REVIEW ARTICLE Review of X-Linked Syndromes with Arthrogryposis or Early Contractures—Aid to Diagnosis and Pathway Identification Jesse M. Hunter, 1 Jeff Kiefer, 2 Christopher D. Balak, 1 Sonya Jooma, 1 Mary Ellen Ahearn, 1 Judith G. Hall, 3 and Lisa Baumbach-Reardon 1 * 1 Integrated Functional Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona 2 Knowledge Mining, Translational Genomics Research Institute, Phoenix, Arizona 3 Departments of Medical Genetics and Pediatrics, University of British Columbia and BC Children’s Hospital Vancouver, British Columbia, Canada Manuscript Received: 19 August 2014; Manuscript Accepted: 5 December 2014 The following is a review of 50 X-linked syndromes and con- ditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X- linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical char- acteristics. Tables are included which help to identify distin- guishing clinical features of each of the conditions. Ó 2015 Wiley Periodicals, Inc. Key words: arthrogryposis; multiple congenital contractures; arthrogryposis multiplex congenita; contractures; X-linked; myopathy; spinal muscular atrophy INTRODUCTION There are over 400 specific disorders that are, or can be, associated with multiple contractures in the newborn [Hall, 2013; Hall, 2014]. A better understanding of disorders with contractures and their associated genetics is critical for accurate diagnosis and optimal treatment. Contractures are defined as joints that have reduced range of motion due to stiffening of normally flexible tissues. Proper central and peripheral nervous system development and function are required for stimulation of muscle movement. Muscle tissue, ligaments, tendons, and skin require movement for normal devel- opment and function, without which, joints develop contractures. Reduced fetal movement in utero due to myopathic processes, motor neuron degeneration, vascular compromise, abnormal skel- etal or connective tissue development, limited space in the uterus, maternal illness, or toxin exposure can lead to multiple congenital contractures [Hall, 2013]. Contractures can develop at any age as a result of neuromuscular dysfunction or limitation of movement, but muscle innervation and movement in utero is particularly critical for normal joint development. The terms arthrogryposis, or arthrogryposis multiplex congenital (AMC), are generally used to describe two congenital contractures of more than one body area [Bamshad et al., 2009; Hall, 2013]. Contractures or arthrogryposis are important, often under-recognized, clinical signs rather than diagnoses. In 1982, Hall et al. described three distinct types of X-linked arthrogryposis. Since that time, many X-linked syndromes have been described with congenital or acquired contractures as part of the phenotype. These conditions appear to be distinguishable on the basis of natural history, clinical findings and/or identified genetic cause. While it is not possible to fully describe all X-linked syndromes with contractures, 50 of these entities are reviewed here How to Cite this Article: Hunter JM, Kiefer J, Balak CD, Jooma S, Ahearn ME, Hall JG, Baumbach-Reardon L. 2015. Review of X-linked syndromes with arthrogryposis or early contractures—aid to diagnosis and pathway identification. Am J Med Genet Part A 167A:931–973. Jesse M. Hunter, Judith G. Hall, and Lisa Baumbach-Reardon contributed equally to this work. Conflict of interest: None. Grant sponsor: Muscular Dystrophy Association; Grant sponsor: TGen- Duke Biomedical Futures Program; Grant sponsor: Helios Education Foundation; Grant sponsor: Freeport-McMoRan Copper & Gold Foundation Science and Technology.  Correspondence to: Lisa Baumbach-Reardon, PhD, FACMG, TGen, Division of Integrated Functional Genomics, 445 N 5th Street, Phoenix, Arizona, 85004. E-mail: lbaumbach@tgen.org. Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 March 2015 DOI 10.1002/ajmg.a.36934 Ó 2015 Wiley Periodicals, Inc. 931