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  • Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

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Phenotypes
Review
Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features
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  1. Marguerite Miguet1,
  2. Laurence Faivre2,
  3. Jeanne Amiel3,
  4. Mathilde Nizon3,
  5. Renaud Touraine4,
  6. Fabienne Prieur4,
  7. Laurent Pasquier5,
  8. Mathilde Lefebvre2,
  9. Julien Thevenon2,
  10. Christèle Dubourg6,
  11. Sophie Julia7,
  12. Catherine Sarret8,
  13. Ganaëlle Remerand8,
  14. Christine Francannet9,
  15. Fanny Laffargue9,
  16. Odile Boespflug-Tanguy10,
  17. Albert David11,
  18. Bertrand Isidor11,
  19. Jacqueline Vigneron12,
  20. Bruno Leheup12,
  21. Laetitia Lambert12,
  22. Christophe Philippe13,
  23. Mylène Béri-Dexheimer13,
  24. Jean-Marie Cuisset14,
  25. Joris Andrieux15,
  26. Ghislaine Plessis16,
  27. Annick Toutain17,
  28. Laurent Guibaud18,
  29. Valérie Cormier-Daire3,
  30. Marlene Rio3,
  31. Jean-Paul Bonnefont19,
  32. Bernard Echenne20,
  33. Hubert Journel21,
  34. Lydie Burglen22,
  35. Sandrine Chantot-Bastaraud22,
  36. Thierry Bienvenu23,
  37. Clarisse Baumann24,
  38. Laurence Perrin24,
  39. Séverine Drunat25,
  40. Pierre-Simon Jouk26,
  41. Klaus Dieterich26,
  42. Françoise Devillard26,
  43. Didier Lacombe27,
  44. Nicole Philip28,
  45. Sabine Sigaudy28,
  46. Anne Moncla29,
  47. Chantal Missirian29,
  48. Catherine Badens30,
  49. Nathalie Perreton31,
  50. Christel Thauvin-Robinet2,
  51. Réseau AChro-Puce32,
  52. Jean-Michel Pedespan33,
  53. Caroline Rooryck27,
  54. Cyril Goizet27,
  55. Catherine Vincent-Delorme34,
  56. Bénédicte Duban-Bedu35,
  57. Nadia Bahi-Buisson36,
  58. Alexandra Afenjar37,
  59. Kim Maincent37,
  60. Delphine Héron38,
  61. Jean-Luc Alessandri39,
  62. Dominique Martin-Coignard40,
  63. Gaëtan Lesca41,42,
  64. Massimiliano Rossi41,42,
  65. Martine Raynaud43,
  66. Patrick Callier44,
  67. Anne-Laure Mosca-Boidron44,
  68. Nathalie Marle44,
  69. Charles Coutton45,
  70. Véronique Satre45,
  71. Cédric Le Caignec46,47,
  72. Valérie Malan48,
  73. Serge Romana48,
  74. Boris Keren49,
  75. Anne-Claude Tabet50,
  76. Valérie Kremer51,
  77. Sophie Scheidecker51,
  78. Adeline Vigouroux52,
  79. Marilyn Lackmy-Port-Lis53,
  80. Damien Sanlaville54,
  81. Marianne Till54,
  82. Maryline Carneiro55,
  83. Brigitte Gilbert-Dussardier56,
  84. Marjolaine Willems57,
  85. Hilde Van Esch58,
  86. Vincent Des Portes59,60,
  87. Salima El Chehadeh1,2
  1. 1 Service de génétique médicale, Institut de Génétique Médicale d’Alsace (IGMA), Centre de Référence Maladies Rares “Anomalies du développement et syndromes malformatifs”, Centre de Référence Maladies Rares “Des déficiences intellectuelles de causes rares”, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
  2. 2 FHU TRANSLAD, Centre de Référence Maladies Rares «Anomalies du développement et syndromes malformatifs», Centre de Génétique, CHU de Dijon, Dijon, France
  3. 3 Service de Génétique Clinique, Hôpital Necker Enfants Malades, APHP, Paris, France
  4. 4 Service de Génétique Clinique, CHU de Saint-Etienne, Saint-Etienne, France
  5. 5 Service de Génétique Clinique, CLAD Ouest, CHU de Rennes, Rennes, France
  6. 6 Laboratoire de Génétique Moléculaire, CHU de Rennes, Rennes, France
  7. 7 Service de Génétique Médicale, CHU de Toulouse, Toulouse, France
  8. 8 Service de Neuropédiatrie, CHU de Clermont-Ferrand, Clermont-Ferrand, France
  9. 9 Service de Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France
  10. 10 Service de Neuropédiatrie et Maladies Métaboliques, Hôpital Robert Debré, APHP, Paris, France
  11. 11 Service de Génétique Médicale, CHU de Nantes, Nantes, France
  12. 12 Service de Génétique Médicale, CHU de Nancy, Nancy, France
  13. 13 Laboratoire de Génétique Médicale, CHU de Nancy, Nancy, France
  14. 14 Service de Neuropédiatrie, CHRU de Lille, Lille, France
  15. 15 Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France
  16. 16 Service de Génétique, CHU de Caen, Caen, France
  17. 17 Service de Génétique, CHRU de Tours, Tours, France
  18. 18 Service de Radiologie, Hôpital Femme Mère Enfant, Bron, France
  19. 19 Laboratoire de Biologie Moléculaire, Hôpital Necker Enfants Malades, APHP, Paris, France
  20. 20 Service de Neurologie pédiatrique, CHU de Montpellier, Montpellier, France
  21. 21 Service de Génétique, Centre Hospitalier de Vannes, Vannes, France
  22. 22 Service de Génétique, Hôpital Armand Trousseau, APHP, Paris, France
  23. 23 Laboratoire de Génétique Moléculaire, GH Cochin-Broca Hôtel Dieu, APHP, Paris, France
  24. 24 Service de Génétique Clinique, Hôpital Robert Debré, APHP, Paris, France
  25. 25 Laboratoire de Biologie Moléculaire, Hôpital Robert Debré, APHP, Paris, France
  26. 26 Département de Génétique et Procréation - UMR CNRS 5525 TIMC-IMAG - équipe DYCTIM, CHU Grenoble, Grenoble, France
  27. 27 Université de Bordeaux, Laboratoire MRGM, INSERM U1211 and Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
  28. 28 Département de Génétique Médicale, Hôpital de la Timone, Marseille, France
  29. 29 Laboratoire de Génétique Chromosomique, Hôpital de la Timone, Marseille, France
  30. 30 Laboratoire de Biologie Moléculaire, Hôpital de la Timone, Marseille, France
  31. 31 CIC1407 Inserm, CHU de Lyon, Lyon, France
  32. 32 Réseau d’Analyse Chromosomique sur Puces à ADN (AChro-Puce)
  33. 33 Unité de Neuropédiatrie, CHU Pellegrin, Bordeaux, France
  34. 34 Clinique de Génétique Guy Fontaine, CHRU de Lille, Hôpital Jeanne de Flandre, Lille, France
  35. 35 Centre de Génétique Chromosomique, GH de l’Institut Catholique de Lille, Hôpital Saint-Vincent-de-Paul, Lille, France
  36. 36 Service de Neuropédiatrie, Hôpital Necker Enfants Malades, APHP, Paris, France
  37. 37 Département de Génétique Médicale, Centre de Référence "Malformations et maladies congénitales du cervelet", APHP, Hôpital Armand Trousseau, APHP, Paris, France
  38. 38 Service de Génétique Clinique, Hôpital Pitié-Salpêtrière, APHP, Paris, France
  39. 39 Service de Pédiatrie, CHU Félix Guyon, Saint-Denis, France
  40. 40 UF génétique médicale, Centre Hospitalier du Mans, Le Mans, France
  41. 41 Service de génétique, Hospices Civils de Lyon, Lyon, France
  42. 42 INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Lyon, France
  43. 43 Laboratoire de Génétique Moléculaire, CHRU de Tours, Tours, France
  44. 44 Laboratoire de Cytogénétique, CHU de Dijon, Dijon, France
  45. 45 Laboratoire de Cytogénétique, CHU de Grenoble, Grenoble, France
  46. 46 Laboratoire de Cytogénétique, CHU de Nantes, Nantes, France
  47. 47 Sarcomes osseux et remodelage des tissus calcifiés, Université Bretagne Loire, INSERM, UMR1238, Nantes, France
  48. 48 Laboratoire de Cytogénétique, Hôpital Necker Enfants Malades, APHP, Paris, France
  49. 49 Laboratoire de Cytogénétique, Hôpital Pitié-Salpêtrière, APHP, Paris, France
  50. 50 Laboratoire de Cytogénétique, Hôpital Robert Debré, APHP, Paris, France
  51. 51 Laboratoire de Cytogénétique, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
  52. 52 Laboratoire de Cytogénétique, CHU de Toulouse, Toulouse, France
  53. 53 Service de Génétique Médicale, CHU de Pointe à Pitre, Pointe à Pitre, France
  54. 54 Laboratoire de Cytogénétique, CHU de Lyon, Lyon, France
  55. 55 Service de Neuropédiatrie, CHU de Lyon, Hôpital Femme-Mère-Enfant, Lyon, France
  56. 56 Service de Génétique Médicale, CHU de Poitiers, Poitiers, France
  57. 57 Service de Génétique Médicale, CHU de Montpellier, Montpellier, France
  58. 58 Laboratory for Genetics of Cognition, Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
  59. 59 Centre de Référence Maladies Rares «Des déficiences intellectuelles de causes rares», HFME, Hospices Civils de Lyon and Université de Lyon, Lyon, France
  60. 60 Institut des Sciences Cognitives, CNRS UMR 5304, Bron, France
  1. Correspondence to Dr Salima El Chehadeh, Service de génétique médicale, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg 67098, France; salima.elchehadeh{at}chru-strasbourg.fr

