International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives

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 inco...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:dnet:r-iibsantpa_::5bb61290248c07b0aadb6a769e0aee51
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=21401
Access Level:acceso abierto
Palabra clave:chorea
benign hereditary chorea
brain-lung-thyroid syndrome
hypothyroidism
neonatal respiratory distress syndrome
neurodevelopmental delay
NKX2-1
TTF-1
Descripción
Sumario: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.

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