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NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES) Judith G. Hall, OC, MD The University of British Columbia and BC Childrens Hospital.

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Presentation on theme: "NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES) Judith G. Hall, OC, MD The University of British Columbia and BC Childrens Hospital."— Presentation transcript:

1 NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES) Judith G. Hall, OC, MD The University of British Columbia and BC Childrens 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 PLAN OF TALK Frequency of congenital contractures Frequency of congenital contractures Ways to approach a diagnosis Ways to approach a diagnosis a.Areas of body involved b.Etiologic groupings c.Similarity groupings d.Genes – pathways/networks Fetal akinesia deformation sequence Fetal akinesia deformation sequence Fetal movement Fetal movement Prenatal diagnosis and therapy Prenatal diagnosis and therapy Effects of non-movement Effects of non-movement Challenges Challenges NO KNOWN CONFLICTS OF INTEREST

4 CONGENITAL CONTRACTURES IN THE NEWBORN Clubfoot…………………………….........1/500 – 1/1000 Clubfoot…………………………….........1/500 – 1/1000 Congenital dislocated hips....................1/200 – 1/500 Congenital dislocated hips....................1/200 – 1/500 Multiple congenital contractures…..1/3000 – 1/6000 Multiple congenital contractures…..1/3000 – 1/6000 All congenital contractures……………..1/100– 1/250 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 VERY heterogeneous No proper ICD code(s) No proper ICD code(s) Need population base Need population base Australia epidemic Australia epidemic North America North America Washington State Washington State British Columbia registry British Columbia registry Others Others Finland Finland Sweden Sweden

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

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

9 ARTHROGRYPOSIS STUDY GROUP 350 Study Group 500Insufficient data 800 Secondary arthrogryposis >1500 casesNot congenital contractures From: Shriners Hospitals, Portland Spokane Childrens Orthopedic Hospital, Seattle University of Washington Hospital Artrhogryposis Association Correspondence, 1975-1978, University of Washington

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

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

12 AREAS OF INVOLVEMENT TOTAL STUDY GROUP Primarily limbs Limbs plus other body areas Limbs plus CNS 18653%12937%3510% 33% 33% 33%

13 Differential diagnosis of multiple congenital contractures

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

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

16 ARTHORGRYPOSIS ETIOLOGIC GROUPING - 1 Muscle (myopathies, and distal arthrogryposes – TNNT3, TPM2, TNN12, MYH3 fast twitch muscle) Muscle (myopathies, and distal arthrogryposes – TNNT3, TPM2, TNN12, MYH3 fast twitch muscle) Tendon length & placement (Trismus pseudocamptodactyly) – MYH8 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 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) CNS function (Trisomy 18) Limiting space (Assymetric) Limiting space (Assymetric) Vascular compromise (Amyoplasia) Vascular compromise (Amyoplasia)

17 TYPES OF MUSCLE Striated/voluntary Striated/voluntary Smooth Smooth Cardiac Cardiac Mixtures Mixtures

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

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

20 CLASSIFICATION OF DISTAL AMCs HallBamshad Gene HallBamshad Gene IDistal 1A TPM2 IIAGordon (cleft palate, SS) 3 IIBOphthalmoplegia(fine muscle) 5 IICCleft Lip (10) IIDScoliosis + DA 4 IIETrismus + Unusual Hand + DA 7B Freeman-Sheldon Syndome 2 MYH3 Sheldon-Hall 2B TNNT3, TNN12 Sheldon-Hall Look Alike 2C MYH3 Deafness + DA 6 11q25 Trismus Pseudocamptodactyly 7A MYH8 AD, Multiple Pterygium 8 Contractural Arachnodactyly 9 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 INHERITANCEDISTINGUISHING GENE FEATURES Popliteal pterygiumADClefts, lip pits normal nail IRF6 Antecubital pterygiumADOnly elbows involved -- Mutiple pterygium (Escobar type) ARCervical vertebral anomalies, CHRNG hands involved, chin- sternum pterygium, facies hands involved, chin- sternum pterygium, facies Lethal mutliple ARExtensive contractures, hypertelorism, pterygium CHRNG, chin-sternum pterygium, CHRNA1, small chest CHRNB1, RAPSN Lethal popliteal pterygium ARFacial cleft, syndactyly IRF6 (Bartoscas Papas) (hands and feet), (Bartoscas Papas) (hands and feet), genital anomaly genital anomaly Pterygium and ectodermal ARFine sparse hair, nail anomalies -- dysplasia (hands and feet) Pterygium and malignant hyperthermiaARTorticolis, scoliosis, MH ?RYR1

22 GENES IDENTIFIED AMONG THE ARTHROGRYPOSES

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

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

25 Maternal Connective tissue illness skeletal dysplasia Maternal Connective tissue illness skeletal dysplasia Fetal Vascular Fetal Vascular crowding compromise Neurologic Muscle deficits defects 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 Starts 8 weeks, proximal limbs 9 weeks, distal 10 weeks Requires intact neuromuscular unit Requires intact neuromuscular unit Maternal injury and CVS/early amniocentesis allow timing of limb involvement Maternal injury and CVS/early amniocentesis allow timing of limb involvement

