NEW DEVELOPMENTS IN NEW DEVELOPMENTS IN ARTHROGRYPOSISARTHROGRYPOSIS

(MULTIPLE CONGENITAL CONTRACTURES)(MULTIPLE CONGENITAL CONTRACTURES)

Judith G. Hall, OC, MDJudith G. Hall, OC, MD

The University of British Columbia and The University of British Columbia and

BC Children’s HospitalBC Children’s Hospital

Vancouver, BC CanadaVancouver, BC Canada

NO KNOWN CONFLICTS OF INTERESTNO KNOWN CONFLICTS OF INTEREST

ARTHROGRYPOSISARTHROGRYPOSIS(MULTIPLE CONGENITAL CONTRACTURES)(MULTIPLE CONGENITAL CONTRACTURES)

Congenital nonprogressive Congenital nonprogressive

limitation of movement of limitation of movement of

two or more joints in two or more joints in

different body areasdifferent body areas

(lots and lots of things get included)(lots and lots of things get included)

PLAN OF TALKPLAN OF TALK Frequency of congenital contracturesFrequency of congenital contractures Ways to approach a diagnosisWays to approach a diagnosis

a.a. Areas of body involvedAreas of body involvedb.b. Etiologic groupingsEtiologic groupingsc.c. Similarity groupingsSimilarity groupingsd.d. Genes – pathways/networksGenes – pathways/networks

Fetal akinesia deformation sequenceFetal akinesia deformation sequence Fetal movementFetal movement Prenatal diagnosis and therapyPrenatal diagnosis and therapy Effects of non-movementEffects of non-movement ChallengesChallenges

NO KNOWN CONFLICTS OF INTERESTNO KNOWN CONFLICTS OF INTEREST

CONGENITAL CONTRACTURES CONGENITAL CONTRACTURES IN THE NEWBORNIN THE NEWBORN

Clubfoot…………………………….........1/500 – 1/1000Clubfoot…………………………….........1/500 – 1/1000

Congenital dislocated hips....................1/200 – 1/500Congenital dislocated hips....................1/200 – 1/500

Multiple congenital contractures…..1/3000 – 1/6000Multiple congenital contractures…..1/3000 – 1/6000

All congenital contractures……………..1/100– 1/250All congenital contractures……………..1/100– 1/250

Arthrogryposis Arthrogryposis

is not a is not a

diagnosis diagnosis ——

it is a signit is a sign

FREQUENCY OF FREQUENCY OF ARTHROGRYPOSISARTHROGRYPOSIS

- Many lethal types, miscarriages, stillborns- Many lethal types, miscarriages, stillborns

VERY heterogeneousVERY heterogeneous No proper ICD code(s)No proper ICD code(s) Need population baseNeed population base Australia epidemicAustralia epidemic North AmericaNorth America

Washington StateWashington State British Columbia registryBritish Columbia registry

OthersOthers FinlandFinland SwedenSweden

EPIDEMIOLOGYEPIDEMIOLOGY

Frequency ~ 1/3000 birthsFrequency ~ 1/3000 birthsPrevalence ~ 1/4,000 – 6,000Prevalence ~ 1/4,000 – 6,000GeographicGeographicGenderGenderParental AgeParental Age““Outbreaks”Outbreaks”

OCCURRENCE OF OCCURRENCE OF ARTHROGRYPOSISARTHROGRYPOSIS

~ 1/3000 – 5000….live births~ 1/3000 – 5000….live births 1/3…………………Amyoplasia1/3…………………Amyoplasia 1/3…………………CNS – newborn lethal1/3…………………CNS – newborn lethal 1-3…………………Heterogeneous group1-3…………………Heterogeneous group

of disordersof disorders

ARTHROGRYPOSIS STUDY GROUPARTHROGRYPOSIS STUDY GROUP

350 Study Group350 Study Group

500500 Insufficient dataInsufficient data

800 800 Secondary arthrogryposisSecondary arthrogryposis

>1500 cases>1500 cases Not congenital contracturesNot congenital contractures

From: Shriner’s Hospitals, Portland Spokane Children’s From: Shriner’s Hospitals, Portland Spokane Children’s

Orthopedic Hospital, Seattle University of Washington Orthopedic Hospital, Seattle University of Washington

Hospital Artrhogryposis Association Correspondence, Hospital Artrhogryposis Association Correspondence,

1975-1978, University of Washington1975-1978, University of Washington

Ways to approach Ways to approach a diagnosis – a diagnosis –

What are useful What are useful clinical discriminators?clinical discriminators?

