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CONTRACTURES & OTHER JOINT DISORDERS

Contractures with myopathy or other neuromuscular disease

Emery-Dreifuss Muscular Dystrophy ²

EMD1: Emerin; Xq28; Recessive EMD2: Lamin A/C; 1q21.2; Dominant EMD3: SYNE1; 6q25; Dominant EMD4: SYNE2; 14q23; Dominant Other: Sporadic & Dominant

from A Kornberg MD

• Emerin gene
  • 6 exons
  • Immediately distal to filamin gene
  • Emerin & filamin genes surrounded by 11 kb inverted repeats
• EDMD Genetic features: Mutations in emerin gene of varied types
  • > 70 different: Unique in each family
  • Types
    • Most common: Point mutations (49%), or small deletions (33%)/ insertions (10%)
      • Small mutations usually result in stop codons
      • Missense mutations rare: Pro183His & Pro183Thr; Q133H; Del236-241; Del95-99
        • Weakened interactions of emerin with nuclear lamina components or membrane
        • Emerin protein in tissues
          • Normal or moderately reduced total amounts in tissues
          • Levels in nucleus reduced: Q133H; Del236-241; Del95-99
        • Later onset contractures & weakness; Same onset cardiac change
          • Pro183His & Pro183Thr
    • Occasional
      • Mutations in start codons: ? Prevent initiation of translation
      • Deletion in promoter: ? Emerin selectively reduced in muscle
      • In-frame deletions: 878 del 15; 1763 del 18
        • Emerin expressed at low, variable level
        • Phenotype: Typical EDMD
      • Mutations in last exon
        • Emerin lacks C-terminal containing transmembrane domain
        • Emerin absent: Even when deletion is in-frame
      • Transpositions
      • Small deletion: Chimeric emerin protein with reduced levels in nuclear membrane
      • Large deletions of whole gene
        • Whole gene deletions related to mispairing of flanking repeat sequences
      • Skewed X-inactivation
  • Mutation Database: HGMD
• Emerin protein⁵
  • 34 kD; Serine rich
  • Protein Family
    • Membrane proteins that interaqct with lamins or chromatin
    • Other family members: Lamina-associated (LAP1; LAP2); MAN1; Lamin B receptor
  • Sub-cellular distribution
    • Nuclear
      • Emerin is attached to
        • Inner nuclear membrane via C-terminus region (hydrophobic)
        • Nuclear lamina
      • Most of protein projects into nucleoplasm
    • Cytoplasm membranes
      • Associated with cadherins & vinculin
  • Tissue distribution
    • Muscle & Nerve
    • Mucosal epithlium & Skin
    • Cardiac: ?? Intercalated discs (focal adhesions), Desmosomes & fasciae adherentes
  • Other properties
    • Emerin contains multiple nuclear-membrane-targeting determinants
    • Emerin Interactions
      • A- & B-type lamins: Lamin A binding region is amino acids 70 to 164
      • Nuclear actin
    • Synthesis pathways
      • Newly synthesized emerin is inserted into endoplasmic reticulum via hydrophobic tail
      • Diffuses freely until trapped at nuclear rim: ? By interactions with chromatin & nuclear lamina
  • Homologies
    • 2 regions with similarities to thymopoetins
    • 1 region with APC tumor suppressor gene
  • Phosphorylated: 36 kD when highly phosphorylated
