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.

The transcription factor NK2 homeobox1 (NKX2-1), associated with brain lung thyroid syndrome, regulates the transcription of surfactant proteins, thyroglobulin (TG) and thyroid peroxidase (TPO). This study explored the pathogenicity of three NKX2-1 variants (p.(Tyr214Cys), p.(Arg165Trp) and p.(Gly147Ala)) that were identified in three infants with lethal forms of childhood interstitial lung disease. HEK293T cells were co-transfected with expression plasmids of NKX2-1 (wild-type (WT) and variants) and PAX8, along with reporter plasmids containing the promoters of SFTPB, SFTPC, TG and TPO). Protein expression was analyzed by western blotting and immunofluorescence. Luciferase assays were performed to evaluate the activation of different promoters. Surfactant protein and NKX2-1 expression were also assessed on patient lung biopsies using immunohistochemistry. All three mutant proteins exhibited nuclear localization. Protein expression was altered in the p.(Tyr214Cys) and p.(Arg165Trp) variants located in NKX2.1 homeodomain. The p.(Tyr214Cys) variant failed to transactivate the tested promoters and was associated with a lack of pro-SP-C and SP-C expression in lung biopsy whereas the p.(Arg165Trp) variant induced both gain- or loss-of-function effects on the tested promoters. Finally, the p.(Gly147Ala) variant transactivated all the promoters tested, as for the WT. Conclusion: Our results demonstrated the pathogenicity of two variants, p.(Tyr214Cys) and p.(Arg165Trp), located within the homeodomain of NKX2-1. Conversely, the p.(Gly147Ala) variant showed no pathogenic effects. To date, the p.(Tyr214Cys) variant is associated with the most severe respiratory phenotype reported for NKX2-1-related disorders. Further studies are needed to understand the specific mechanisms underlying the pathogenicity of NKX2.1 variants located in the homeodomain.

This study presents a case of brain-lung-thyroid syndrome caused by a pathogenic variant in the NKX2-1 gene, which is characterized by interstitial lung disease. A 7-month-old female infant was hospitalized for over half a month for cyanosis. The full-term infant developed respiratory distress syndrome soon after delivery, requiring mechanical ventilation, and was diagnosed with congenital hypothyroidism. In the first seven months of life, the infant also showed hypotonia, feeding difficulties, and developmental delays. Chest CT findings demonstrated generalized ground-glass opacities in both lung fields. A heterozygous pathogenic variant of the NKX2-1 gene [NM_001079668.3:c.583C>T (p.Arg195Trp)] was identified by whole-exome sequencing. The infant received a combination therapy, comprising supplementary thyroxine, nutritional support, high-flow nasal cannula oxygen therapy, and exploratory treatment with hydroxychloroquine. High-flow nasal cannula oxygen therapy was administered after discharge. The patient was followed up for over 2 months, and the patient had changed to low-flow oxygen therapy, although she developed radiographic progression. Studies on hydroxychloroquine for the treatment of interstitial lung diseases are limited. This article describes a case of interstitial lung disease caused by a pathogenic variant in the NKX2-1 gene, whose oxygen demand decreased after treatment with hydroxychloroquine.

To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS). A child who had presented at the Children's Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis. The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c.674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation. Discovery of the novel c.674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.