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

28 EMBRYONIC/FETAL MOVEMENT Week 4Heart beating begins 5-6Head and trunk stirs 5-6Head and trunk stirs 7Shoulders shrug 8Rhythmic breathing begins even though larynx not open Jaw starts to move 9Upper arms moving 10Hips, lower arms moving 10Hips, lower arms moving 11Lower limbs kicking 11Lower limbs kicking 12Hands open and ankles moving into correct position 12Hands 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 Usually not picked up without long careful real time US study – 45 min – 1 hr Nuchal edema Nuchal edema Thin undercalcified bones Thin undercalcified bones Movement may start any time from 11 weeks to 34 weeks Movement may start any time from 11 weeks to 34 weeks Small lungs Small lungs Diaphragm defect or decreased movements Diaphragm defect or decreased movements Other structure or space constraints (amniotic bands, uterine fibroid, amount of amniotic fluid) Other structure or space constraints (amniotic bands, uterine fibroid, amount of amniotic fluid)

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

31 PREGNANCY HISTORIES 828 cases of all types AllAmyoplasiaBackground Decreased movement 50%29%3% Maternal illness 8%15%7% Maternal medications 5%10% 3 – 10% Maternal bleeding 7.4%8%8% Uterine anomaly 2.3%2% 2 – 3% Polyhydramnios6.6%3% 0.5 – 2% Oligohydramnios3.3%2%<1%

32 DELIVERIES AT 39 WEEKS Cephalic60% Cephalic60% Breech37% Breech37% Transverse 3% Transverse 3% C-section45% C-section45% Fractures10% - 20% Fractures10% - 20% Birth weight30 th centile Birth weight30 th centile

33 Is intrauterine therapy possible? - Physical Therapy in utero-

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

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

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

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

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

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

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

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

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

43 FAMILYS JOB Ask questions Ask questions Take photographs Take photographs Make a notebook Make a notebook Keep records Keep records Ask questions Ask questions

44 DOCUMENTATION Photographs and videos Photographs and videos Notebook Notebook Changes over time Changes over time New observations 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% 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 should a 5% recurrence risk estimation be given risk estimation be given

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

48 WEB ADDRESS FOR THE BOOK http://www.global-help.org/publications/ books/help_arthrogryposis.pdf

49 LAY GROUPS AROUND THE WORLD Australia: http://www.taag.org.au/ Australia: http://www.taag.org.au/ Germany, Austria & Switzerland: Germany, Austria & Switzerland:http://www.arthrogryposis.de/iga/info_en Sweden: http://www.amcforeningen.se/ Sweden: http://www.amcforeningen.se/ UK: http://www.tagonline.org.uk/index.html UK: http://www.tagonline.org.uk/index.html

50 REFERENCES Staheli LT, Hall JG, Jaffe KM, Paholke DO. Arthrogryposis: A text atlas. Cambridge University Press; Cambridge, UK, 1998. 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 Rimoins principle and practice of medical genetics. Vol 3, 5 th edition. Eds. Rimoin, DL, Connor JM, Pyeritz RE, Kork BR. Churchill Livingstone: New York, Chapter 168, p. 3785-3856, 2007. Hall, JG. Arthrogryposes (Multiple congenital contractures). In: Emery and Rimoins principle and practice of medical genetics. Vol 3, 5 th edition. Eds. Rimoin, DL, Connor JM, Pyeritz RE, Kork BR. Churchill Livingstone: New York, Chapter 168, p. 3785-3856, 2007. Hall JG, Vincent A. Arthrogryposis. In: Neuromuscular diseases of infancy, childhood, adolescence – a clinicians approach. Eds H Jones, DC De Vivo, BT Darris. Butterworth: Boston, Chapter 7, p. 123 – 141, 2003. Hall JG, Vincent A. Arthrogryposis. In: Neuromuscular diseases of infancy, childhood, adolescence – a clinicians approach. Eds H Jones, DC De Vivo, BT Darris. Butterworth: Boston, Chapter 7, p. 123 – 141, 2003. Hall JG. Arthrogryposis. In: Management of genetic syndromes, 2 nd ed. Eds. Cassidy SB, Allanson JE. Wiley- Liss: Hoboken, NJ, Chapter 7, p. 63 – 86, 2005. Hall JG. Arthrogryposis. In: Management of genetic syndromes, 2 nd 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 63:506-516, 1998. 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 63:506-516, 1998. Michalk A, Stricker S, Becker J, et al. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 82:464-476, 2008. Michalk A, Stricker S, Becker J, et al. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 82:464-476, 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 81:530- 539, 2007. 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 81:530- 539, 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 81:589-595, 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 81:589-595, 2007. Nousianen HO, Kestila M, Pakkasjarvi N et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40:155-157, 2008. Nousianen HO, Kestila M, Pakkasjarvi N et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40:155-157, 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, 2007. 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, 2007. 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 82:188-193, 2008. 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 82:188-193, 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 82:222-227. 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 82:222-227. 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:344- 348, 2005. 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:344- 348, 2005. Zhou H, Brockington M, Jungbluth H, et al. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet 79:859-868, 2006. Zhou H, Brockington M, Jungbluth H, et al. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet 79:859-868, 2006.


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