1. NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES)
Judith G. Hall, OC, MD
The University of British Columbia and
BC Children’s Hospital
Vancouver, BC Canada
NO KNOWN CONFLICTS OF INTEREST

2. ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES)
Congenital nonprogressive limitation of movement of two or more joints in different body areas
(lots and lots of things get included)

3. NO KNOWN CONFLICTS OF INTEREST
PLAN OF TALK
Frequency of congenital contractures
Ways to approach a diagnosis
Areas of body involved
Etiologic groupings
Similarity groupings
Genes – pathways/networks
Fetal akinesia deformation sequence
Fetal movement
Prenatal diagnosis and therapy
Effects of non-movement
Challenges
NO KNOWN CONFLICTS OF INTEREST

4. CONGENITAL CONTRACTURES IN THE NEWBORN
Clubfoot…………………………… /500 – 1/1000
Congenital dislocated hips /200 – 1/500
Multiple congenital contractures…..1/3000 – 1/6000
All congenital contractures……………..1/100– 1/250

5. Arthrogryposis is not a diagnosis —it is a sign

6. FREQUENCY OF ARTHROGRYPOSIS - Many lethal types, miscarriages, stillborns
VERY heterogeneous
No proper ICD code(s)
Need population base
Australia epidemic
North America
Washington State
British Columbia registry
Others
Finland
Sweden

7. EPIDEMIOLOGY Frequency ~ 1/3000 births Prevalence ~ 1/4,000 – 6,000
Geographic
Gender
Parental Age
“Outbreaks”

8. OCCURRENCE OF ARTHROGRYPOSIS
~ 1/3000 – 5000….live births
1/3…………………Amyoplasia
1/3…………………CNS – newborn lethal
1-3…………………Heterogeneous group
of disorders

9. ARTHROGRYPOSIS STUDY GROUP
500 Insufficient data
Secondary arthrogryposis
>1500 cases Not congenital contractures
From: Shriner’s Hospitals, Portland Spokane Children’s Orthopedic Hospital, Seattle University of Washington Hospital Artrhogryposis Association Correspondence, , University of Washington

10. Ways to approach. a diagnosis – What are useful
Ways to approach a diagnosis – What are useful clinical discriminators?

11. APPROACH TO MULTIPLE CONGENITAL CONTRACTURES - CLINICAL
Mainly limbs
Limbs and other body areas
Limbs and CNS/lethal

12. AREAS OF INVOLVEMENT TOTAL STUDY GROUP
Primarily limbs
Limbs plus other body areas
Limbs plus CNS
186
53%
129
37% 35
10%
33% % %

13. Differential diagnosis of multiple congenital contractures

14. AMYOPLASIA “CLASSICAL ARTHROGRYPOSIS”
Typical symmetric positions of limbs
Usually “teratogenic” clubfoot
Absent muscles with fibrotic replacement
Mid facial hemangioma
10% abdominal structural anomaly
(vascular accident) and other vascular compromise (lost fingers or toes)
Apparent increase in one of monozygotic twins
Surprisingly good response to early physical therapy
No apparent recurrence risk or risk for other congenital anomalies

15. WAYS TO APPROACH ARTHROGRYPOSIS BY ETIOLOGIC GROUPING
Muscle
Tendon length & placement
Peripheral nerve and end plate
CNS function
Bone
Limiting space
Maternal illness, medications or trauma
Vascular disruption

16. ARTHORGRYPOSIS ETIOLOGIC GROUPING - 1
Muscle (myopathies, and distal arthrogryposes – TNNT3, TPM2, TNN12, MYH3 fast twitch muscle)
Tendon length & placement (Trismus pseudocamptodactyly) – MYH8
Peripheral nerve and end plate (Multiple Pterygium Syndrome – Escobar type and lethal) (CHRNG, CHRNA1, CHRNBi, CHRND, RAPSN and antibodies to these) – compromises of Ach receptor
CNS function (Trisomy 18)
Limiting space (Assymetric)
Vascular compromise (Amyoplasia)

17. TYPES OF MUSCLE
Striated/voluntary
Smooth
Cardiac
Mixtures

18. ARTHORGRYPOSIS ETIOLOGIC GROUPING - 2
Spinal cord – X-linked lethal – ubiquitin
Fetal akinesia deformation sequence
LCCS1 – 3, GLE1 (mRNA xport mediation), ERBB3, PIPSKIC (phosphotidyl inosotol pathway—also involved in muscle mRMA export)
Bone dysplasia (Diastrophic dysplasia)
Limiting space (Assymetric)
Maternal illness
Medication
Trauma

19. ARTHROGRYPOSIS – OBVIOUS OTHER WAYS OF GROUPING
Amyoplasia and other vascular compromise
Distal arthrogryposes
Pterygium syndromes
Bony fusions
Myopathies
Lethal SMA, X-linked lethal arthrogryposis
Lethal Pena Shokeir Phenotype (CNS structure subtypes)
COFS (Cerebro Oculo Facial syndrome)
LCCS 1-3 (Lethal Congenital Contracture syndromes)
Neu Laxova syndrome
Camptodactylies
Skeletal dysplasias
Malformations syndromes
Chromosomal abnormalities