APPROACH TO MULTIPLE APPROACH TO MULTIPLE CONGENITAL CONTRACTURES - CONGENITAL CONTRACTURES -

CLINICALCLINICAL

Mainly limbsMainly limbs

Limbs and other body areasLimbs and other body areas

Limbs and CNS/lethalLimbs and CNS/lethal

AREAS OF INVOLVEMENT AREAS OF INVOLVEMENT TOTAL STUDY GROUPTOTAL STUDY GROUP

Primarily Primarily limbslimbs

Limbs plus Limbs plus other body other body

areasareas

Limbs plus Limbs plus CNSCNS

186186

53%53%

129129

37%37%

3535

10%10%

33% 33% 33%

Differential diagnosis of Differential diagnosis of multiple congenital multiple congenital

contracturescontractures

AMYOPLASIAAMYOPLASIA“CLASSICAL ARTHROGRYPOSIS”“CLASSICAL ARTHROGRYPOSIS” Typical symmetric positions of limbsTypical symmetric positions of limbs Usually “teratogenic” clubfootUsually “teratogenic” clubfoot Absent muscles with fibrotic replacementAbsent muscles with fibrotic replacement Mid facial hemangiomaMid facial hemangioma 10% abdominal structural anomaly10% abdominal structural anomaly

(vascular accident) and other vascular (vascular accident) and other vascular compromise (lost fingers or toes)compromise (lost fingers or toes)

Apparent increase in one of monozygotic Apparent increase in one of monozygotic twinstwins Surprisingly good response to early physical Surprisingly good response to early physical

therapytherapy No apparent recurrence risk or risk for other No apparent recurrence risk or risk for other

congenital anomaliescongenital anomalies

WAYS TO APPROACH WAYS TO APPROACH ARTHROGRYPOSIS BY ARTHROGRYPOSIS BY ETIOLOGIC GROUPINGETIOLOGIC GROUPING

MuscleMuscle Tendon length & placementTendon length & placement Peripheral nerve and end platePeripheral nerve and end plate CNS functionCNS function BoneBone Limiting spaceLimiting space Maternal illness, medications or traumaMaternal illness, medications or trauma Vascular disruptionVascular disruption

ARTHORGRYPOSIS ETIOLOGIC ARTHORGRYPOSIS ETIOLOGIC GROUPING - 1GROUPING - 1

Muscle (myopathies, and distal arthrogryposes – Muscle (myopathies, and distal arthrogryposes – TNNT3, TPM2, TNN12, MYH3 fast twitch muscle)TNNT3, TPM2, TNN12, MYH3 fast twitch muscle)

Tendon length & placement (Trismus Tendon length & placement (Trismus pseudocamptodactyly) – MYH8pseudocamptodactyly) – MYH8

Peripheral nerve and end plate (Multiple Peripheral nerve and end plate (Multiple Pterygium Syndrome – Escobar type and lethal) Pterygium Syndrome – Escobar type and lethal) (CHRNG, CHRNA1, CHRNBi, CHRND, RAPSN and (CHRNG, CHRNA1, CHRNBi, CHRND, RAPSN and antibodies to these) – compromises of Ach antibodies to these) – compromises of Ach receptorreceptor

CNS function (Trisomy 18)CNS function (Trisomy 18) Limiting space (Assymetric)Limiting space (Assymetric) Vascular compromise (Amyoplasia)Vascular compromise (Amyoplasia)

TYPES OF MUSCLETYPES OF MUSCLE

Striated/voluntaryStriated/voluntarySmoothSmoothCardiacCardiacMixturesMixtures

ARTHORGRYPOSIS ETIOLOGIC ARTHORGRYPOSIS ETIOLOGIC GROUPING - 2GROUPING - 2

Spinal cord – X-linked lethal – ubiquitinSpinal cord – X-linked lethal – ubiquitin Fetal akinesia deformation sequenceFetal akinesia deformation sequence

LCCS1 – 3, GLE1 (mRNA xport mediation), LCCS1 – 3, GLE1 (mRNA xport mediation), ERBB3, PIPSKIC (phosphotidyl inosotol ERBB3, PIPSKIC (phosphotidyl inosotol pathway—also involved in muscle mRMA pathway—also involved in muscle mRMA export)export)

