Presentation on theme: "NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES)"— Presentation transcript:
1 NEW DEVELOPMENTS IN ARTHROGRYPOSIS (MULTIPLE CONGENITAL CONTRACTURES) Judith G. Hall, OC, MDThe University of British Columbia andBC Children’s HospitalVancouver, BC CanadaNO 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 TALKFrequency of congenital contracturesWays to approach a diagnosisAreas of body involvedEtiologic groupingsSimilarity groupingsGenes – pathways/networksFetal akinesia deformation sequenceFetal movementPrenatal diagnosis and therapyEffects of non-movementChallengesNO KNOWN CONFLICTS OF INTEREST
6 FREQUENCY OF ARTHROGRYPOSIS - Many lethal types, miscarriages, stillborns VERY heterogeneousNo proper ICD code(s)Need population baseAustralia epidemicNorth AmericaWashington StateBritish Columbia registryOthersFinlandSweden
9 ARTHROGRYPOSIS STUDY GROUP 500 Insufficient dataSecondary arthrogryposis>1500 cases Not congenital contracturesFrom: 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 limbsLimbs and other body areasLimbs and CNS/lethal
12 AREAS OF INVOLVEMENT TOTAL STUDY GROUP Primarily limbsLimbs plus other body areasLimbs plus CNS18653%12937%3510%33% % %
13 Differential diagnosis of multiple congenital contractures
14 AMYOPLASIA “CLASSICAL ARTHROGRYPOSIS” Typical symmetric positions of limbsUsually “teratogenic” clubfootAbsent muscles with fibrotic replacementMid facial hemangioma10% abdominal structural anomaly(vascular accident) and other vascular compromise (lost fingers or toes)Apparent increase in one of monozygotic twinsSurprisingly good response to early physical therapyNo apparent recurrence risk or risk for other congenital anomalies
15 WAYS TO APPROACH ARTHROGRYPOSIS BY ETIOLOGIC GROUPING MuscleTendon length & placementPeripheral nerve and end plateCNS functionBoneLimiting spaceMaternal illness, medications or traumaVascular disruption
16 ARTHORGRYPOSIS ETIOLOGIC GROUPING - 1 Muscle (myopathies, and distal arthrogryposes – TNNT3, TPM2, TNN12, MYH3 fast twitch muscle)Tendon length & placement (Trismus pseudocamptodactyly) – MYH8Peripheral nerve and end plate (Multiple Pterygium Syndrome – Escobar type and lethal) (CHRNG, CHRNA1, CHRNBi, CHRND, RAPSN and antibodies to these) – compromises of Ach receptorCNS function (Trisomy 18)Limiting space (Assymetric)Vascular compromise (Amyoplasia)
17 TYPES OF MUSCLEStriated/voluntarySmoothCardiacMixtures
19 ARTHROGRYPOSIS – OBVIOUS OTHER WAYS OF GROUPING Amyoplasia and other vascular compromiseDistal arthrogryposesPterygium syndromesBony fusionsMyopathiesLethal SMA, X-linked lethal arthrogryposisLethal Pena Shokeir Phenotype (CNS structure subtypes)COFS (Cerebro Oculo Facial syndrome)LCCS 1-3 (Lethal Congenital Contracture syndromes)Neu Laxova syndromeCamptodactyliesSkeletal dysplasiasMalformations syndromesChromosomal abnormalities
20 CLASSIFICATION OF DISTAL AMCs Hall Bamshad GeneI Distal A TPM2IIA Gordon (cleft palate, SS)IIB Ophthalmoplegia (fine muscle)IIC Cleft Lip (10)IID Scoliosis + DAIIE Trismus + Unusual Hand + DA 7BFreeman-Sheldon Syndome MYH3Sheldon-Hall B TNNT3, TNN12Sheldon-Hall Look Alike 2C MYH3Deafness + DA q25Trismus Pseudocamptodactyly 7A MYH8AD, Multiple PterygiumContractural Arachnodactyly FBN2Absent 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 IRF6Antecubital pterygium AD Only elbows involvedMutiple pterygium (Escobar type) AR Cervical vertebral anomalies, CHRNGhands involved, chin sternum pterygium, faciesLethal mutliple AR Extensive contractures, hypertelorism, pterygium CHRNG, chin-sternum pterygium, CHRNA1, small chest CHRNB1, RAPSNLethal popliteal pterygium AR Facial cleft, syndactyly IRF6(Bartoscas Papas) (hands and feet),genital anomalyPterygium and ectodermal AR Fine sparse hair, nail anomalies dysplasia (hands and feet)Pterygium and malignant hyperthermia AR Torticolis, scoliosis, MH ?RYR1
