The neuromuscular differential diagnosis of joint hypermobility

Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers–Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult‐onset inherited myopathies also present with joint hypermobility in the context of often only mild‐to‐moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers–Danlos syndrome, Marfan syndrome and Loeys‐Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers–Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1‐ and SEPN1‐related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders. © 2015 Wiley Periodicals, Inc.

[1]  M. Goumans,et al.  Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections , 2015, Journal of the American College of Cardiology.

[2]  M. Castori,et al.  Neurological manifestations of Ehlers-Danlos syndrome(s): A review , 2014, Iranian journal of neurology.

[3]  M. Lek,et al.  G.P.35 Analysis of a large patient cohort with recessive truncating TTN mutations reveals novel clinical features and a diverse range of muscle pathologies , 2014, Neuromuscular Disorders.

[4]  C. Bönnemann,et al.  Molecules in Focus: Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils , 2014 .

[5]  G. Sobey Ehlers–Danlos syndrome: how to diagnose and when to perform genetic tests , 2014, Archives of Disease in Childhood.

[6]  K. Bushby,et al.  Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/β‐Cardiac Myosin (MYH7) Distal Myopathy , 2014, Human mutation.

[7]  P. Byers,et al.  FKBP14‐related Ehlers‐Danlos syndrome: Expansion of the phenotype to include vascular complications , 2014, American Journal of Medical Genetics. Part A.

[8]  E. Malfatti,et al.  Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene , 2014, Journal of Neurology, Neurosurgery & Psychiatry.

[9]  M. Devoto,et al.  Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. , 2014, Human molecular genetics.

[10]  K. Bushby,et al.  Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. , 2014, Human molecular genetics.

[11]  H. Dietz,et al.  Loeys–Dietz syndrome: a primer for diagnosis and management , 2014, Genetics in Medicine.

[12]  N. Hübner,et al.  Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. , 2014, Human molecular genetics.

[13]  Ching H. Wang,et al.  Diagnostic approach to the congenital muscular dystrophies , 2014, Neuromuscular Disorders.

[14]  E. Bertini,et al.  Natural history of pulmonary function in collagen VI-related myopathies. , 2013, Brain : a journal of neurology.

[15]  R. Weiss,et al.  Position of Glycine Substitutions in the Triple Helix of COL6A1, COL6A2, and COL6A3 is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies , 2013, Human mutation.

[16]  A. Janecke,et al.  Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome. , 2013, Human molecular genetics.

[17]  J. Schalkwijk,et al.  Compound heterozygous mutations of the TNXB gene cause primary myopathy , 2013, Neuromuscular Disorders.

[18]  F. Muntoni,et al.  RyR1 Deficiency in Congenital Myopathies Disrupts Excitation–Contraction Coupling , 2013, Human mutation.

[19]  L. Wilkins Severe congenital RYR1-associated myopathy: The expanding clinicopathologic and genetic spectrum , 2013, Neurology.

[20]  G. Mortier,et al.  Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome , 2013, Orphanet Journal of Rare Diseases.

[21]  R. Finkel,et al.  Severe congenital RYR1-associated myopathy , 2013, Neurology.

[22]  Mark R. Morris,et al.  Perlman Syndrome: Overgrowth, Wilms Tumor Predisposition and DIS3L2. , 2013, American Journal of Medical Genetics. Part C, Seminars in Medical Genetics.

[23]  F. Muntoni,et al.  Congenital myopathies – Clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom , 2013, Neuromuscular Disorders.

[24]  N. Voermans Corrigendum to: “Myopathy in a 20‐Year‐Old Female Patient With D4ST‐1 Deficient Ehlers‐Danlos Syndrome Due to a Homozygous CHST14 Mutation, Am J Med Genet A. 2012 Apr; 158A(4):850–855” , 2013 .

[25]  S. Apte,et al.  The biology of the extracellular matrix: novel insights , 2013, Current opinion in rheumatology.

[26]  A. de Haan,et al.  Neuromuscular properties of the thigh muscles in patients with ehlers–danlos syndrome , 2013, Muscle & nerve.

[27]  F. Muntoni,et al.  Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement , 2012, Neuromuscular Disorders.

[28]  C. Bönnemann,et al.  Spontaneous keloid formation in patients with Bethlem myopathy , 2012, Neurology.

[29]  E. Fishman,et al.  Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm , 2012, Nature Genetics.

[30]  K. Bushby,et al.  Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene‐associated myopathies , 2012, Human mutation.

[31]  P. Guicheney,et al.  Selenoprotein N in skeletal muscle: from diseases to function , 2012, Journal of Molecular Medicine.

[32]  T. Irving,et al.  Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome. , 2012, Journal of applied physiology.

[33]  N. van Alfen,et al.  Myopathy in a 20‐year‐old female patient with D4ST‐1 deficient Ehlers‐Danlos syndrome due to a homozygous CHST14 mutation , 2012, American journal of medical genetics. Part A.

