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

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)

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

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

Arthrogryposis is not a diagnosis —it is a sign

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

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

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

ARTHROGRYPOSIS STUDY GROUP 500 Insufficient data 800 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, 1975-1978, University of Washington

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

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

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

Differential diagnosis of multiple congenital contractures

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

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

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)

TYPES OF MUSCLE Striated/voluntary Smooth Cardiac Mixtures

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

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

CLASSIFICATION OF DISTAL AMCs Hall Bamshad Gene I Distal 1A TPM2 IIA Gordon (cleft palate, SS) 3 IIB Ophthalmoplegia (fine muscle) 5 IIC Cleft Lip (10) IID Scoliosis + DA 4 IIE Trismus + 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)

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

GENES IDENTIFIED AMONG THE ARTHROGRYPOSES

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

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

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)

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

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

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

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)

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

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%

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

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

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

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

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

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

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

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.

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

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)

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

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

DOCUMENTATION Photographs and videos Notebook Changes over time New observations

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%

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

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

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

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

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. 3785-3856, 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, 2003. 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.

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. 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, 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.

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. 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. 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.