23 FETAL AKINESIA DEFORMATION SEQUENCE PENA SHOKIER PHENOTYPE Intrauterine growth retardationCongenital contractures of the limbsHypoplastic lungsShort umbilical cordPolyhydramnios – short gutCraniofacial anomaliesMicrognathia +/- small mouth+/- cleft palateHigh bridge of noseDepressed tip of nose
24 Lack of normal mechanical forces may lead to secondary deformations “Use” is essential for normal development
26 HUMAN FETAL LIMB MOVEMENT Starts 8 weeks, proximal limbs 9 weeks, distal 10 weeksRequires intact neuromuscular unitMaternal injury and CVS/early amniocentesis allow timing of limb involvement
27 EMBRYONIC LIMB DEVELOPMENT Cranial caudal progressionUpper limbs before lowerRight side before leftVascular supply to CNS shifting
28 EMBRYONIC/FETAL MOVEMENT Week4 Heart beating begins5-6 Head and trunk “stirs”7 Shoulders “shrug”8 Rhythmic “breathing” begins even though larynx not openJaw starts to move9 Upper arms moving10 Hips, lower arms moving11 Lower limbs kicking12 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 hrNuchal edemaThin undercalcified bones Movement may start any time from 11 weeks to 34 weeksSmall lungsDiaphragm defect or decreased movementsOther 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 movement50%29%3%Maternal illness8%15%7%Maternal medications5%10%3 – 10%Maternal bleeding7.4%Uterine anomaly2.3%2%2 – 3%Polyhydramnios6.6%0.5 – 2%Oligohydramnios3.3%<1%
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- CaffeineEarly delivery if lungs mature
36 FETAL MOVEMENT Essential for normal development of limbs Mechanical transduction of cellsLack of movement leads to fetal akinesia deformation sequenceMaternal activity may affect outcomeGrace period of 3 – 4 months
37 CATCH-UP (3 – 4 MONTH WINDOW AFTER BIRTH) Lung - avelolar growthGut - motility and absorptionJoints - loosening of contracturesMuscle - use reverses atrophyGrowth - bone mineralization, increase in length
38 LACK OF MECHANICAL FORCES LEADS TO DEFORMATION “Use” is essential for normal developmentDisuse leads toMuscle atrophyIncreased connective tissueAbnormal non-functional positionsChanges in joint surface
39 SECONDARY EFFECTS FROM LACK OF MOVEMENT IN UTERO IUGR – limbs are shortContractures with “collagenosis”, extra connective tissue, thick capsuleAbnormal relationship of limb to weight bearing – joints at odd anglesMuscle – disuse atrophy, decreased massDimples – attached to overlying skinOther changes of FADS – lungs, gut, craniofacial, etc.
40 EFFECTS OF FADS ONOn musculoskeletal systemOn lungsOn gutOn growthOn development of motor skills
41 GROWTH AMC affected limbs - short and small Final height ~ 5th centile for familyLess muscle and less calcification of bone means less weightAvoid obesity – makes for more workSome limbs grow even less normally (like post-polio)
42 CHALLENGES – Not miss opportunities Stretching, weight bearing Avoid muscle atrophy, night splintsPreventionI°, II°, III°Prenatal therapyAvoid scarringNot harm joint cartilageNot allow atrophy of what is thereKeep from returning to “in utero position”Intercede along mechanistic pathwaysCytokines, alternative metabolic pathways, fetal effectsMulti-system considerationsEnormous heterogeneityBut 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 limbsLimbs plus other areasLimbs plus CNSTotalEstimated RR for overall groupParents: 4.0%Self: 6.5%10.8%10.4%5.7%6.8%Estimated RR when knowns excludedParents: 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% recurrencerisk 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 REFERENCESStaheli 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 REFERENCESMakela-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 REFERENCESProntera 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.
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