, confirmed genetic diagnosis, or associated syndrome such as Freeman-Sheldon syndrome)
    • 15.8% were classified as other types (presence of pterygium, X-linked conditions, involvement of central nervous system, or other syndromic-type features in addition to multiple congenital contractures)
  • mean patient age at last clinic follow-up was 10 years (range 2 months to 2 years)
  • 17 patients (14.9%) did not have any surgery; among patients having orthopedic interventions, procedures included bony surgeries, soft tissue releases, and internal or external fixator and serial casting
  • comparing patients with amyoplasia vs. distal arthrogryposis vs. other type (no p values reported)
    • joint involvement
      • all upper extremity joints affected in 55.5% vs. 14.3% vs. 23.5%
      • all lower extremity joints affected in 63.8% vs. 33.3% vs. 58.8%
    • for functional status
      • ambulation
        • community ambulation (ability to ambulate long distances without device) in 28.2% vs. 97.7% vs. 35.3%
        • ambulation with device in 30.8% vs. 0% vs. 17.6%
        • no ambulation (use of wheelchair for mobility) in 41% vs. 2.3% vs. 47%
      • self-care abilities
        • independent in 24% vs. 78.4% vs. 64.3%
        • independent with minimal assistance in 36% vs. 16.2% vs. 5.6%
        • dependent in 40% vs. 5.4% vs. 28.6%
      • transfers abilities
        • independent in 42.3% vs. 97.3% vs. 71.4%
        • independent with minimal assistance in 30.8% vs. 0% vs. 0%
        • dependent in 26.9% vs. 2.7% vs. 28.6%
  • Reference – J Pediatr Rehabil Med 2020;13(3):263

Prognosis

•  not progressive, but change occurs due to growth and development or treatment⁽¹⁾
•  good prognosis for ambulation without aid in distal arthrogryposis (Orthopade 2007 Mar;36(3):281)
•  dependency on mobility aids more likely with amyoplasia (Orthopade 2007 Mar;36(3):281)
•  children are usually adaptive in overcoming loss of function⁽¹⁾
•  lifespan not affected but physical handicap may have deleterious effect in certain communities⁽¹⁾
• average expected functional improvement⁽¹⁾
  •  elbow – 30-100 degrees flexion (average 49 degrees)
  •  wrist – 10-30 degrees extension (average 27 degrees active motion)
  • fingers
    •  metacarpophalangeal (MCP) joint – 20-85 degrees flexion (average 65 degrees)
    •  proximal interphalangeal (PIP) joints – 20-80 degrees flexion (average 45 degrees)
    •  distal interphalangeal (DIP) joints – 15-35 degrees flexion (average 20 degrees)
• type I has good functional prognosis⁽¹⁾
  •  clinically correctable
  •  minor walking difficulty
  •  secondary operations usually unnecessary
• patients with arthrogryposis multiplex congenita (AMC) might have lower physical function but similar quality of life as United States general population
  •  based on cross-sectional survey
  •  177 patients (age 19-84 years, 74% female) with AMC were evaluated for quality of life and physical activity outcomes at mean age 39 years
  • health-related quality of life evaluated with
    •  Short Form-36 (SF-36), with scores ranging from 0 (maximum disability) to 100 (minimum disability), and
    •  Physical Activity Scale for Individuals with Physical Disabilities (PASIPD), where healthy adult defined as PASIPD score ≥ 22
  •  AMC involved in upper or lower limbs in 159-168 patients (90%-95%), spine (scoliosis or lordosis) in 62 patients (35%), or jaw in 28 patients (16%)
  • at follow-up, patients had
    •  average SF-36 score 58.3
    •  average PASIPD score 13.5
  •  patients had mean 9 surgeries (range 0-70) at follow-up
  •  Reference – Am J Med Genet A 2017 May;173(5):1270full-text

Prevention and Screening

•  not applicable

Guidelines and Resources

Guidelines

•  American Academy of Pediatrics (AAP) guideline on prescribing therapy services for children with motor disabilities can be found in Pediatrics 2004 Jun;113(6):1836full-text, reaffirmed 2012 Jan

Review Articles

•  review can be found in Pediatr Ann 2020 Jul 1;49(7):e299
• review can be found in Front Med 2017 Mar;11(1):48
• review can be found in Foot Ankle Clin 2015 Dec;20(4):619
•  review can be found in J Pediatr Orthop 2007 Jul-Aug;27(5):594

MEDLINE Search

•  to search MEDLINE for (Arthrogryposis multiplex congenita) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

•  handout from National Center for Advancing Translational Sciences or Spanish
•  handout from National Organization for Rare Disorders
•  handout from American Association of Neuromuscular & Electrodiagnostic Medicine

References

1. Mennen U, van Heest A, Ezaki MB, Tonkin M, Gericke G. Arthrogryposis multiplex congenita. J Hand Surg [Br]. 2005 Oct;30(5):468-74.