[34]  F. Muntoni,et al.  Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. , 2012, American journal of human genetics.

[35]  I. Higuchi [Collagen VI-related muscle disorders]. , 2011, Brain and nerve = Shinkei kenkyu no shinpo.

[36]  M. Pane,et al.  Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. , 2011, Archives of neurology.

[37]  Y. Fukushima,et al.  Delineation of dermatan 4‐O‐sulfotransferase 1 deficient Ehlers–Danlos syndrome: Observation of two additional patients and comprehensive review of 20 reported patients , 2011, American journal of medical genetics. Part A.

[38]  C. Bönnemann The collagen VI-related myopathies: muscle meets its matrix , 2011, Nature Reviews Neurology.

[39]  A. Krol,et al.  Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency. , 2011, Human Molecular Genetics.

[40]  G. Vriend,et al.  Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis , 2011, Nature Genetics.

[41]  Straub,et al.  RYR1 mutations are a common cause of congenital myopathies with central nuclei , 2010, Annals of neurology.

[42]  N. Maraldi,et al.  Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration , 2010, Nature Medicine.

[43]  P. Huijing,et al.  Muscle characteristics and altered myofascial force transmission in tenascin-X-deficient mice, a mouse model of Ehlers-Danlos syndrome. , 2010, Journal of applied physiology.

[44]  H. Dietz,et al.  Musculoskeletal findings of Loeys-Dietz syndrome. , 2010, The Journal of bone and joint surgery. American volume.

[45]  Y. Fukushima,et al.  Loss‐of‐function mutations of CHST14 in a new type of Ehlers‐Danlos syndrome , 2010, Human mutation.

[46]  Laurence Faivre,et al.  The revised Ghent nosology for the Marfan syndrome , 2010, Journal of Medical Genetics.

[47]  G. Vasco,et al.  Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine , 2010, Annals of neurology.

[48]  G. Utermann,et al.  Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. , 2009, American journal of human genetics.

[49]  C. Bönnemann,et al.  Myopathy and polyneuropathy in an adolescent with the kyphoscoliotic type of Ehlers–Danlos syndrome , 2009, American journal of medical genetics. Part A.

[50]  A. Krol,et al.  Selenoprotein N is dynamically expressed during mouse development and detected early in muscle precursors , 2009, BMC Developmental Biology.

[51]  S. Pillen,et al.  Neuromuscular features in Marfan syndrome , 2009, Clinical genetics.

[52]  I. V. van Rooij,et al.  Neuromuscular involvement in various types of Ehlers–Danlos syndrome , 2009, Annals of neurology.

[53]  B. Engelen,et al.  Joint hypermobility as a distinctive feature in the differential diagnosis of myopathies , 2009, Journal of Neurology.

[54]  P. Huijing,et al.  Clinical and molecular overlap between myopathies and inherited connective tissue diseases , 2008, Neuromuscular Disorders.

[55]  P. Bonaldo,et al.  Autosomal recessive myosclerosis myopathy is a collagen VI disorder , 2008, Neurology.

[56]  R. Sciot,et al.  Predominant fiber atrophy and fiber type disproportion in early ullrich disease , 2008, Muscle & nerve.

[57]  F. Muntoni,et al.  Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm. , 2008, Current opinion in pharmacology.

[58]  B. Engelen,et al.  Differential diagnosis of muscular hypotonia in infants: The kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI) , 2008, Neuromuscular Disorders.

[59]  B. V. van Engelen,et al.  Ehlers–Danlos syndrome due to tenascin‐X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies , 2007, American journal of medical genetics. Part A.

[60]  B. Engelen,et al.  Reduced quantitative muscle function in tenascin-X deficient Ehlers-Danlos patients , 2007, Neuromuscular Disorders.

[61]  Susan C. Brown,et al.  Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. , 2007, Brain : a journal of neurology.

[62]  H. Jungbluth Multi-minicore Disease , 2007, Orphanet journal of rare diseases.

[63]  F. Muntoni,et al.  Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene , 2007, Neuromuscular Disorders.

[64]  Kevin B. Jones,et al.  Symposium on the musculoskeletal aspects of marfan syndrome: Meeting report and state of the science , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[65]  E. Bertini,et al.  Cardiac and pulmonary investigations in Bethlem myopathy. , 2006, Archives of neurology.

[66]  I. Thiffault,et al.  A new form of congenital muscular dystrophy with joint hyperlaxity maps to 3p23-21. , 2006, Brain : a journal of neurology.

[67]  H. F. Carvalho,et al.  Identification, content, and distribution of type VI collagen in bovine tendons , 2006, Cell and Tissue Research.

[68]  Wolfram Kress,et al.  A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2 , 2005, Nature Genetics.

[69]  J. Weis,et al.  Homozygous microdeletion of chromosome 4q11‐q12 causes severe limb‐girdle muscular dystrophy type 2E with joint hyperlaxity and contractures , 2005, Human mutation.