Bone dysplasia (Diastrophic dysplasia)Bone dysplasia (Diastrophic dysplasia) Limiting space (Assymetric)Limiting space (Assymetric) Maternal illnessMaternal illness

MedicationMedication TraumaTrauma

ARTHROGRYPOSIS – OBVIOUS ARTHROGRYPOSIS – OBVIOUS OTHER WAYS OF GROUPINGOTHER WAYS OF GROUPING

Amyoplasia and other vascular compromiseAmyoplasia and other vascular compromise Distal arthrogryposesDistal arthrogryposes Pterygium syndromesPterygium syndromes Bony fusionsBony fusions MyopathiesMyopathies Lethal SMA, X-linked lethal arthrogryposisLethal SMA, X-linked lethal arthrogryposis Lethal Pena Shokeir Phenotype (CNS structure subtypes)Lethal Pena Shokeir Phenotype (CNS structure subtypes)

COFS (Cerebro Oculo Facial syndrome)COFS (Cerebro Oculo Facial syndrome)LCCS 1-3 (Lethal Congenital Contracture LCCS 1-3 (Lethal Congenital Contracture

syndromes)syndromes)Neu Laxova syndromeNeu Laxova syndrome

CamptodactyliesCamptodactylies Skeletal dysplasiasSkeletal dysplasias Malformations syndromes Malformations syndromes Chromosomal abnormalitiesChromosomal abnormalities

CLASSIFICATION OF DISTAL AMCsCLASSIFICATION OF DISTAL AMCs HallHall BamshadBamshad Gene Gene

II DistalDistal 1A 1A TPM2 TPM2IIAIIA Gordon (cleft palate, SS)Gordon (cleft palate, SS) 3 3 IIBIIB OphthalmoplegiaOphthalmoplegia (fine muscle) (fine muscle) 5 5IICIIC Cleft LipCleft Lip (10) (10)IIDIID Scoliosis + DAScoliosis + DA 4 4IIEIIE Trismus + Unusual Hand + DATrismus + Unusual Hand + DA 7B 7B

Freeman-Sheldon SyndomeFreeman-Sheldon Syndome 2 2 MYH3 MYH3Sheldon-Hall Sheldon-Hall 2B 2B TNNT3, TNN12 TNNT3, TNN12Sheldon-Hall Look AlikeSheldon-Hall Look Alike 2C 2C MYH3 MYH3Deafness + DADeafness + DA 6 6 11q25 11q25Trismus PseudocamptodactylyTrismus Pseudocamptodactyly 7A 7A MYH8 MYH8AD, Multiple PterygiumAD, Multiple Pterygium 8 8Contractural ArachnodactylyContractural Arachnodactyly 9 9 FBN2 FBN2Absent Teeth + DAAbsent Teeth + DA (11) (11)Chitayat, AR, DDChitayat, AR, DD (12) (12)X-linkedX-linked (13) (13)Stavit, S. African, NaguibStavit, S. African, Naguib (14) (14)Moore-Weaver DistalMoore-Weaver Distal (15) (15)MR, DDMR, DD (16) (16)

PTERYGIUM SYNDROMESPTERYGIUM SYNDROMESTYPETYPE INHERITANCE INHERITANCE DISTINGUISHING DISTINGUISHING GENE GENE

FEATURES FEATURES

Popliteal pterygiumPopliteal pterygium ADAD Clefts, lip pits normal nailClefts, lip pits normal nail IRF6 IRF6

Antecubital pterygiumAntecubital pterygium ADAD Only elbows involvedOnly elbows involved -- --

Mutiple pterygium (Escobar type) Mutiple pterygium (Escobar type) ARAR Cervical vertebral anomalies, CHRNGCervical vertebral anomalies, CHRNG

hands involved, chin-hands involved, chin- sternum pterygium, sternum pterygium, facies facies

Lethal mutliple Lethal mutliple ARAR Extensive contractures, Extensive contractures, hypertelorism, pterygium hypertelorism, pterygium CHRNG, CHRNG,

chin-sternum pterygium, chin-sternum pterygium, CHRNA1, CHRNA1, small chest small chest CHRNB1, CHRNB1,