  • Mutations predict
    • Usually absent emerin protein
    • Rarely reduced, but present, emerin
  • Disease pathogenesis: Disorder of nuclear proteins
    • Lamin A/C–emerin complex
    • Members of large nuclear complex: Chromatin, Lamina, Membrane & associated nuclear rim proteins
• Clinical Features
  • Clinical-Genetic
    • Variation: Prominent inter- & intrafamilial, even with same mutation
    • No clear difference in families between mutation types
    • Skewed X-inactivation may produce
      • Pseudo-dominant inheritance
      • Females with typical EDMD phenotype
    • Occasional sporadic patients have emerin deficiency
  • Onset: Contractures & Weakness
    • Age: Neonatal hypotonia to 3rd decade; Mean in teens
    • Function: Difficulty walking or climbing stairs
    • Contractures before weakness
  • Weakness: Humeroperoneal
    • Bilateral
    • Symmetrical
    • Arms: Biceps & triceps; Deltoids spared
    • Scapular winging
    • Legs: Late
    • Face: Mild weakness or normal
  • Wasting: Biceps & triceps; Later Calf
  • Contractures: Often more limiting to function than weakness
    • Elbow
    • Spine
      • Posterior neck (extension)
      • Lower back: Usually later onset, but may present with rigid spine syndrome
      • Back pain
    • Ankle: Gait limitation
    • Progression: Slow; Loss of ambulation rare
  • Cardiac Disease
    • Frequency: Almost invariable
    • Onset
      • Early 2nd decade to 40's
      • Usually after some weakness or contractures
      • Occasional presenting feature in 1st decade: Associated with high CK⁶
    • Progression
      • Syncope: Onset late 2nd & early 3rd decade
      • Usually require pacing by age 30
      • Severe: Emboli; Sudden death
    • Bradycardia
    • Atrial rhythm disturbances & paralysis; A-V conduction defects
    • Late: ± Left ventricular myocardial dysfunction (fibrosis)
    • EKG changes
      • Slow heart rate
      • P waves: Absent or Small
      • Rhythms: Regular nodal or Atrial fibrillation/flutter
    • Treatment: Pacemaker when rate < 50
    • Female carriers: 10% to 20% have
      • Conduction defects & arrhythmias: Monitor with annual EKG's
      • Weakness
• Laboratory
  • Serum CK: Mildly elevated to < 10x normal; Reduction in levels with age
  • EMG: Predominantly myopathic; Occasional fibrillations & high amplitude potentials
  • MRI of posterior calf: Soleus involved, Gastrocnemius relatively spared⁷
• Muscle Pathology: Muscle & Other
  • Myopathic
    • Muscle fiber size: Variable
    • Endomysial fibrosis
  • Fiber type disorders
    • Type I fiber atrophy
    • Type I or II predominance
  • Nuclear pathology¹⁴
    • Breakdown of nuclear membrane
    • Nucleoplasm extrusion
  • Other muscle changes in some patients: "IBM-like"¹³
    • Rimmed vacuoles
    • Inflammation
    • Nuclear tubulofilamentous inclusions
  • Emerin absent in nuclei
    • Emerin loss in muscle in > 95% of patients
    • Skin or leukocytes
      • Emerin often lost
      • Residual or normal emerin with some missense or promoter mutations
  • Ultrastructure: Nuclei
    • Detachment of nuclear membrane & lamina
    • Detachment of heterochromatin from nuclear rim

