International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives
Por:
Nou-Fontanet, L, Ravelli, C, Burglen, L, Mejia, SB, Valls-Villalba, A, Schiffels, ER, Innocenti, A, Villafuerte, B, Salazar-Villacorta, A, Quiroz, V, Jamardo, AS, Bonato, G, Díaz-Gomez, A, Afenjar, A, Vilain, C, Möller, PDD, Nuñez, DG, Krygier, M, Molnar, MJ, Milanowski, L, Ounap, K, Pauni, M, Vega, P, Borie, R, Villamil-Osorio, M, Yilmaz, S, Zádori, D, Zawadzka, M, Barakat, TS, Neuens, S, Benito, DD, 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, 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:
Nou-Fontanet, L:
ERN EpiCARE, Dept Neuropediat, Barcelona, Spain
Ravelli, C:
Sorbonne Univ, Armand Trousseau Hosp,APHP, Neurogenet Reference Ctr Rare Neurol Dis, Pediat Neurol Dept, Paris, France
Burglen, L:
Sorbonne Univ, Armand Trousseau Hosp, AP HP, Dept Genet,Reference Ctr Cerebellar Malformat & Co, Paris, France
Mejia, SB:
Univ Barcelona, St Joan de Deu Res Fdn, Barcelona, Spain
Valls-Villalba, A:
Univ Autonoma Barcelona, Vall Hebron Univ Hosp, Internal Med Dept, Barcelona, Spain
Schiffels, ER:
Univ Barcelona, St Joan de Deu Res Fdn, Barcelona, Spain
Innocenti, A:
Bambino Gesu Pediat Hosp, Epilepsy & Movement Disorders Unit, Neurol, IRCCS, Rome, Italy
EpiCARE, Rome, Italy
Villafuerte, B:
La Paz Univ Hosp Res Inst IdiPAZ, Inst Med & Mol Genet INGEMM, Thyroid Mol Lab, Madrid, Spain
Salazar-Villacorta, A:
UCL GOS Inst Child Hlth, Zayed Ctr Res Rare Dis Children, Dev Neurosci Dept, London, England
Quiroz, V:
Harvard Med Sch, Boston Childrens Hosp, Pediat Neurol Dept, Boston, MA USA
Jamardo, AS:
Marques de Valdecilla Univ Hosp, Pediat Neurol Unit, Santander, Spain
Bonato, G:
Univ Padua, Ctr Rare Neurol Dis ERN RND, Dept Neurosci, Parkinson & Movement Disorders Unit, Padua, Italy
Díaz-Gomez, A:
Univ Autonoma Barcelona, Hosp Santa Creu i Sant Pau, Pediat Neurol Unit, Barcelona, Spain
Afenjar, A:
Sorbonne Univ, Armand Trousseau Hosp, AP HP, Dept Genet,Reference Ctr Cerebellar Malformat & Co, Paris, France
Vilain, C:
Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Hop Univ Bruxelles, Dept Genet, Brussels, Belgium
Nuñez, DG:
Caceres Univ Hosp Complex, Pediat Neurol Unit, Caceres, Spain
Krygier, M:
Med Univ Gdansk, Dept Dev Neurol, Gdansk, Poland
Molnar, MJ:
Semmelweis Univ, Inst Genom Med & Rare Disorders, Budapest, Hungary
Milanowski, L:
Med Univ Warsaw, Fac Hlth Sci, Neurol Dept, Warsaw, Poland
Ounap, K:
Univ Tartu, Inst Clin Med, Tartu, Estonia
Genet & Personalized Med Clin, Tartu, Estonia
Tartu Univ Hosp, ERN ITHACA, Tartu, Estonia
Pauni, M:
Italian Hosp Buenos Aires, Pediat Neurol Dept, Buenos Aires, Argentina
Vega, P:
Italian Hosp Buenos Aires, Pediat Neurol Dept, Buenos Aires, Argentina
Borie, R:
Univ Paris Cite, Hop Bichat,AP AP,FHU INFIRE, Ctr Constitut Ctr Reference Malad Plum Rares,CRI, Serv Pneumol Allergol & Transplantat,UMR 1149,Inse, Paris, France
Villamil-Osorio, M:
Fdn Hosp Pediat Misericordia HOMI, Pediat Resp Dept, Bogota, Colombia
Yilmaz, S:
Ege Univ, Pediat Neurol Dept, Med Fac, Izmir, Turkiye
Zádori, D:
Univ Szeged, Neurol Dept, Szeged, Hungary
Zawadzka, M:
Med Univ Gdansk, Dept Dev Neurol, Gdansk, Poland
Barakat, TS:
Erasmus MC Univ Med Ctr Rotterdam, Dept Clin Genet, Rotterdam, Netherlands
Neuens, S:
Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Hop Univ Bruxelles, Dept Genet, Brussels, Belgium
Benito, DD:
ERN EpiCARE, Dept Neuropediat, Barcelona, Spain
Casas-Alba, D:
Univ Barcelona, Barcelona Childrens Hosp St Joan de Deu, Genet Dept, Barcelona, Spain
Soliani, L:
IRCCS Ist Sci Neurol Bologna, UOC Neuropsichiat Eta Pediat, Bologna, Italy
Garone, G:
Bambino Gesu Pediat Hosp, Epilepsy & Movement Disorders Unit, Neurol, IRCCS, Rome, Italy
EpiCARE, Rome, Italy
Specchio, N:
Bambino Gesu Pediat Hosp, Epilepsy & Movement Disorders Unit, Neurol, IRCCS, Rome, Italy
EpiCARE, Rome, Italy
Carecchio, M:
Univ Padua, Ctr Rare Neurol Dis ERN RND, Dept Neurosci, Parkinson & Movement Disorders Unit, Padua, Italy
Moreno, JC:
La Paz Univ Hosp Res Inst IdiPAZ, Inst Med & Mol Genet INGEMM, Thyroid Mol Lab, Madrid, Spain
Magrinelli, F:
UCL, UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England
Bhatia, KP:
UCL, UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England
Ebrahimi-Fakhari, D:
Harvard Med Sch, Boston Childrens Hosp, Pediat Neurol Dept, Boston, MA USA
Castiglioni, C:
Clin Meds Santiago, Pediat Neurol Dept, Santiago, Chile
Finis Terrae Univ, Fac Med, Santiago, Chile
Kurian, MA:
UCL GOS Inst Child Hlth, Zayed Ctr Res Rare Dis Children, Dev Neurosci Dept, London, England
Carvalho, JN:
Garcia De Orta Hosp, Ctr Desenvolvimento Crianca Torrado da Silva, Pediat Neurol, Almada, Portugal
Pons, R:
Childrens Hosp Agia Sofia, Pediat Neurol Dept, Athens, Greece
Roze, E:
Sorbonne Univ, Paris Brain Inst, AP HP, INSERM,CNRS,Inst Neurol, Paris, France
Doummar, D:
Sorbonne Univ, Armand Trousseau Hosp,APHP, Neurogenet Reference Ctr Rare Neurol Dis, Pediat Neurol Dept, Paris, France
Ortigoza-Escobar, JD:
ERN EpiCARE, Dept Neuropediat, Barcelona, Spain
Univ Barcelona, Barcelona Childrens Hosp St Joan de Deu, ERN RND, Barcelona, Spain
Harvard Med Sch, Div Movement Disorders, Deparment Neurol, Mass Gen Brigham, Boston, MA USA
Univ Sao Paulo, Pediat Neurol Dept, Sao Paulo, Brazil
Jose Alencar Brasilia Childrens Hosp, Neurol Dept, Brasilia, Brazil
Green Submitted, hybrid
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