Abstract

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

  • X-linked
  • genetic counselling
  • MECP2duplication syndrome
  • MECP2gene
  • Xq28 duplication
  • facial dysmorphism

https://doi.org/10.1136/jmedgenet-2017-104956

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    Footnotes

    • Contributors MM wrote the paper, MN, CD, CP, JA, JPB, SCB, TB, MT, SDS, SD, AM, CB, CRT, GL, MR, CM, JT, MBD, DS, PC, ALM, NM, CC, VS, VM, SR, BK, ACT, VK, SS, AV and RAP analysed the cytogenetic and molecular data. LF, JA, RT, FP, LP, ML, SJ, CS, CF, FL, OBT, AD, BI, JV, BL, LL, JMC, GP, AT, AG, VCD, MR, BE, GR, HJ, LB, CB, LP, PSJ, KD, FD, DL, NP, SS, CTR, JMP, CG, CVD, BDB, NBB, AA, KM, CLC, DH, JLA, GL, MLPL, MR, BGD, MW, MC, HVE and DMC are the referring clinicians. LG interpreted brain MRI of many patients of the cohort, VD and NP respectively directed and organised the PHRC RMLX, SEC collected the clinical and molecular data and the photographs during consultations (for 25 patients) or by contacting the clinicians and the labs, and supervised this work.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval The ethics committee “Comité de Protection des Personnes SUD-EST II” delivered a favourable opinion (22 September 2010) with regard to the realisation of the XLID Research Project 2008-2016 (RMLX).

    • Provenance and peer review Not commissioned; externally peer reviewed.