• Genetic: Lamin A/C Mutations⁴
  • Mutation types: Nonsense & Missense
  • Locations in gene: N-terminal head; Rod (Most common); Globular tail
  • Common dominant EMD2 lamin A/C mutation locations
    • Missense in hydrophobic C-terminal region: R453W; I469T R527P; L530P
    • Alter both Lamin A & C
  • Other dominant EMD2 Lamin A/C Mutations
    • 2A rod domain: R249Q
    • Atypical mutation
      • Causes early stop codon after 6 amino acids (E6Ter)
      • EDMD phenotype caused by absence of 1 allele
    • Trp520Ser: Adds potential new glycosylation site
  • Recessive (or Sporadic) EMD2 Lamin A/C Mutations
    • EMD2 syndrome: R249Q; E358K; R453W; R527P; T528K; R624H
    • No cardiac pathology: H222Y; R336Q; R453W
    • Mostly in males
  • Neuromuscular syndromes: Genotype-Phenotype correlations
    • Missense mutations
      • Onset: Childhood; Mean 2.4 years
      • Weakness: Scapuloperoneal & Facial; Paravertebral weakness or rigidity
      • Tendon contractures (70%)
      • EMG: Myopathy + Distal denervation
      • Mechanism: Dominant negative or Toxic gain of function
    • Frameshift mutations (? Truncated protein)
      • Onset
        • Age: Adult; Mean 30.5 years; Range
        • Cardiomyopathy more frequent than Weakness
      • Cardiac disorders: Common at onset
      • Weakness: Limb girdle distribution; Paravertebral
      \
      • No tendon contractures
      • EMG: Myopathy + Distal denervation
      • Mechanism: Haploinsufficiency
  • Other syndromes with lamin A/C mutations
    • Cardiac
      • Mutations in rod domain: Autosomal dominant dilated cardiomyopathy with A-V block (CMD1A)
      • Atrial fibrillation: Early onset; Missense (E161K) mutation¹⁰
    • Myopathy
      • EMD2
      • LGMD 1B
      • Quadriceps myopathy with dilated cardiomyopathy: Missense (R377H) mutation
      • Congenital myopathy with rigid spine
    • Neuropathy: AR-CMT2A
    • Familial partial lipodystrophy (Köbberling-Dunnigan Syndrome): Mutations in globular C-terminal domain
    • Mandibuloacral dysplasia :
      • Mutation: R527H (C-terminal domain), Recessive
      • May be associated with partial lipodystrophy
    • Premature aging
      • Hutchinson–Gilford progeria : Recessive; Abnormal nuclear architecture
      • Werner’s syndrome, atypical : Dominant; More severe
  • Lamin A/C null mouse
    • Muscular dystrophy: Onset soon after birth
    • Cardiomyopathy
    • Nucleus
      • Ultrastructural pathology
      • Mislocalization of emerin
• Lamin A/C proteins ⁵
  • Products of alternate splicing of 3' end of same gene; Lamin A longer
  • Protein type: Nuclear lamina protein; Intermediate filament family
  • Subcellular location: Inner nuclear membrane
  • Structure: Similar to other IF proteins
  • Central α-helical rod domain flanked by
  • Non-α-helical head
  • Globular carboxy-terminal tail domain
  • Expression
    • Onset: Late in embryonic development
    • Location: All somatic tissues except erythrocytes
  • Functions
    • Provides framework for nuclear envelope
    • May interact with chromatin
  • Protein associations
    • Lamina-associated protein 1 (LAP1)
    • Emerin
    • Formation of nuclear lamina: Lamins assemble into filaments
      • Lamin B1 assembles first, then lamin A & finally lamin C
      • The lamina extends throughout the nuclear interior
        • Partly as invaginations of the nuclear membrane
        • Also as a matrix component
    • Sun-1
    • Sun-2
  • Phosphorylation
    • Mitosis: Phosphorylation of lamins increases before nuclear envelope disintegration
    • Down regulates lamin associations with other proteins
• Clinical features³
  

