Félixe Pelletier1,2,3,4,5,6, Stefanie Perrier1,4, Ferdy K Cayami7,8, Amytice Mirchi1,2,3,4,5, Stephan Saikali9, Luan T Tran1,2,3,4, Nicole Ulrick10, Kether Guerrero1,2,3,4, Emmanouil Rampakakis2, Rosalina M L van Spaendonk11, Sakkubai Naidu12, Daniela Pohl13, William T Gibson14, Michelle Demos15, Cyril Goizet16, Ingrid Tejera-Martin17, Ana Potic18, Brent L Fogel19, Bernard Brais1,3,20, Michel Sylvain21, Guillaume Sébire2,22, Charles Marques Lourenço23, Joshua L Bonkowsky24, Coriene Catsman-Berrevoets25, Pedro S Pinto26, Sandya Tirupathi27, Petter Strømme28, Ton de Grauw29, Dorota Gieruszczak-Bialek30,31, Ingeborg Krägeloh-Mann32, Hanna Mierzewska33, Heike Philippi34, Julia Rankin35, Tahir Atik36, Brenda Banwell37, William S Benko38, Astrid Blaschek39, Annette Bley40, Eugen Boltshauser41, Drago Bratkovic42, Klara Brozova43, Icíar Cimas44, Christopher Clough45, Bernard Corenblum46, Argirios Dinopoulos47, Gail Dolan48, Flavio Faletra49, Raymond Fernandez50, Janice Fletcher51, Maria Eugenia Garcia Garcia52, Paolo Gasparini53, Janina Gburek-Augustat54, Dolores Gonzalez Moron55, Aline Hamati56, Inga Harting57, Christoph Hertzberg58, Alan Hill59, Grace M Hobson60, A Micheil Innes61, Marcelo Kauffman62, Susan M Kirwin63, Gerhard Kluger64, Petra Kolditz65, Urania Kotzaeridou66, Roberta La Piana67, Eriskay Liston68, William McClintock69,70, Meriel McEntagart71, Fiona McKenzie72,73, Serge Melançon74, Anjum Misbahuddin75, Mohnish Suri76, Fernando I Monton17, Sebastien Moutton77, Raymond P J Murphy78, Miriam Nickel79, Hüseyin Onay80, Simona Orcesi81, Ferda Özkınay82, Steffi Patzer83, Helio Pedro84, Sandra Pekic85, Mercedes Pineda Marfa86, Amy Pizzino87,88, Barbara Plecko89, Bwee Tien Poll-The90, Vera Popovic91, Dietz Rating92, Marie-France Rioux93, Norberto Rodriguez Espinosa17, Anne Ronan94, John R Ostergaard95, Elsa Rossignol96, Rocio Sanchez-Carpintero97, Anna Schossig98, Nesrin Senbil99, Laura K Sønderberg Roos100, Cathy A Stevens101, Matthis Synofzik102, László Sztriha103, Daniel Tibussek104, Dagmar Timmann105, Davide Tonduti106, Bart P van de Warrenburg107, Maria Vázquez-López108, Sunita Venkateswaran109, Pontus Wasling110, Evangeline Wassmer111, Richard I Webster112, Gert Wiegand113,114, Grace Yoon115, Joost Rotteveel116, Raphael Schiffmann117, Marjo S van der Knaap7,118, Adeline Vanderver10,119, Gabriel Á Martos-Moreno120,121,122, Constantin Polychronakos123, Nicole I Wolf7, Geneviève Bernard1,2,3,4,5. 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. Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada. 7. Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 8. Center of Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia. 9. Department of Pathology, Centre Hospitalier Universitaire de Québec, Québec City, QC, Canada. 10. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 11. Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 12. Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA. 13. Division of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada. 14. Department of Medical Genetics, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, BC, Canada. 15. Division of Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada. 16. Centre de Référence Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital, and Laboratoire MRGM, INSERM U1211, Université de Bordeaux, Bordeaux, France. 17. Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Canary Islands, Spain. 18. Department of Neurology, Clinic for Child Neurology and Psychiatry, Medical Faculty University of Belgrade, Belgrade, Serbia. 19. Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. 20. Montreal Neurological Institute, Montreal, QC, Canada. 21. Centre Mère Enfant, CHU de Québec, Québec City, QC, Canada. 22. Department of Pediatrics, Université de Sherbrooke, Sherbrooke, QC, Canada. 23. Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, SP, Brazil. 24. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. 25. Department of Paediatric Neurology, Erasmus University Hospital - Sophia Children's Hospital, 3015 CN Rotterdam, The Netherlands. 26. Neuroradiology Department, Centro Hospitalar do Porto, Porto, Portugal. 27. Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK. 28. Division of Pediatrics and Adolescent Medicine, Oslo University Hospital, Ullevål, 0450 Oslo, and University of Oslo, Oslo, Norway. 29. Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA. 30. Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland. 31. Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland. 32. Department of Child Neurology, University Children's Hospital Tübingen, Tübingen, Germany. 33. Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland. 34. Center of Developmental Neurology (SPZ Frankfurt Mitte), Frankfurt, Germany. 35. Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 36. Division of Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey. 37. Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 38. Division of Pediatric Neurology, Department of Neurology, UC Davis Health System, Sacramento, CA, USA. 39. Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany. 40. University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 41. Department of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland. 42. Metabolic Clinic, Women's and Children's Hospital, North Adelaide, South Australia, Australia. 43. Department of Child Neurology, Thomayers Hospital, Prague, Czech Republic. 44. Department of Neurology, Povisa Hospital, Vigo, Spain. 45. Department of Neurology, King's College Hospital, London, UK. 46. Division of Endocrinology & Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada. 47. Third Department of Pediatrics, National and Kapodistrian University of Athens, "Attikon" Hospital, Athens, Greece. 48. Bristow Pediatrics, Bristow, VA, USA. 49. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. 50. Pediatric Neurology Associates, Tampa, FL, USA. 51. Genetics and Molecular Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia. 52. Department of Neurology, The Royal London Hospital, London, UK. 53. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34100 Trieste, and University of Trieste, Trieste, Italy. 54. Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany. 55. Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia, ADC, Buenos Aires, Argentina. 56. Department of Child Neurology, Indiana University, Indianapolis, IN, USA. 57. Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany. 58. Department of Child Neurology, Vivantes Klinikum, Berlin, Germany. 59. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. 60. Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA. 61. Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada. 62. Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia and CONICET, ADC, Buenos Aires, Argentina. 63. Molecular Diagnostics Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA. 64. PMU Salzburg, 5020 Salzburg, Austria; Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany. 65. Department of Child Neurology, Kantonsspital Luzern, Luzern, Switzerland. 66. Department of Child Neurology, University Children's Hospital Heidelberg, Heidelberg, Germany. 67. Department of Neuroradiology, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada. 68. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. 69. Pediatric Specialists of Virginia, Fairfax, VA, USA. 70. Department of Neurology, Children's National Medical Center, Washington, DC, USA. 71. South West Thames Regional Genetics Service, St. George's Hospital, London, UK. 72. Genetic Services of Western Australia, Subiaco, WA, Australia. 73. School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia. 74. Department of Medical Genetics, McGill University Health Centre, Montreal Children's Hospital, Montreal, QC, Canada. 75. Essex Centre for Neurological Sciences, Queen's Hospital, Romford, UK. 76. Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK. 77. Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France. 78. Department of Neurology, Tallaght University Hospital, Tallaght, Ireland. 79. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 80. Department of Medical Genetics, Ege University, Izmir, Turkey. 81. Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy. 82. Department of Pediatrics, Subdivision of Pediatric Genetics, Faculty of Medicine, Ege University, Izmir, Turkey. 83. Children's Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany. 84. Department of Pediatrics, The Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA. 85. Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center, Belgrade & School of Medicine, University of Belgrade, Belgrade, Serbia. 86. Hospital Sant Joan de Deu, Passeig de Sant Joan de Deu nº2, Barcelona, Spain. 87. Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 88. Department of Genetics, MetroHealth Hospital, Cleveland, OH, USA. 89. Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria. 90. Department of Pediatric Neurology, Emma Children's Hospital, 1105 Amsterdam, The Netherlands. 91. Medical Faculty, University of Belgrade, Belgrade, Serbia. 