Cheryl Longman Consultant Clinical Geneticist Arthrogryposis Cheryl Longman Consultant Clinical Geneticist

Arthrogryposis ARTHRON - joint GRYPOSIS - curvature MULTIPLEX - multiple CONGENITA - born with it …affecting two or more different joints …symmetrical and non-progressive

Arthrogryposis 1 in 3-5,000 live births Male = female Not a single condition: end result of fetal akinesia >400 conditions >150 genes

Non-specific features Fusiform limbs Absent/reduced creases Dimpling Craniofacial: micrognathia, cleft palate, hypertelorism Osteoporosis and fractures Early onset merges with lethal contracture syndromes Pterygia IUGR Pulmonary hypoplasia

Diagnosis matters because it informs Risk to sibs (0-100%), offspring, wider family Risk of complications Respiratory failure Malignant hyperthermia Cardiomyopathy Treatment Occasionally specific treatments Management of contractures

An Approach To Diagnosis Amyoplasia Maternal factors Connective tissue/skeletal Central Peripheral neuromuscular Nerve NMJ Muscle: distal arthrogryposis & congenital myopathies

Amyoplasia One third of arthrogryposis Presumed vascular Typical arm posture Forehead haemangioma Gastroschisis 10%

Amyoplasia: Management Orthopaedic-led WoS MDT clinic Treat as soon after birth as possible Aim to allow milestones at the right time Judicious surgery "Lifetime" orthoses

Maternal Factors Illness eg Myasthenia, MS, infection, trauma ….. Hyperthermia Drugs eg cocaine, alcohol excess Uterine constraint

8.9M livebirths , fetal deaths from 20 wk and TOPs coded AMC over 26y 757 cases ~ 1 in 11,000 Maternal details for a third: vast majority no illnesses or drug use 2300 cases over 35 yrs 33 with uterine structural anomalies 29 had a specific recognisable form of arthrogryposis 2 where constraint likely cause- craniofacial asymmetry & early resolution > Caution in ascribing arthrogryposis to maternal factors

Central Clues Dysmorphic/multisystem features Cognitive involvement Spasticity/seizures Abnormal brain imaging Genetic testing Array CGH Single gene test vs ID panels ZC4H2

Nerve: SMA and motor neuronopathies Clues: Distal weakness and wasting, neurophysiology, brain MRI Phenotypic spectrum of some genes can extend to severe prenatal contractures with pterygia Some carry respiratory risk Genetic testing SMA panel covers dHMNs BICD2

Neuromuscular junction Genes encode NMJ components Same genes cause “lethal pterygium syndromes” Clues: fatiguable weakness, fluctuations, ptosis, opthalmoplegia, apnoeas Neurophysiology Specific medication RAPSN

Distal Arthrogryposes Common inherited cause, often dominant Characteristic patterns Overlap with congenital myopathies Genetic testing via arthrogryposis panel TNNT3

Congenital Myopathies Phenotypic spectrum can be wide Wide intra-familial variability Caution in predicting prognosis early- treat the person not the gene Associated risks in some Respiratory weakness Malignant hyperthermia

Conclusions Arthrogryposis is a description Diagnosis informs Recurrence risk Risk of associated complications eg respiratory weakness Management Phenotypic spectrum of many genes ranges from lethal contracture syndromes > arthrogryposis > milder phenotypes Advances in genetic testing are improving the ability to make timely genetic diagnoses

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