  From: A Kornberg Emery-Dreifuss: Rigid spine

  • Onset
    • Most common: 1st or 2nd decade
    • Early features
      • Some weakness may be detectable in many between 3 to 6 years
      • Occasional patients as early as 2nd year
    • Clinical features
      • Scapuloperoneal weakness
      • Contractures
  • Variable penetrance of same mutation
    • Similar to emerin mutations in some patients
    • Other patients with mutations but no clinical manifestation
  • Weakness
    • Proximal ± Distal leg
    • Humeroperoneal: More severe weakness in biceps brachii than EMD1
    • Bilateral
    • Symmetrical
    • Calf wasting
    • Progression
      • Slow to moderate
      • Some patients with loss of ambulation by 8 to 13 years
  • Contractures
    • Usual onset 2nd decade
    • Locations
      • Upper extremity: Elbows
      • Trunk: Back (Rigid spine); Neck
      • Lower extremity: Ankles; Knee
  • Cardiac
    • Onset
      • Age: 2nd to 4th decade
      • Later in patients with frameshift mutations
    • Conduction defect
    • Arrhythmias: Brady or Tachy
    • Cardiomyopathy: Dilated or Restrictive
    • Often require pacing or heart transplant
    • Comparison to emerin (EMD1) mutations
      • Isolated cardiac involvement more frequent
      • Ventricular fibrillation more common
      • Dilated cardiomyopathy more common
• Homozygous mutation: Severe phenotype
  • Fetal akinesia
  • Multiple joint contractures
  • Lung hypoplasia
  • Muscle: Severe dystrophy with fibrosis; Especially severe in diaphragm
• Laboratory
  • Serum CK: Normal or mildly elevated to 1,500
  • Electromyography: Myopathic
  • Muscle pathology
    • Myopathic (Dystrophic)
    • Nuclear¹⁴
      • Chromatin reorganization
      • Loss of nucleoplasm volume
      • H222P mutation in mouse model: Increased intranuclear SMAD
  • MRI⁷: T1W sequences
    • Posterior calf: Medial head of gastrocnemius involved, lateral head spared
    • Soleus: Spared in patients < 20 years or with milder phenotype
    • Thigh: Involvement correlates with clinical severity

• Epidemiology: 3 patients in 3 families
• Genetics
  • Mutations
    • Location: Nesprin-1α
    • Type: Missense; R257H, E646K
  • Combined mutations in SYNE1 & SYNE2: More severe phenotype
• Proteins: Nesprin-1
  • Spectrin-repeat
  • Multiple isoforms: Vary greatly in size
  • Localization: Nuclear membrane & other subcellular regions
  • Bind actin
  • Inner nuclear membrane isoforms
    • Highly expressed in muscle & heart
    • Bind lamin A & emerin
    • Link nucleoskeleton & INM to Outer nuclear membrane (ONM) & cytoskeleton
      • Form a bridging LINC complex with SUN1 and SUN2
      • Location of LINC complex: Across luminal space between the inner & outer nuclear membranes
  • Muscle specific isoform: Nesprin-1α₁
• Clinical
  • Onset: 11 years or Asymptomatic (E646K mutation)
  • Weakness
    • Shoulder girdle
    • Preogressive
    • Severe patient: Wheelchair at 26 years
  • Contractures: Limbs; Progressive
  • Cardiac involvement: No clinical changes
• Laboratory
  • Electromyography: Myopathic
  • Histopathology:
    • Muscular dystrophy
    • Normal dystrophin staining
  • Creatinine kinase (serum): Mildly elevated
  • ECG monitoring and echocardiography: Normal or mild changes

• Epidemiology: 2 patients in 2 families
• Genetics
  • Mutations
    • Location: Nesprin-2β
    • Type: Missense; T89M
  • Combined mutations in SYNE1 & SYNE2: More severe phenotype
• Proteins: Nesprin-2
  • Spectrin-repeat
  • Multiple isoforms: Vary greatly in size
  • Localization: Nuclear membrane & other subcellular regions
  • Bind actin
  • Inner nuclear membrane isoforms
    • Highly expressed in muscle & heart
    • Bind lamin A & emerin
    • Link nucleoskeleton & INM to Outer nuclear membrane (ONM) & cytoskeleton
      • Form a bridging LINC complex with SUN1 and SUN2
      • Location of LINC complex: Across luminal space between the inner & outer nuclear membranes
  • Muscle specific isoform: Nesprin-2α₁
• Clinical
  • Weakness
    • Onset: Childhood to 4th decade
    • Symmetric
    • Scapular winging: Variable
    • Respiratory insufficiency: Minor
    • Ptosis: 1 patient
  • Cardiomyopathy
• Laboratory
  • Serum CK: Elevated 2 to 14 fold
  • Muscle pathology
    • Internal nuclei
    • Muscle fiber size: Varied
    • Fat deposition
    • Subsarcolemmal metachromasia
    • Normal emerin, lamin A/C, sarcoglycan, desmin, emerin & caveolin staining