[70]  J. Allsop,et al.  Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy , 2005, Neuromuscular Disorders.

[71]  Wall Me,et al.  Early responses to mechanical load in tendon: role for calcium signaling, gap junctions and intercellular communication. , 2005 .

[72]  G. Bydder,et al.  Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations , 2004, Neuromuscular Disorders.

[73]  Susan C. Brown,et al.  Congenital muscular dystrophy with short stature, proximal contractures and distal laxity. , 2004, Neuropediatrics.

[74]  F. Hanefeld,et al.  Muscle ultrasound in Bethlem myopathy. , 2003, Neuropediatrics.

[75]  Ivan Stamenkovic,et al.  Functional structure and composition of the extracellular matrix , 2003, The Journal of pathology.

[76]  A. Malandrini,et al.  Neurological presentation of Ehlers–Danlos syndrome type IV in a family with parental mosaicism , 2003, Clinical Genetics.

[77]  A. Child,et al.  Muscle fibrillin deficiency in Marfan’s syndrome myopathy , 2003, Journal of neurology, neurosurgery, and psychiatry.

[78]  A. Superti-Furga,et al.  The Ehlers‐Danlos Syndrome , 2003 .

[79]  F. Muntoni,et al.  Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. , 2002, American journal of human genetics.

[80]  I. Nonaka,et al.  Ullrich disease: Collagen VI deficiency: EM suggests a new basis for muscular weakness , 2002, Neurology.

[81]  Susan C. Brown,et al.  Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores , 2002, Neurology.

[82]  Susan C. Brown,et al.  Collagen VI involvement in Ullrich syndrome: A clinical, genetic, and immunohistochemical study , 2002, Neurology.

[83]  E. Bertini,et al.  Bethlem myopathy (BETHLEM) 86th ENMC International Workshop, 10–11 November 2000, Naarden, The Netherlands , 2002, Neuromuscular Disorders.

[84]  Nimish J. Thakore,et al.  Novel mutations in collagen VI genes: Expansion of the Bethlem myopathy phenotype , 2002, Neurology.

[85]  J. Schalkwijk,et al.  A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. , 2001, The New England journal of medicine.

[86]  F. Muntoni,et al.  Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome , 2001, Nature Genetics.

[87]  L. Lagae,et al.  Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. , 2000, American journal of human genetics.

[88]  P. Beighton,et al.  Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). , 1998, American journal of medical genetics.

[89]  P. Beighton,et al.  Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). , 1998, American journal of medical genetics.

[90]  S. Kügler,et al.  Ehlers-Danlos syndrome type VI: lysyl hydroxylase deficiency due to a novel point mutation (W612C) , 1998, Archives of Dermatological Research.

[91]  F. Baas,et al.  Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures , 1996, Nature Genetics.

[92]  W. Hu,et al.  Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils , 1995, The Journal of cell biology.

[93]  R. Grahame,et al.  The Marfan syndrome: joint and skin manifestations are prevalent and correlated. , 1995, British journal of rheumatology.

[94]  S. Pinnell,et al.  A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. , 1994, Journal of Clinical Investigation.

[95]  S. Pinnell,et al.  Ehlers-Danlos syndromes , 2019, BMJ.

[96]  A. Julià,et al.  Ehlers-Danlos syndrome, clotting disorders and muscular dystrophy. , 1989, Annals of the rheumatic diseases.

[97]  J. Gamble,et al.  Orthopaedic aspects of central core disease. , 1988, The Journal of bone and joint surgery. American volume.

[98]  T. Baxter,et al.  Muscle formation in Ehlers-Danlos syndrome. , 1981, Archives of physical medicine and rehabilitation.

[99]  J. Timmermans,et al.  Mutations in a TGF- b Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections , 2015 .

[100]  K. Bushby,et al.  Collagen type VI myopathies. , 2014, Advances in experimental medicine and biology.

[101]  C. Bönnemann,et al.  Chapter 70 – ECM-Related Myopathies and Muscular Dystrophies , 2012 .

[102]  E. Olson,et al.  Muscle : fundamental biology and mechanisms of disease , 2012 .

[103]  F. Muntoni,et al.  Core myopathies. , 2011, Seminars in Pediatric Neurology.

[104]  B. Thisse,et al.  Loss of selenoprotein N function causes disruption of muscle architecture in the zebrafish embryo. , 2007, Experimental Cell Research.

[105]  A. Banes,et al.  Early responses to mechanical load in tendon: role for calcium signaling, gap junctions and intercellular communication. , 2005, Journal of musculoskeletal & neuronal interactions.

[106]  T. Godwin,et al.  Congenital Muscular Dystrophy , 2015 .

[107]  A. Bulbena,et al.  Clinical assessment of hypermobility of joints: assembling criteria. , 1992, The Journal of rheumatology.