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Introduction <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Discussion <p>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.</p>

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A novel NKX2-1 frameshift variant expanding the genetic landscape of benign hereditary chorea

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Simone Aloisio,
  • Martina De Riggi,
  • Adriana Martini,
  • Sofia Grandolfo,
  • Daniele Birreci,
  • Luca Angelini,
  • Bianca Laura Cinicola,
  • Alberto Spalice,
  • Matteo Bologna

摘要

Introduction

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.

Methods

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.

Results

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.

Discussion

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.