Arthrogryposis multiplex congenita (AMC)

• Distal Arthrogryposis, type IA (DA 1A)
  l Tropomyosin 2 (TPM2) ; Chromosome 9p21-q21; Dominant
  • Mutation⁸
    • Missense: Arg91Gly
    • Other DA 1A families with no mutations in TPM2
    • TPM2 mutations may also cause: Rod myopathy
  • Tropomyosin 2 protein: Present in fast skeletal muscle fibers
  • Clinical features
    • Flexion contractures at birth
    • Predominant involvement of hands & feet
      • Hands: Tight fist with medial overlapping of fingers & adducted thumb
        
      • Feet: Equinovarus
    • Face: Not usually involved
    • Normal: Intelligence; Neurologic exam
    • Marked intrafamilial variation
    • Good response to physical therapy
      • Adults with residual overlapping of toes & absent distal interphalangeal creases
  • Laboratory: Some patients with high serum CK
  • Muscle pathology: No rods
  
  
• Distal Arthrogryposis, type 2 (Freeman-Sheldon syndrome) (DA2A)
  l MYH3 ; Chromosome 17p13.1; Dominant
  • Genetics
    • Mostly missense mutations
    • Common mutations: R672H; R672C; T178I
  • Other myosin disorders
  • Clinical features
    • Mouth: Small; Pursed lips; Paramedian grooves between lower lip & tip of chin
    • Palpebral fissures: Down slanting
    • Face (Whistling): Hypoplastic alae nasi; Prominent nasolabial folds; Long philtrum
    • Cervical pterygia: Mild
    • Scoliosis
    • CNS
      • Dominant forms: Normal intelligence
      • Recessive forms: Some with developmental retardation
      
      
• Distal Arthrogryposis, type 2B (Freeman-Sheldon variant) (DA2B)
  l Troponin I, Fast-twitch skeletal muscle (TNNI2) ; Chromosome 11p15.5; Dominant
  l Troponin T, Fast-twitch skeletal muscle (TNNT3) ; Chromosome 11p15.5; Dominant
  l MYH3 ; Chromosome 17p13.1; Dominant
  l Other genes: Many unidentified
  • TNNI2⁸
    • TNNI2 mutations
      • Locations: Missense Arg174Glu; Nonsense C-T466
      • Predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI)
      • Drosophila TNNI2 mutants
        • Hypercontracted intercostal flight muscles (IFM)
        • Protracted elevation of the wings
        • Reduced frequency of wing beats
        • Awkward, irregular gait
    • TNNI2 protein
      • Specific to troponin-tropomyosin (Tc-Tm) complex of fast-twitch muscle fibers
  • TNNT3⁹
    • TNNT3 mutation: Missense; Arg63His
    • TNNT3 protein: Binds actin & β-tropomyosin
  • Clinical features
    • Face: Triangular; Small mouth; Prominent nasolabial folds
    • Palpebral fissures: Down slanting
    • Attached earlobes; Cervical webbing
    • Camptodactyly; Ulnar deviation; Positional foot deformities
    • Scoliosis
    • Vertical talus
      
      
• Distal Arthrogryposis, type 3 (Gordon syndrome) (DA3)
  l Autosomal Dominant
  
  • Clinical features
    • Camptodactyly
    • Club feet
    • Short stature
    • Ptosis
    • Vertebral abnormalities
    • Pterygium colli
    • ± Cleft palate
      
      
• Distal Arthrogryposis with scoliosis (DA4)
  l Autosomal Dominant
  • Clinical features
    • Short stature
    • Short neck
    • Ptosis
    • Immobile facial expression
    • Camptodactyly with absent flexion creases on hands
      