20. CLASSIFICATION OF DISTAL AMCs
Hall Bamshad Gene
I Distal A TPM2
IIA Gordon (cleft palate, SS)
IIB Ophthalmoplegia (fine muscle)
IIC Cleft Lip (10)
IID Scoliosis + DA
IIE Trismus + Unusual Hand + DA 7B
Freeman-Sheldon Syndome MYH3
Sheldon-Hall B TNNT3, TNN12
Sheldon-Hall Look Alike 2C MYH3
Deafness + DA q25
Trismus Pseudocamptodactyly 7A MYH8
AD, Multiple Pterygium
Contractural Arachnodactyly FBN2
Absent Teeth + DA (11)
Chitayat, AR, DD (12)
X-linked (13)
Stavit, S. African, Naguib (14)
Moore-Weaver Distal (15)
MR, DD (16)

21. PTERYGIUM SYNDROMES TYPE INHERITANCE DISTINGUISHING GENE FEATURES
Popliteal pterygium AD Clefts, lip pits normal nail IRF6
Antecubital pterygium AD Only elbows involved
Mutiple pterygium (Escobar type) AR Cervical vertebral anomalies, CHRNG
hands involved, chin sternum pterygium, facies
Lethal mutliple AR Extensive contractures, hypertelorism, pterygium CHRNG, chin-sternum pterygium, CHRNA1, small chest CHRNB1, RAPSN
Lethal popliteal pterygium AR Facial cleft, syndactyly IRF6
(Bartoscas Papas) (hands and feet),
genital anomaly
Pterygium and ectodermal AR Fine sparse hair, nail anomalies dysplasia (hands and feet)
Pterygium and malignant hyperthermia AR Torticolis, scoliosis, MH ?RYR1

22. GENES IDENTIFIED AMONG THE ARTHROGRYPOSES

23. FETAL AKINESIA DEFORMATION SEQUENCE PENA SHOKIER PHENOTYPE
Intrauterine growth retardation
Congenital contractures of the limbs
Hypoplastic lungs
Short umbilical cord
Polyhydramnios – short gut
Craniofacial anomalies
Micrognathia +/- small mouth
+/- cleft palate
High bridge of nose
Depressed tip of nose

24. Lack of normal mechanical forces may lead to secondary deformations
“Use” is essential for normal development

25. LIMITATION OF FETAL JOINT MOBILITY MULTIPLE CONGENITAL CONTRACTURES
Maternal Connective tissue illness skeletal dysplasia
Fetal Vascular
crowding compromise
Neurologic Muscle
deficits defects
LIMITATION OF FETAL JOINT MOBILITY
MULTIPLE CONGENITAL CONTRACTURES
(ARTHROGRYPOSIS)

26. HUMAN FETAL LIMB MOVEMENT
Starts 8 weeks, proximal limbs 9 weeks, distal 10 weeks
Requires intact neuromuscular unit
Maternal injury and CVS/early amniocentesis allow timing of limb involvement

27. EMBRYONIC LIMB DEVELOPMENT
Cranial caudal progression
Upper limbs before lower
Right side before left
Vascular supply to CNS shifting

28. EMBRYONIC/FETAL MOVEMENT
Week
4 Heart beating begins
5-6 Head and trunk “stirs”
7 Shoulders “shrug”
8 Rhythmic “breathing” begins even though larynx not open
Jaw starts to move
9 Upper arms moving
10 Hips, lower arms moving
11 Lower limbs kicking
12 Hands open and ankles moving into correct position

29. PRENATAL DIAGNOSIS BY ULTRASOUND (WHAT ARE THE CLUES, WHAT TO LOOK FOR)
Usually not picked up without long careful real time US study – 45 min – 1 hr
Nuchal edema
Thin undercalcified bones
 Movement may start any time from 11 weeks to 34 weeks
Small lungs
Diaphragm defect or decreased movements
Other structure or space constraints (amniotic bands, uterine fibroid, amount of amniotic fluid)

30. As organs begin to function. muscles begin to contract
As organs begin to function muscles begin to contract stretching developing tissues from inside and outside

31. PREGNANCY HISTORIES 828 cases of all types All Amyoplasia Background
Decreased movement
50%
29% 3%
Maternal illness 8%
15% 7%
Maternal medications 5%
10%
3 – 10%
Maternal bleeding
7.4%
Uterine anomaly
2.3% 2%
2 – 3%
Polyhydramnios
6.6%
0.5 – 2%
Oligohydramnios
3.3%
<1%

32. DELIVERIES AT 39 WEEKS Cephalic 60% Breech 37% Transverse 3%
C-section 45%
Fractures 10% - 20%
Birth weight 30th centile

33. Is intrauterine therapy possible?
- “Physical Therapy in utero”-

34. DEPENDS ON Functional CNS Intact end plate Functional muscles
Space to move

35. IN UTERO THERAPY Fetal movement relates to maternal movement
- Exercise
- Deep breathing
- Caffeine
Early delivery if lungs mature

