International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives
Por:
Nou-Fontanet L, Ravelli C, Burglen L, Balsells S, Valls-Villalba A, Schiffels ER, Innocenti A, Villafuerte B, Salazar-Villacorta A, Quiroz V, Sariego Jamardo A, Bonato G, Díaz-Gomez A, Afenjar A, Vilain C, da Silva Möller PD, Garcia-Navas Nuñez D, Krygier M, Molnar MJ, Milanowski L, Õunap K, Pauni M, Vega P, Borie R, Villamil-Osorio M, Yilmaz S, Zádori D, Zawadzka M, Barakat TS, Neuens S, Natera-de Benito D, Casas-Alba D, Soliani L, de Gusmao CM, Garone G, Specchio N, Carecchio M, Moreno JC, Magrinelli F, Bhatia KP, Ebrahimi-Fakhari D, Castiglioni C, Kurian MA, Carvalho JN, Pons R, Roze E, Doummar D and Ortigoza-Escobar JD
Publicada:
1 abr 2026
Ahead of Print:
1 ene 2026
Resumen:
Background NKX2-1-related disorders result from heterozygous variants in NKX2-1, a gene crucial for brain, lung, and thyroid development. Although movement disorders, hypothyroidism, and neonatal respiratory distress are recognized, the full phenotype and genotype-phenotype relationships remain incompletely defined.
Objectives To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories - particularly chorea - and explore genotype-phenotype associations with clinical relevance.
Methods We conducted a multicenter, cross-sectional study recruiting participants through referral clinicians and European networks. Standardized clinical and genetic data were captured in an electronic database and analyzed with descriptive and inferential statistics.
Results Sixty-eight individuals (37 female; median age 16 years, range 2-60 years) were included. Motor delay was the commonest presenting feature (similar to 60%); neonatal respiratory distress syndrome occurred in one-third of cases. The brain-lung-thyroid triad was present in almost half. Chorea affected over 90% and began in early childhood; it was more frequent with single nucleotide variants than with deletions. Deletions are associated with better gross motor function. Frameshift or nonsense variants showed greater respiratory involvement, and variants in the exon-3 homeobox region were associated with age-related reduction of chorea. Neonatal respiratory distress predicted later respiratory symptoms. Greater abnormal involuntary movement severity correlated with poorer manual and gross motor function. Hypotonia and untreated hypothyroidism are associated with more severe chorea. Psychiatric comorbidity occurred in over one-third of cases, mainly attention-deficit/hyperactivity symptoms.
Conclusions This largest cohort to date shows early neurological onset, genotype-specific outcomes, and frequent psychiatric comorbidity in NKX2-1-related disorders, refining clinical expectations and supporting genotype-informed diagnosis, counseling, and management. (c) 2026 International Parkinson and Movement Disorder Society.
Filiaciones:
:
Neurology Department, Coordinating Member of the ERN EpiCARE and ERN-RND Member, Barcelona Children's Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Ravelli C:
Pediatric Neurology Department, Neurogenetic Reference Centre for Rare Neurological Diseases, Armand Trousseau Hospital APHP, Sorbonne Université, Paris, France
Burglen L:
Reference Center for Cerebellar Malformations and Congenital Diseases and Pediatric Neurogenetics Laboratory, Department of Genetics, AP-HP. Sorbonne University, Armand Trousseau Hospital, Paris, France
Balsells S:
Statistician, Sant Joan de Déu Research Foundation, University of Barcelona, Barcelona, Spain
Valls-Villalba A:
Internal Medicine Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain
:
Statistician, Sant Joan de Déu Research Foundation, University of Barcelona, Barcelona, Spain
Innocenti A:
Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of EpiCARE, Rome, Italy
Villafuerte B:
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Madrid, Spain
Salazar-Villacorta A:
Developmental Neurosciences Department, UCL GOS Institute of Child Health/Zayed Center for Research into Rare Disease in Children, London, UK
Quiroz V:
Pediatric Neurology Department, Boston Children's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA
Sariego Jamardo A:
Pediatric Neurology Unit, Marques de Valdecilla University Hospital, Santander, Spain
Bonato G:
Parkinson and Movement Disorders Unit, Department of Neuroscience, Centre for Rare Neurological Diseases (ERN-RND), University of Padova, Padova, Italy
Díaz-Gomez A:
Pediatric Neurology Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Afenjar A:
Reference Center for Cerebellar Malformations and Congenital Diseases and Pediatric Neurogenetics Laboratory, Department of Genetics, AP-HP. Sorbonne University, Armand Trousseau Hospital, Paris, France
Vilain C:
Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
da Silva Möller PD:
Neurology Department, Jose Alencar Brasilia Children's Hospital, Brasilia, Brazil
Garcia-Navas Nuñez D:
Pediatric Neurology Unit, Cáceres University Hospital Complex, Cáceres, Spain
Krygier M:
Department of Developmental Neurology, Medical University of Gdansk, Gdansk, Poland
Molnar MJ:
Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary
Milanowski L:
Neurology Department, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland
Õunap K:
Institute of Clinical Medicine, University of Tartu and Genetics and Personalized Medicine Clinic, Member of the ERN-ITHACA, Tartu University Hospital, Tartu, Estonia
Pauni M:
Pediatric Neurology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
Vega P:
Pediatric Neurology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
Borie R:
Université Paris Cité, UMR Inserm 1149, CRI, Hôpital Bichat, AP-HP, Service de Pneumologie Allergologie et Transplantation, Centre Constitutif du Centre de Référence des Maladies Pulmonaires Rares, FHU INFIRE, Paris, France
Villamil-Osorio M:
Pediatric Respiratory Department, Fundación Hospital Pediátrico la Misericordia HOMI, Bogotá, Colombia
Yilmaz S:
Pediatric Neurology Department, Ege University Medical Faculty, Izmir, Turkey
Zádori D:
Neurology Department, University of Szeged, Szeged, Hungary
Zawadzka M:
Department of Developmental Neurology, Medical University of Gdansk, Gdansk, Poland
Barakat TS:
Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
Neuens S:
Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
Natera-de Benito D:
Neurology Department, Coordinating Member of the ERN EpiCARE and ERN-RND Member, Barcelona Children's Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Casas-Alba D:
Genetics Department, Barcelona Children's Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Soliani L:
IRCCS Istituto Delle Scienze Neurologiche Di Bologna UOC Neuropsichiatria dell'età Pediatrica, Bologna, Italy
de Gusmao CM:
Pediatric Neurology Department, University of Sao Paulo, Sao Paulo, Brazil
Deparment of Neurology, Division of Movement Disorders, Mass General Brigham, Harvard Medical School, Boston, USA
Garone G:
Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of EpiCARE, Rome, Italy
Specchio N:
Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of EpiCARE, Rome, Italy
Carecchio M:
Parkinson and Movement Disorders Unit, Department of Neuroscience, Centre for Rare Neurological Diseases (ERN-RND), University of Padova, Padova, Italy
Moreno JC:
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Madrid, Spain
Magrinelli F:
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
Bhatia KP:
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
Ebrahimi-Fakhari D:
Pediatric Neurology Department, Boston Children's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA
Castiglioni C:
Pediatric Neurology Department, Clinica Meds Santiago, Santiago, Chile
Faculty of Medicine, Finis Terrae University, Santiago, Chile
Kurian MA:
Developmental Neurosciences Department, UCL GOS Institute of Child Health/Zayed Center for Research into Rare Disease in Children, London, UK
Carvalho JN:
Pediatric Neurology, Centro de Desenvolvimento da Criança Torrado da Silva, Garcia de Orta Hospital, Almada, Portugal
Pons R:
Pediatric Neurology Department, Children's Hospital Agia Sofia, Athens, Greece
Roze E:
Sorbonne University, INSERM, CNRS, Paris Brain Institute, AP-HP, Institute of Neurology, Paris, France
Doummar D:
Pediatric Neurology Department, Neurogenetic Reference Centre for Rare Neurological Diseases, Armand Trousseau Hospital APHP, Sorbonne Université, Paris, France
Ortigoza-Escobar JD:
Neurology Department, Coordinating Member of the ERN EpiCARE and ERN-RND Member, Barcelona Children's Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Jose Alencar Brasilia Childrens Hosp, Neurol Dept, Brasilia, Brazil
Univ Sao Paulo, Pediat Neurol Dept, Sao Paulo, Brazil
Harvard Med Sch, Div Movement Disorders, Deparment Neurol, Mass Gen Brigham, Boston, MA USA
Jose Alencar Brasilia Childrens Hosp, Neurol Dept, Brasilia, Brazil
Univ Sao Paulo, Pediat Neurol Dept, Sao Paulo, Brazil
Harvard Med Sch, Div Movement Disorders, Deparment Neurol, Mass Gen Brigham, Boston, MA USA
Green Submitted, Green Published, hybrid
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