      
• Arthrogryposis with oculomotor limitation & electroretinal abnormalities (DA 5)
  l Autosomal Dominant
  
  • Clinical features¹²
    • Contractures
      • Limb: Hands; Elbows (Supination); Feet (50%)
      • Trunk: Rigid spine; Restricted pulmonary function (Adults); Scoliosis (25%)
      • Shoulders: Hunched
      • Course: Improvement with age
    • Face
      • Limited expression
      • Mouth: Narrow; Horizontal
    • Ocular
      • Movement limitation
        • Restrictive
        • All muscles
      • Ptosis: Occasional
      • Macula: Pigmentation; Retinal folds
      • Optic nervehead: Dysplastic
      • Malformations
        • Epicanthal folds
        • Keratoglobus
        • Corneal leukoma & high astigmatism
      • Deep set eyes
    • Limb muscles: Aplasia (Decreased mass)
    • Pyloric stenosis: Hypertrophic
      
      
  • Laboratory
    • Serum CK: Normal
    • NCV & EMG: Normal
    • Muscle pathology: Normal
    
    
• Distal arthrogryposis with sensorineural hearing loss (DA6)
  l Autosomal Dominant
  • Clinical features
    • Sensorineural hearing loss
    • Camptodactyly
    • Microcephaly
      
      
• Distal arthrogryposis with trismus pseudo-camptodactyly (DA7)
  l Autosomal Dominant
  • Clinical features
    • Camptodactyly of digits on hand dorsiflexion
    • Trismus: Inability to open mouth completely
    • Short stature
    • Short leg muscles
      
      
• Multiple pterygium syndromes (DA8)
  l Autosomal Dominant
  • Clinical features
    • Distal limb contractures
    • Multiple pterygia: Including neck
    • Facial anomalies; Ptosis
    • Short stature
    • Spine: Scoliosis; Hemivertebrae
    • Muscle: Atrophy
  
  l X-linked
  
  
• Multiple pterygium syndrome (Escobar syndrome )¹⁵
  l Cholinergic receptor, nicotinic, gamma (γ) polypeptide (CHRNG); Chromosome 2q33-q34; Recessive
  l Cholinergic receptor, nicotinic, alpha 1 (α1) polypeptide (CHRNA1); Chromosome 2q24-q32; Recessive
  l Cholinergic receptor, nicotinic, delta (δ) polypeptide (CHRND); Chromosome 2q33-q34; Recessive
  
  • Epidemiology
    • Geography: Arab, Pakistani, Turkish & Caucasian families
    • Many consanguinous families
  • Genetics
    • Mutations: Truncating
      • Nonsense, splice site or frameshift
  • Mutation effects on AChR proteins & subunits
    • Fetal: AChR subunits present intracellular but not on cell surface
    • Normal expression of adult AChRs
  • Clinical
    • Onset
      • Age: Congenital
      • Decreased movements
      • Facial weakness
      • Respiratory insufficiency
    • Pterygia: Elbows, Axillae, Poplitea, Thumb, Neck
    • Contractures: Congenital
    • Face & Palate
      • Dysmorphic
      • Cleft palate
    • Pulmonary hypoplasia: Bilateral
    • Cardiac: Small heart
    • GI: Absene appendix; Attenuation of ascending and transverse colon
    • Skeletal
      • Vertebrae: Cervical (Klippel-Feil syndrome) or thoracic fusion
      • Kyphoscoliosis
      • Arachnodactyly
      • Short stature
      • Rocker-bottom feet
    • Muscle
      • Strength: Normal after neonatal period
      • Bulk: Normal
    • Disease course
      • Variable among families
      • Survival: Stillborn to adulthood
  • Laboratory
    • Repetitive nerve stimulation: Normal
    • Muscle histopathology: Denervation-like changes
      • Type I muscle fibers: Predominance; Small
      • Fiber-type grouping
      • Fat infiltration
  • Analogous human immune disorder
    • Recurrent congenital arthrogryposis
  • Variant syndrome: Fetal hypokinesia with inborn contractures (arthrogryposis)
    • Mutated subunits: CHRNA1; CHRND; RAPSN
    • Mutations: Missense or Stop
  • Mouse model
    • γ-AChR subunit inactivation: Lethal
  