36. FETAL MOVEMENT Essential for normal development of limbs
Mechanical transduction of cells
Lack of movement leads to fetal akinesia deformation sequence
Maternal activity may affect outcome
Grace period of 3 – 4 months

37. CATCH-UP (3 – 4 MONTH WINDOW AFTER BIRTH)
Lung - avelolar growth
Gut - motility and absorption
Joints - loosening of contractures
Muscle - use reverses atrophy
Growth - bone mineralization, increase in length

38. LACK OF MECHANICAL FORCES LEADS TO DEFORMATION
“Use” is essential for normal development
Disuse leads to
Muscle atrophy
Increased connective tissue
Abnormal non-functional positions
Changes in joint surface

39. SECONDARY EFFECTS FROM LACK OF MOVEMENT IN UTERO
IUGR – limbs are short
Contractures with “collagenosis”, extra connective tissue, thick capsule
Abnormal relationship of limb to weight bearing – joints at odd angles
Muscle – disuse atrophy, decreased mass
Dimples – attached to overlying skin
Other changes of FADS – lungs, gut, craniofacial, etc.

40. EFFECTS OF FADS ON
On musculoskeletal system
On lungs
On gut
On growth
On development of motor skills

41. GROWTH AMC affected limbs - short and small
Final height ~ 5th centile for family
Less muscle and less calcification of bone means less weight
Avoid obesity – makes for more work
Some limbs grow even less normally (like post-polio)

42. CHALLENGES – Not miss opportunities Stretching, weight bearing
Avoid muscle atrophy, night splints
Prevention
I°, II°, III°
Prenatal therapy
Avoid scarring
Not harm joint cartilage
Not allow atrophy of what is there
Keep from returning to “in utero position”
Intercede along mechanistic pathways
Cytokines, alternative metabolic pathways, fetal effects
Multi-system considerations
Enormous heterogeneity
But commonalities as well

43. FAMILY’S JOB Ask questions Take photographs Make a notebook
Keep records

44. DOCUMENTATION Photographs and videos Notebook Changes over time
New observations

45. AREA OF INVOLVEMENT RECURRENCE RISK
Primarily limbs
Limbs plus other areas
Limbs plus CNS
Total
Estimated RR for overall group
Parents: 4.0%
Self: 6.5%
10.8%
10.4%
5.7%
6.8%
Estimated RR when knowns excluded
Parents: 4.7%
1.4% 7% 3%

46. If and only if a specific. diagnosis cannot be made
If and only if a specific diagnosis cannot be made should a 5% recurrence
risk estimation be given

47. Prognosis depends on the. specific diagnosis and the
Prognosis depends on the specific diagnosis and the natural history of that disorder

48. WEB ADDRESS FOR THE BOOK
books/help_arthrogryposis.pdf

49. LAY GROUPS AROUND THE WORLD
Australia:
Germany, Austria & Switzerland:
Sweden:
UK:

50. REFERENCES
Staheli LT, Hall JG, Jaffe KM, Paholke DO. Arthrogryposis: A text atlas. Cambridge University Press; Cambridge, UK, 1998.
Hall, JG. Arthrogryposes (Multiple congenital contractures). In: Emery and Rimoin’s principle and practice of medical genetics. Vol 3, 5th edition. Eds. Rimoin, DL, Connor JM, Pyeritz RE, Kork BR. Churchill Livingstone: New York, Chapter 168, p , 2007.
Hall JG, Vincent A. Arthrogryposis. In: Neuromuscular diseases of infancy, childhood, adolescence – a clinician’s approach. Eds H Jones, DC De Vivo, BT Darris. Butterworth: Boston, Chapter 7, p. 123 – 141,
Hall JG. Arthrogryposis. In: Management of genetic syndromes, 2nd ed. Eds. Cassidy SB, Allanson JE. Wiley- Liss: Hoboken, NJ, Chapter 7, p. 63 – 86, 2005.

51. REFERENCES
Makela-Bengs P, Jarvinen N, Vuopala K, et al. Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals. Am J Hum Genet 63: , 1998.
Michalk A, Stricker S, Becker J, et al. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 82: , 2008.
Narkis G, Ofir R, Landau D, et al. Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKIү of the phosphatidylinsitol pathway. Am J Hum Genet 81: , 2007.
Narkis G, Ofir R, Manor E, et al. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet 81: , 2007.
Nousianen HO, Kestila M, Pakkasjarvi N et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40: , 2008.

52. REFERENCES
Prontera P, Vogt J, McKeown, et al. Familial multiple pterygium syndrome (MPS) is not associated with CHRNG gene mutation. Am J Med Genet 143A:1129,
Ramser J, Ahearn ME, Lenski C, et al. Rare Missense and synonymous variants in UBE1 are associated with X- linked infantile spinal muscular atrophy. Am J Hum Genet 82: , 2008.
Vogt J, Harrison BJ, Spearman H, et al. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet 82:
Watanabe M, Kobayashi K, Kin F, et al. Founder SVA Retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and northeast Asian populations. Am J Med Genet 138A: , 2005.
Zhou H, Brockington M, Jungbluth H, et al. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet 79: , 2006.