RAPSN RAPSN

Lethal popliteal pterygium Lethal popliteal pterygium ARAR Facial cleft, syndactyly Facial cleft, syndactyly IRF6 IRF6

(Bartoscas Papas) (Bartoscas Papas) (hands and feet), (hands and feet),

genital anomalygenital anomaly

Pterygium and ectodermal Pterygium and ectodermal ARAR Fine sparse hair, nail anomaliesFine sparse hair, nail anomalies -- -- dysplasia (hands and feet) dysplasia (hands and feet)

Pterygium and malignant hyperthermiaPterygium and malignant hyperthermia ARAR Torticolis, scoliosis, MH Torticolis, scoliosis, MH ?RYR1 ?RYR1

GENES IDENTIFIED AMONG THE GENES IDENTIFIED AMONG THE ARTHROGRYPOSESARTHROGRYPOSES

FETAL AKINESIA FETAL AKINESIA DEFORMATION SEQUENCEDEFORMATION SEQUENCE

PENA SHOKIER PHENOTYPEPENA SHOKIER PHENOTYPE

Intrauterine growth retardationIntrauterine growth retardation Congenital contractures of the limbsCongenital contractures of the limbs Hypoplastic lungsHypoplastic lungs Short umbilical cordShort umbilical cord Polyhydramnios – short gutPolyhydramnios – short gut Craniofacial anomaliesCraniofacial anomalies

Micrognathia +/- small mouthMicrognathia +/- small mouth +/- cleft palate+/- cleft palate High bridge of noseHigh bridge of nose Depressed tip of noseDepressed tip of nose

Lack of normal mechanical Lack of normal mechanical

forces may lead to secondaryforces may lead to secondary

deformationsdeformations““Use” is essential for normal Use” is essential for normal

developmentdevelopment

Maternal Maternal Connective tissue Connective tissue illness illness skeletal dysplasia skeletal dysplasia

Fetal Fetal Vascular Vascular crowdingcrowding compromise compromise

Neurologic Neurologic Muscle Muscle deficitsdeficits defects defects

LIMITATION OF FETAL JOINT MOBILITYLIMITATION OF FETAL JOINT MOBILITY

MULTIPLE CONGENITAL CONTRACTURESMULTIPLE CONGENITAL CONTRACTURES

(ARTHROGRYPOSIS)(ARTHROGRYPOSIS)

HUMAN FETAL LIMB HUMAN FETAL LIMB MOVEMENTMOVEMENT

Starts 8 weeks, proximal limbs 9 Starts 8 weeks, proximal limbs 9 weeks, distal 10 weeksweeks, distal 10 weeks

Requires intact neuromuscular unitRequires intact neuromuscular unit Maternal injury and CVS/early Maternal injury and CVS/early

amniocentesis allow timing of amniocentesis allow timing of limb involvementlimb involvement

EMBRYONIC LIMB EMBRYONIC LIMB DEVELOPMENTDEVELOPMENT

Cranial caudal progressionCranial caudal progression

Upper limbs before lowerUpper limbs before lower

Right side before leftRight side before left

Vascular supply to CNS shifting Vascular supply to CNS shifting

EMBRYONIC/FETAL MOVEMENTEMBRYONIC/FETAL MOVEMENTWeekWeek

44 Heart beating beginsHeart beating begins 5-65-6 Head and trunk “stirs”Head and trunk “stirs”

77 Shoulders “shrug”Shoulders “shrug”88 Rhythmic “breathing” begins Rhythmic “breathing” begins

even though larynx not openeven though larynx not openJaw starts to moveJaw starts to move

99 Upper arms movingUpper arms moving 1010 Hips, lower arms movingHips, lower arms moving 1111 Lower limbs kickingLower limbs kicking 1212 Hands open and ankles moving Hands open and ankles moving

into into correct positioncorrect position

PRENATAL DIAGNOSIS BY PRENATAL DIAGNOSIS BY ULTRASOUNDULTRASOUND

(WHAT ARE THE CLUES, WHAT TO LOOK FOR)(WHAT ARE THE CLUES, WHAT TO LOOK FOR)

Usually not picked up without long careful real time Usually not picked up without long careful real time US study – 45 min – 1 hrUS study – 45 min – 1 hr