  
• Congenital contractural arachnodactyly (DA 9)
  l Fibrillin-2 ; Chromosome 5q23-q31; Dominant
  • Clinical features
    • Marfanoid habitus
    • Kyphoscoliosis: Severe
    • Osteopenia: Generalized
    • Contractures: Proximal involvement more common; Flexion of fingers
    • Ears: Crumpled
    • Cardiac: Aortic and valvular
    • Muscular hypoplasia
  
  
• Distal arthrogryposis with cardiac myxomas¹¹
  l Myosin, heavy chain 8, Skeletal muscle, perinatal (MYH8) ; Chromosome 17p13.1; Dominant
  • Mutation: Missense; Arg674Gln
  • Clinical features
    • Trismus: Inability to open the mouth fully
    • Pseudocamptodactyly
      • Shortened flexor muscle-tendon units;
      • Wrist dorsiflexion produces flexion of distal and proximal interphalangeal joints
      • Foot contractures
    • Carney complex : Some families
      • Cardiac myxomas
      • Spotty skin pigmentation
  
  
• Distal arthrogryposis with plantar flexion contractures¹⁶
  l Dominant
  • Epidemiology: Utah family
  • Onset: Childhood; Time of ambulation
  • Clinical
    • Contractures
      • Plantar feet: Flexion; Surgical treatment
      • Other (Milder): Elbows, Fingers, Wrists (Reduced extension & supination)
    • Gait: Toe walking
  • Laboratory
    • Serum CK: Normal
    • EKG: Normal
  
  
• Cerebrooculofacioskeletal syndrome
  l ERCC6 ; Chromosome 10q11; Recessive
  • Genetics
    • ERCC6: Same gene as Cockayne syndrome, Type B
  • Clinical features
    • Microcephaly,
    • Hypotonia
    • Face: Eye defects; Large nose & ears; Overhanging upper lip; Micrognathia
    • Trunk: Widely set nipples; Kyphoscoliosis
    • Osteoporosis
    • Arthrogryposis
  
  
• Adducted thumb-Club foot syndrome
  l Recessive
  • CNS: Psychomotor delay
  • Eye: Anterior chamber abnormality
  • Face: Broad, bossed forehead; Telecanthus; Downturned mouth
  • Skeletal: Arachnodactyly; Distal arthrogryposis; Adducted thumbs & clubfeet
  
  
• Saethre-Chotzen syndrome
  l TWIST ; Chromosome 7p21; Dominant
  • Face: Flat; Long nose; Hypertelorism; Plagiocephaly; Long and prominent ear crus
  • Eyes: Strabismus; Hydrophthalmos
  • Skull: Craniosynostosis; Acrocephaly; Cranial asymmetry
  • Limbs: Syndactyly; Bifid terminal phalanges (2 & 3); Absent first metatarsal
  • Cardiac: Congenital heart defect
  • Joints: Contractures of elbows and knees
  
  
• Arthropathy-camptodactyly-pericarditis syndrome
  l Proteoglycan 4 (Megakaryocyte-stimulating factor) ; Chromosome 1q25-q31; Recessive
  • Joints
    • Arthropathy
    • Generalized morning stiffness
    • Large joint arthritis: Polyarticular
    • Contractures
      • Finger flexion contractures: Congenital or childhood onset
      • Elbow & wrist
    • Synovial hypertrophy
  • Coxa vara
  • Constrictive pericarditis
  
  
• X-linked arthrogryposis
  • Infantile Spinal Muscular Atrophy with Arthrogryposis: Xp11.3-q11.2
  • AMCX5 : Xq23-q27
    • Mild
    • Only in lower extremities
  • Other
  
