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. To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories - particularly chorea - and explore genotype-phenotype associations with clinical relevance. 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. Sixty-eight individuals (37 female; median age 16 years, range 2-60 years) were included. Motor delay was the commonest presenting feature (~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. 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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Benign hereditary chorea (BHC) is a rare childhood-onset hyperkinetic disorder caused by pathogenic variants in NKX2-1. It typically follows a stationary or only mildly progressive course and may be associated with thyroid and respiratory involvement, constituting the "brain-lung-thyroid" syndrome. We report the case of a girl carrying a novel heterozygous NKX2-1 frameshift variant. Clinical assessment included longitudinal neurological examinations, neuroimaging, laboratory testing, cardiological evaluation, and genetic analysis. A 6-year-old girl, first evaluated at age 3 for delayed psychomotor milestones, showed choreiform movements with motor impersistence, milkmaid's grip, and imbalance, sparing the forehead. Brain MRI was normal. Thyroid dysfunction was documented since foster care, while no respiratory involvement was reported. Genetic testing in August 2024 identified a novel heterozygous NKX2-1 frameshift variant (c.246_250del p.Met83AlafsTer354), classified as likely pathogenic. At last follow-up, movements persisted but remained non-progressive. This case expands the mutational spectrum of NKX2-1-related disorders. The stationary course of chorea, together with thyroid involvement and absence of pulmonary disease, aligns with previous literature. Recognition of novel NKX2-1 variants is essential to improve genotype-phenotype correlations, avoid misdiagnosis with progressive pediatric choreic or ataxic syndromes, and provide accurate prognostic counselling, as most affected individuals achieve a favorable long-term functional outcome.

Hereditary choreas are a clinically and genetically heterogeneous group of monogenic disorders in which chorea constitutes the core or an early-dominant feature. These conditions result from various genetic mutations affecting the structures and pathways involved in movement control, primarily the caudate and putamen, ultimately impairing the basal ganglia circuits involved in the regulation of movement, cognition, and behavior. This review focuses on the main forms of hereditary choreas, including Huntington's disease, neuroacanthocytosis syndromes, Huntington's disease phenocopies, benign hereditary chorea, and other less common genetic disorders presenting with chorea. We discuss the clinical, genetic, and pathophysiological features of each condition, alongside key aspects of phenomenology, examination, and complementary tests-including laboratory findings-to guide phenotype-driven genetic testing. We detail the characteristic features of key disorders while also highlighting less common but emerging conditions. This review aims to assist neurologists in recognizing and diagnosing hereditary choreas efficiently, including guidance on the selection of appropriate genetic tests, thereby reducing diagnostic delays, informing accurate counseling, and facilitating access to disease-specific interventions and clinical trials.

NKX2-1-related disorders (NKX2-1-RD) encompass a spectrum of conditions arising from pathogenic deletions or variants in the NKX2-1 gene, crucial for thyroid, lung, and brain development. Respiratory manifestations in NKX2-1-RD range from neonatal respiratory distress to severe lung diseases, constituting a leading cause of mortality. This study will review and synthesize NKX2-1-RD respiratory phenotypes, genetic alterations, and long-term trajectories. We conducted a systematic review using PRISMA and PICO question formats. From January 2002 to July 2023, major biomedical databases and rare disease resources were searched. Genetically confirmed NKX2-1-RD patients with respiratory symptoms were eligible for this study. Out of 4,569 studies, 38 met inclusion criteria, predominantly case reports and series. The study included 148 patients, revealing diverse respiratory phenotypes and treatments. Respiratory manifestations emerged at various ages, with neonatal respiratory distress, asthma, interstitial lung disease, and lung cancer observed. Nonsense mutations in NKX2-1 were linked to lung cancer. Treatment varied, including oxygen supplementation, ventilation, antibiotics, and lung transplantation. Long-term follow-up disclosed heterogeneous respiratory outcomes, with some patients asymptomatic while others faced chronic insufficiency or recurrent infections. The overall survival of informed cases was about 60%. This study highlights the complex respiratory manifestations of NKX2-1-RD and their impact on patient outcomes. The findings support standardized respiratory follow-up protocols and provide clinical management insights despite study quality and sample size limitations. We discuss the challenges of treating diverse respiratory conditions in this rare clinical entity and lay the groundwork for future research.

Chorea is a clinical sign characterized by involuntary, rapid, unpredictable, and irregular muscle movements that can affect various parts of the body. It can be seen in various medical conditions, both neurological and systemic, of genetic and acquired etiology. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been used to treat various types of chorea. The aim of this study was to evaluate the efficacy of GPi DBS for chorea in pediatric patients. The authors undertook a single-center retrospective study of all pediatric patients who underwent DBS in the period from July 2017 to April 2024 to identify those presenting with chorea. Three patients with chorea underwent bilateral posteroventral GPi DBS without surgical complications. The mean age at operation was 14.2 years (range: 1.5 years), and the mean follow-up was 49 months (range: 15 months). Two of the 3 patients experienced a positive effect on chorea with an improvement in functional status. In one patient, the pre- and postop Gross Motor Function Classification System (GMFCS) score was 4, while his Burke-Fahn-Marsden Dystonia Scale (BFMDS) score improved from 102/20 pre- to 53.5/20 postop. In the other patient the GMFCS score improved from 4 preop to 3 postop. His preop BFMDS score was not available, postop it was 83/120. In the patient who did not experience a positive effect on chorea the pre- and postop GMFCS score was 4, her BFMDS score was 84.5/120 pre- and 100/120 postop. Bilateral GPi DBS can be safely administered to pediatric patients with choreiform movement disorders, and it could be an effective treatment option for managing chorea in certain patients.