Nuchal edemaNuchal edema Thin undercalcified bonesThin undercalcified bones Movement may start any time from 11 weeks to 34 Movement may start any time from 11 weeks to 34

weeks weeks Small lungsSmall lungs Diaphragm defect or decreased movementsDiaphragm defect or decreased movements Other structure or space constraints (amniotic Other structure or space constraints (amniotic

bands, uterine fibroid, amount of amniotic fluid)bands, uterine fibroid, amount of amniotic fluid)

As organs begin to function As organs begin to function muscles muscles

begin to contract begin to contract stretching developing stretching developing

tissues from tissues from inside inside and outsideand outside

PREGNANCY HISTORIESPREGNANCY HISTORIES

828 cases of all types828 cases of all types AllAll AmyoplasiaAmyoplasia BackgroundBackground

Decreased movementDecreased movement 50%50% 29%29% 3%3%

Maternal illnessMaternal illness 8%8% 15%15% 7%7%

Maternal medicationsMaternal medications 5%5% 10%10% 3 – 10%3 – 10%

Maternal bleedingMaternal bleeding 7.4%7.4% 8%8% 8%8%

Uterine anomalyUterine anomaly 2.3%2.3% 2%2% 2 – 3%2 – 3%

PolyhydramniosPolyhydramnios 6.6%6.6% 3%3% 0.5 – 2%0.5 – 2%

OligohydramniosOligohydramnios 3.3%3.3% 2%2% <1%<1%

DELIVERIES AT 39 WEEKSDELIVERIES AT 39 WEEKS

CephalicCephalic 60%60% BreechBreech 37%37% TransverseTransverse 3% 3% C-sectionC-section 45%45% FracturesFractures 10% - 20%10% - 20% Birth weightBirth weight 3030thth centile centile

Is intrauterine therapy possible?Is intrauterine therapy possible?

- “Physical Therapy in utero”-- “Physical Therapy in utero”-

DEPENDS ONDEPENDS ON

Functional CNSFunctional CNS Intact end plateIntact end plateFunctional musclesFunctional musclesSpace to moveSpace to move

IN UTERO IN UTERO THERAPYTHERAPY

Fetal movement relates to Fetal movement relates to maternal movementmaternal movement

- Exercise- Exercise

- Deep breathing- Deep breathing

- Caffeine- CaffeineEarly delivery if lungs matureEarly delivery if lungs mature

FETAL MOVEMENTFETAL MOVEMENT

Essential for normal development Essential for normal development of limbsof limbs

Mechanical transduction of cellsMechanical transduction of cells Lack of movement leads to fetal Lack of movement leads to fetal

akinesia deformation akinesia deformation sequencesequence

Maternal activity may affect Maternal activity may affect outcomeoutcome

Grace period of 3 – 4 monthsGrace period of 3 – 4 months

CATCH-UPCATCH-UP(3 – 4 MONTH WINDOW AFTER BIRTH)(3 – 4 MONTH WINDOW AFTER BIRTH)

Lung - avelolar growthLung - avelolar growth Gut - motility and absorptionGut - motility and absorption Joints - loosening of contracturesJoints - loosening of contractures Muscle - use reverses atrophyMuscle - use reverses atrophy Growth - bone mineralization, Growth - bone mineralization,

increase in lengthincrease in length

LACK OF MECHANICAL FORCES LACK OF MECHANICAL FORCES LEADS TO DEFORMATIONLEADS TO DEFORMATION

““Use” is essential for normal Use” is essential for normal developmentdevelopment

Disuse leads toDisuse leads to Muscle atrophyMuscle atrophy Increased connective tissueIncreased connective tissue Abnormal non-functional positionsAbnormal non-functional positions Changes in joint surfaceChanges in joint surface

SECONDARY EFFECTS FROM SECONDARY EFFECTS FROM LACK OF MOVEMENT IN UTEROLACK OF MOVEMENT IN UTERO

IUGR – limbs are shortIUGR – limbs are short Contractures with “collagenosis”, extra Contractures with “collagenosis”, extra

connective tissue, thick capsuleconnective tissue, thick capsule Abnormal relationship of limb to weight Abnormal relationship of limb to weight

bearing – joints at odd anglesbearing – joints at odd angles Muscle – disuse atrophy, decreased massMuscle – disuse atrophy, decreased mass Dimples – attached to overlying skinDimples – attached to overlying skin Other changes of FADS – lungs, gut, Other changes of FADS – lungs, gut,

craniofacial, etc.craniofacial, etc.