  
• Neurogenic
  • 5q-linked Congenital Spinal muscular atrophy
  • X-linked Infantile Spinal Muscular Atrophy
  • Benign congential spinal muscular atrophy with contractures
    l Dominant
    • Selectively involves lower extremities
    • Non-progressive
  • Arthrogryposis: Neurogenic, Mild
    l Chromosome 5q35; Recessive
    • Epidemiology
      • Israeli-Arab family
      • Male/Female 2:1: ? Incomplete penetrance in females
    • Onset: Birth
    • Flexion contractures: Elbows & Knees
    • Equinovarus: Marked
    • Weakness: Around involved joints
  
  
• "Amyoplasia" syndrome
  • Sporadic
  • Contractures: Symmetric
    • Shoulders: Internal rotation
    • Elbows: Extended
    • Wrists: Flexed
    • Knees: Flexed or extended
    • Feet: Equinovarus
  • Forehead: Hemangioma
  • IQ: Normal
  
  
• Lethal congenital contracture syndromes
  • General
    • All genes implicated in LCCS syndromes linked to InsP₆-Gle1–mediated mRNA export pathway
  • LCCS1 with anterior horn cell degeneration
    l GLE1 ; Chromosome 9q34; Recessive
    
    • Epidemiology
      • Finnish families
      • Carrier frequency: Finland 1%; Northeastern Finland 2%
    • Mutation
      • Homozygous: c.432-10A4G; Located within intron 3
      • Most Finnish patients with same mutation
      • Effect of mutation: Insertion of 3 amino acids (Pro, Phe, Glu) into predicted coiled-coil domain
    • GLE1 protein: mRNA export mediator
      • Function: Export of mRNAs from nucleus to cytoplasm
      • Expression: High in ventral spinal cord cell population
      • GLE1 binds to inositol hexakisphosphate (InsP₆)
    • Clinical
      • Immobility of the fetus at all ultrasound examinations,
      • Multiple joint contractures: Upper & lower limbs
      • Hydrops
      • Fetal death: Before 32 weeks of pregnancy
    • Pathology
      • Anterior horn motor neurons: Degeneration
      • Ventral spinal cord: Atrophy & Hypoplastic
      • Skeletal muscles: Nearly absent
    • Variant syndrome: Lethal arthrogryposis with anterior horn cell disease (LAAHD)
      • Fetal akinesia
      • Arthrogryposis
      • Fetuses often survive delivery
      • Death: Early due to respiratory failure
      • Pathology: Motor neuron loss
    
    
  • LCCS2 ¹⁸
    l ERBB3 (Her3) ; Chromosome 12q13; Recessive
    • Epidemiology: Israeli-Bedouin kindreds
    • Mutation: Truncation
    • ERBB3 function
      • Epidermal growth factor (EGF) receptor
      • Modulator of Phosphatidylinositol-3-Kinase/Akt Pathway
      • Null mouse mutant: Death of sensory ganglion cells & motor neurons
    • Clinical
      • Joint contractures: Multiple
      • Urinary bladder: Markedly distended
      • Spinal cord: Anterior horn atrophy
    
    
  • LCCS3¹⁹
    l PIP5K1C ; Chromosome 19p13; Recessive
    • Epidemiology: Israeli-Bedouin family
    • Mutation: Missense; D253N
    • PIPKIγ protein
      • Function: Phosphatidylinositol pathway; Synthesis of PIP₂
      • Mutation: Abrogates kinase activity
      • Knockout mouse: Lethal; Abnormal synaptic vesicle cycle
    • Clinical: Multiple contractures
  
  
• Other: Recessive
  • Spondylospinal Thoracic dysostosis
  • Jarcho-Levin Syndrome
  • Prenatal growth retardation; Pelvic hypoplasia; Arthrogryposis in lower limbs