92. Department of Paediatric Neurology, University Children's Hospital, Heidelberg, Germany. 93. Centre Hospitalier Universitaire de Sherbrooke - Hôpital Fleurimont, Sherbrooke, QC, Canada. 94. Hunter New England LHD, University of Newcastle, NSW, Australia. 95. Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark. 96. Departments of Neurosciences and Pediatrics, CHU-Sainte-Justine, Université de Montréal, Montreal, QC, Canada. 97. Pediatric Neurology Unit, Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain. 98. Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria. 99. Department of Child Neurology, Kırıkkale University Medical Faculty, Kırıkkale, Turkey. 100. Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. 101. Department of Pediatrics, Division of Medical Genetics, University of Tennessee College of Medicine, Chattanooga, TN, USA. 102. 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. 103. Department of Paediatrics, University of Szeged, Szeged, Hungary. 104. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany. 105. Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany. 106. Child Neurology Unit, V. Buzzi Children's Hospital, Milano, Italy. 107. Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands. 108. Sección Neuropediatría. Hospital Maternoinfantil Gregorio Marañón, Madrid, Spain. 109. Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. 110. Department of Neuroscience and Rehabilitation, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 111. Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK. 112. 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. 113. Department of Pediatric Neurology, University Hospital Kiel, Germany. 114. Neuropediatrics Section of the Department of Pediatrics, Asklepios Clinic Hamburg Nord-Heidberg, Hamburg, Germany. 115. Division of Clinical and Metabolic Genetics, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. 116. Emma Children's Hospital, Amsterdam UMC, Pediatric Endocrinology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 117. Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA. 118. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands. 119. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 120. Department of Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain. 121. Department of Pediatrics, Universidad Autónoma de Madrid, 28049 Madrid, Spain. 122. CIBER de Fisiopatologia de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 123. Division of Endocrinology, Montreal Children's Hospital and the Endocrine Genetics Lab, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
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.
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 4Hleukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4Hleukodystrophy 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 4Hleukodystrophy 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 4Hleukodystrophy. 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.
Authors: Sumit Parikh; Geneviève Bernard; Marc C Patterson; Ryan J Taft; Adeline Vanderver; Richard J Leventer; Marjo S van der Knaap; Johan van Hove; Amy Pizzino; Nathan H McNeill; Guy Helman; Cas Simons; Johanna L Schmidt; William B Rizzo Journal: Mol Genet Metab Date: 2014-12-29 Impact factor: 4.797
Authors: Roberta La Piana; Ferdy K Cayami; Luan T Tran; Kether Guerrero; Rosalina van Spaendonk; Katrin Õunap; Sander Pajusalu; Tobias Haack; Evangeline Wassmer; Dagmar Timmann; Hanna Mierzewska; Bwee T Poll-Thé; Chirag Patel; Helen Cox; Tahir Atik; Huseyin Onay; Ferda Ozkınay; Adeline Vanderver; Marjo S van der Knaap; Nicole I Wolf; Geneviève Bernard Journal: Neurology Date: 2016-03-30 Impact factor: 9.910
Authors: E Jurkiewicz; D Dunin-Wąsowicz; D Gieruszczak-Białek; K Malczyk; K Guerrero; M Gutierrez; L Tran; G Bernard Journal: Clin Neuroradiol Date: 2015-10-19 Impact factor: 3.649
Authors: Isabelle Thiffault; Nicole I Wolf; Diane Forget; Kether Guerrero; Luan T Tran; Karine Choquet; Mathieu Lavallée-Adam; Christian Poitras; Bernard Brais; Grace Yoon; Laszlo Sztriha; Richard I Webster; Dagmar Timmann; Bart P van de Warrenburg; Jürgen Seeger; Alíz Zimmermann; Adrienn Máté; Cyril Goizet; Eva Fung; Marjo S van der Knaap; Sébastien Fribourg; Adeline Vanderver; Cas Simons; Ryan J Taft; John R Yates; Benoit Coulombe; Geneviève Bernard Journal: Nat Commun Date: 2015-07-07 Impact factor: 14.919
Authors: Emilio Merheb; Min-Hui Cui; Juwen C DuBois; Craig A Branch; Maria Gulinello; Bridget Shafit-Zagardo; Robyn D Moir; Ian M Willis Journal: Proc Natl Acad Sci U S A Date: 2021-10-05 Impact factor: 11.205