On musculoskeletal systemOn musculoskeletal systemOn lungsOn lungsOn gutOn gutOn growthOn growthOn development of motor skillsOn development of motor skills

EFFECTS OF FADS ONEFFECTS OF FADS ON

GROWTHGROWTH

AMC affected limbs - short and AMC affected limbs - short and smallsmall

Final height ~ 5Final height ~ 5thth centile for family centile for family Less muscle and less calcification of Less muscle and less calcification of

bone means less weightbone means less weight Avoid obesity – makes for more Avoid obesity – makes for more

workwork Some limbs grow even less Some limbs grow even less

normally (like post-polio)normally (like post-polio)

CHALLENGES – CHALLENGES – Not miss opportunities Not miss opportunities

Stretching, weight bearingStretching, weight bearing Avoid muscle atrophy, night splintsAvoid muscle atrophy, night splints

PreventionPrevention II°°, II, II°°, III, III°° Prenatal therapyPrenatal therapy Avoid scarringAvoid scarring Not harm joint cartilageNot harm joint cartilage Not allow atrophy of what is thereNot allow atrophy of what is there Keep from returning to “Keep from returning to “in uteroin utero position” position”

Intercede along mechanistic pathwaysIntercede along mechanistic pathways Cytokines, alternative metabolic pathways, fetal Cytokines, alternative metabolic pathways, fetal effectseffects

Multi-system considerationsMulti-system considerations Enormous heterogeneityEnormous heterogeneity

But commonalities as wellBut commonalities as well

FAMILY’S JOBFAMILY’S JOB

Ask questionsAsk questionsTake photographsTake photographsMake a notebookMake a notebookKeep recordsKeep recordsAsk questionsAsk questions

DOCUMENTATIONDOCUMENTATION

Photographs and videosPhotographs and videos

NotebookNotebook

Changes over timeChanges over time

New observationsNew observations

AREA OF INVOLVEMENT AREA OF INVOLVEMENT RECURRENCE RISKRECURRENCE RISK

Primarily Primarily limbslimbs

Limbs Limbs plus plus other other areasareas

Limbs Limbs plus plus CNSCNS

TotalTotal

Estimated Estimated RR for RR for overall overall groupgroup

Parents: 4.0%Parents: 4.0%

Self: 6.5%Self: 6.5%

10.8%10.8%

10.4%10.4%

5.7%5.7% 6.8%6.8%

Estimated Estimated RR when RR when knowns knowns excludedexcluded

Parents: 4.7%Parents: 4.7% 1.4%1.4% 7%7% 3%3%

If and only if a specific If and only if a specific diagnosis cannot be made diagnosis cannot be made should a 5% recurrenceshould a 5% recurrence

risk estimation be givenrisk estimation be given

Prognosis depends on the Prognosis depends on the specific diagnosis and the specific diagnosis and the

natural history of that natural history of that disorderdisorder

WEB ADDRESS FOR THE BOOKWEB ADDRESS FOR THE BOOK

http://www.global-help.org/publications/ http://www.global-help.org/publications/ books/help_arthrogryposis.pdfbooks/help_arthrogryposis.pdf

LAY GROUPS AROUND THE LAY GROUPS AROUND THE WORLDWORLD

AustraliaAustralia: http://www.taag.org.au/: http://www.taag.org.au/ Germany, Austria & SwitzerlandGermany, Austria & Switzerland: :

http://www.arthrogryposis.de/iga/info_enhttp://www.arthrogryposis.de/iga/info_en SwedenSweden: http://www.amcforeningen.se/: http://www.amcforeningen.se/ UKUK: : http://www.tagonline.org.uk/index.htmlhttp://www.tagonline.org.uk/index.html

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Hall, JG. Arthrogryposes (Multiple congenital contractures). Hall, JG. Arthrogryposes (Multiple congenital contractures). In: Emery and Rimoin’s principle and practice of In: Emery and Rimoin’s principle and practice of

medical medical genetics. Vol 3, 5genetics. Vol 3, 5thth edition. Eds. Rimoin, DL, edition. Eds. Rimoin, DL, Connor JM, Connor JM, Pyeritz RE, Kork BR. Churchill Livingstone: Pyeritz RE, Kork BR. Churchill Livingstone: New York, New York, Chapter 168, p. 3785-3856, 2007.Chapter 168, p. 3785-3856, 2007.

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