Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Author:

Pelletier Félixe12345,Perrier Stefanie14ORCID,Cayami Ferdy K67ORCID,Mirchi Amytice12345ORCID,Saikali Stephan8ORCID,Tran Luan T1234,Ulrick Nicole9,Guerrero Kether1234ORCID,Rampakakis Emmanouil2ORCID,van Spaendonk Rosalina M L10ORCID,Naidu Sakkubai11,Pohl Daniela12ORCID,Gibson William T13ORCID,Demos Michelle14,Goizet Cyril15,Tejera-Martin Ingrid16ORCID,Potic Ana17,Fogel Brent L18,Brais Bernard1319ORCID,Sylvain Michel20,Sébire Guillaume221,Lourenço Charles Marques22ORCID,Bonkowsky Joshua L23,Catsman-Berrevoets Coriene24,Pinto Pedro S25ORCID,Tirupathi Sandya26,Strømme Petter27,de Grauw Ton28ORCID,Gieruszczak-Bialek Dorota2930ORCID,Krägeloh-Mann Ingeborg31ORCID,Mierzewska Hanna32,Philippi Heike33,Rankin Julia34,Atik Tahir35ORCID,Banwell Brenda36,Benko William S37,Blaschek Astrid38,Bley Annette39,Boltshauser Eugen40,Bratkovic Drago41,Brozova Klara42,Cimas Icíar43,Clough Christopher44,Corenblum Bernard45,Dinopoulos Argirios46,Dolan Gail47,Faletra Flavio48ORCID,Fernandez Raymond49,Fletcher Janice50,Garcia Garcia Maria Eugenia51,Gasparini Paolo52,Gburek-Augustat Janina53,Gonzalez Moron Dolores54,Hamati Aline55,Harting Inga56ORCID,Hertzberg Christoph57,Hill Alan58,Hobson Grace M59ORCID,Innes A Micheil60ORCID,Kauffman Marcelo61,Kirwin Susan M62ORCID,Kluger Gerhard63,Kolditz Petra64,Kotzaeridou Urania65,La Piana Roberta66ORCID,Liston Eriskay67,McClintock William6869,McEntagart Meriel70ORCID,McKenzie Fiona7172,Melançon Serge73,Misbahuddin Anjum74,Suri Mohnish75ORCID,Monton Fernando I16ORCID,Moutton Sebastien76ORCID,Murphy Raymond P J77,Nickel Miriam78ORCID,Onay Hüseyin79ORCID,Orcesi Simona80ORCID,Özkınay Ferda81ORCID,Patzer Steffi82,Pedro Helio83,Pekic Sandra84ORCID,Pineda Marfa Mercedes85ORCID,Pizzino Amy8687,Plecko Barbara88,Poll-The Bwee Tien89,Popovic Vera90,Rating Dietz91,Rioux Marie-France92,Rodriguez Espinosa Norberto16ORCID,Ronan Anne93ORCID,Ostergaard John R94ORCID,Rossignol Elsa95,Sanchez-Carpintero Rocio96ORCID,Schossig Anna97,Senbil Nesrin98,Sønderberg Roos Laura K99,Stevens Cathy A100,Synofzik Matthis101ORCID,Sztriha László102ORCID,Tibussek Daniel103ORCID,Timmann Dagmar104ORCID,Tonduti Davide105ORCID,van de Warrenburg Bart P106ORCID,Vázquez-López Maria107,Venkateswaran Sunita108,Wasling Pontus109ORCID,Wassmer Evangeline110,Webster Richard I111,Wiegand Gert112113ORCID,Yoon Grace114,Rotteveel Joost115ORCID,Schiffmann Raphael116ORCID,van der Knaap Marjo S6117,Vanderver Adeline9118ORCID,Martos-Moreno Gabriel Á119120121ORCID,Polychronakos Constantin122ORCID,Wolf Nicole I6ORCID,Bernard Geneviève12345

Affiliation:

1. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

2. Department of Pediatrics, McGill University, Montreal, QC, Canada

3. Department of Human Genetics, McGill University, Montreal, QC, Canada

4. Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada

5. Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada

6. Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

7. Center of Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

8. Department of Pathology, Centre Hospitalier Universitaire de Québec, Québec City, QC, Canada

9. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

10. Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

11. Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

12. Division of Neurology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada

13. Department of Medical Genetics, University of British Columbia, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

14. Division of Neurology, Department of Pediatrics, University of British Columbia, BC Children’s Hospital, Vancouver, BC, Canada

15. Centre de Référence Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital, and Laboratoire MRGM, INSERM U1211, Université de Bordeaux, Bordeaux, France

16. Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Canary Islands, Spain

17. Department of Neurology, Clinic for Child Neurology and Psychiatry, Medical Faculty University of Belgrade, Belgrade, Serbia

18. Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

19. Montreal Neurological Institute, Montreal, QC, Canada

20. Centre Mère Enfant, CHU de Québec, Québec City, QC, Canada

21. Department of Pediatrics, Université de Sherbrooke, Sherbrooke, QC, Canada

22. Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, SP, Brazil

23. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

24. Department of Paediatric Neurology, Erasmus University Hospital - Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands

25. Neuroradiology Department, Centro Hospitalar do Porto, Porto, Portugal

26. Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK

27. Division of Pediatrics and Adolescent Medicine, Oslo University Hospital, Ullevål, 0450 Oslo, and University of Oslo, Oslo, Norway

28. Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA

29. Department of Medical Genetics, Children’s Memorial Health Institute, Warsaw, Poland

30. Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland

31. Department of Child Neurology, University Children’s Hospital Tübingen, Tübingen, Germany

32. Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland

33. Center of Developmental Neurology (SPZ Frankfurt Mitte), Frankfurt, Germany

34. Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

35. Division of Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

36. Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

37. Division of Pediatric Neurology, Department of Neurology, UC Davis Health System, Sacramento, CA, USA

38. Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany

39. University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

40. Department of Child Neurology, University Children’s Hospital Zurich, Zurich, Switzerland

41. Metabolic Clinic, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia

42. Department of Child Neurology, Thomayers Hospital, Prague, Czech Republic

43. Department of Neurology, Povisa Hospital, Vigo, Spain

44. Department of Neurology, King’s College Hospital, London, UK

45. Division of Endocrinology & Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada

46. Third Department of Pediatrics, National and Kapodistrian University of Athens, “Attikon” Hospital, Athens, Greece

47. Bristow Pediatrics, Bristow, VA, USA

48. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy

49. Pediatric Neurology Associates, Tampa, FL, USA

50. Genetics and Molecular Pathology, Women’s and Children’s Hospital, Adelaide, South Australia, Australia

51. Department of Neurology, The Royal London Hospital, London, UK

52. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34100 Trieste, and University of Trieste, Trieste, Italy

53. Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany

54. Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia, ADC, Buenos Aires, Argentina

55. Department of Child Neurology, Indiana University, Indianapolis, IN, USA

56. Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany

57. Department of Child Neurology, Vivantes Klinikum, Berlin, Germany

58. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

59. Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

60. Department of Medical Genetics and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada

61. Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia and CONICET, ADC, Buenos Aires, Argentina

62. Molecular Diagnostics Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

63. PMU Salzburg, 5020 Salzburg, Austria; Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany

64. Department of Child Neurology, Kantonsspital Luzern, Luzern, Switzerland

65. Department of Child Neurology, University Children’s Hospital Heidelberg, Heidelberg, Germany

66. Department of Neuroradiology, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada

67. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

68. Pediatric Specialists of Virginia, Fairfax, VA, USA

69. Department of Neurology, Children’s National Medical Center, Washington, DC, USA

70. South West Thames Regional Genetics Service, St. George’s Hospital, London, UK

71. Genetic Services of Western Australia, Subiaco, WA, Australia

72. School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia

73. Department of Medical Genetics, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada

74. Essex Centre for Neurological Sciences, Queen’s Hospital, Romford, UK

75. Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK

76. Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France

77. Department of Neurology, Tallaght University Hospital, Tallaght, Ireland

78. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

79. Department of Medical Genetics, Ege University, Izmir, Turkey

80. Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy

81. Department of Pediatrics, Subdivision of Pediatric Genetics, Faculty of Medicine, Ege University, Izmir, Turkey

82. Children’s Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany

83. Department of Pediatrics, The Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ, USA

84. Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center, Belgrade & School of Medicine, University of Belgrade, Belgrade, Serbia

85. Hospital Sant Joan de Deu, Passeig de Sant Joan de Deu nº2, Barcelona, Spain

86. Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

87. Department of Genetics, MetroHealth Hospital, Cleveland, OH, USA

88. Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria

89. Department of Pediatric Neurology, Emma Children’s Hospital, 1105 Amsterdam, The Netherlands

90. Medical Faculty, University of Belgrade, Belgrade, Serbia

91. Department of Paediatric Neurology, University Children’s Hospital, Heidelberg, Germany

92. Centre Hospitalier Universitaire de Sherbrooke - Hôpital Fleurimont, Sherbrooke, QC, Canada

93. Hunter New England LHD, University of Newcastle, NSW, Australia

94. Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark

95. Departments of Neurosciences and Pediatrics, CHU-Sainte-Justine, Université de Montréal, Montreal, QC, Canada

96. Pediatric Neurology Unit, Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain

97. Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

98. Department of Child Neurology, Kırıkkale University Medical Faculty, Kırıkkale, Turkey

99. Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark

100. Department of Pediatrics, Division of Medical Genetics, University of Tennessee College of Medicine, Chattanooga, TN, USA

101. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

102. Department of Paediatrics, University of Szeged, Szeged, Hungary

103. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany

104. Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany

105. Child Neurology Unit, V. Buzzi Children’s Hospital, Milano, Italy

106. Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands

107. Sección Neuropediatría. Hospital Maternoinfantil Gregorio Marañón, Madrid, Spain

108. Division of Neurology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

109. Department of Neuroscience and Rehabilitation, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

110. Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, UK

111. T. Y. Nelson Department of Neurology and Neurosurgery and the Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia

112. Department of Pediatric Neurology, University Hospital Kiel, Germany

113. Neuropediatrics Section of the Department of Pediatrics, Asklepios Clinic Hamburg Nord-Heidberg, Hamburg, Germany

114. Division of Clinical and Metabolic Genetics, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

115. Emma Children’s Hospital, Amsterdam UMC, Pediatric Endocrinology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

116. Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA

117. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands

118. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

119. Department of Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain

120. Department of Pediatrics, Universidad Autónoma de Madrid, 28049 Madrid, Spain

121. CIBER de Fisiopatologia de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

122. Division of Endocrinology, Montreal Children’s Hospital and the Endocrine Genetics Lab, Research Institute of the McGill University Health Centre, Montreal, QC, Canada

Abstract

Abstract Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Funder

Canadian Institutes of Health Research

Fonds de Recherche du Québec–Santé

Compute Canada

McGill Faculty of Medicine

Ministry of National Education, Republic of Indonesia

BC Children’s Hospital Foundation

National Institute of Neurological Disorders and Stroke

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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