Dear Editor,

NKX2-1-related disorder or benign hereditary chorea (BHC) is a rare disorder with heterogeneous clinical features characterized by childhood-onset chorea combined with other neurological, pulmonary and endocrinological abnormalities [1]. We report the first Indian patient with BHC due to a de novo mutation in the NKX2-1 gene.

A 5-year-old male patient, first born to nonconsanguineous parents, presented with abnormal “fidgetiness” from early infancy. He was born at term by normal delivery. There were no perinatal complications. He was noted to have exhibited abnormal movements at 12 months of age, which had since been nonprogressive. He had delayed motor milestones. Although he was able to sit without support at one year of age, he tended to fall forward when seated. He also required two-person support to ambulate from the age of three years. His speech was mildly dysarthric. He had a history of recurrent pulmonary infections. He was found to have hypothyroidism at the age of 2.5 years, at which point he was on levothyroxine supplementation, with good control. There was no worsening during the night, seizures, or behavioral issues. There was no significant family history. Upon examination, the child was alert and found to have continuous generalized chorea (Supplementary Video 1 in the online-only Data Supplement). He had truncal and gait instability and central hypotonia. The deep tendon reflexes were normal.

Hemogram, liver and renal function tests were normal. MRI of the brain and chest X-ray were normal. Whole exome sequencing of the proband revealed a heterozygous variant on chr14: 36517778:T>C (c.706A>G; p.Lys236Glu/K236E) in the NKX2-1 gene (ENST00000354822.7) in exon 3. This variation was located in the DNA binding domain of NKX2-1 and is a hotspot region for reported pathogenic variations (with a length of 17 amino acids, 15 reported pathogenic variations exist, for example, ACMG:PM1). This variation was not detected in the 1000 Genomes Project, gnomAD, TOPMed or Exome sequencing project (ACMG:PM2), and multiple lines of computation predictions were supportive of likely pathogenic outcomes (ACMG: PP3; based on a Mendelian clinically applicable pathogenicity score of 0.9307 and MetaRNN of -0.9551 and a CADD score of 31). The variant was not reported in the HGMD or ClinVar. The reference codon is conserved across species. Neither of the parents harbored this variation, confirming its de novo nature. Together, we considered this variation to be likely pathogenic (ACMG criteria-PP3, PM1 and PM2). Moreover, a recent study showed that the same K236E variant observed in our patient has a dominant negative effect on wild-type NK2X-1 by impairing its binding to the thyroglobulin promoter. This study provided functional evidence of the pathogenic nature of this variant [2]. In addition, we also observed a heterozygous variant on chr7:152262989delA (c.1326delA; p.Phe442LeufsTer28) in the KMT2C gene (ENST00000681082) in exon 9. This latter variant was also likely pathogenic (ACMG-PVS1 and PM2) and is known to cause Kleefstra syndrome type 2 [3]. Sanger sequencing revealed that this latter variant was present in the father, who was asymptomatic, but was not present in the mother. A diagnosis of BHC due to a novel de novo variant in the NKX2-1 gene was made. The patient was treated with a combination of levodopa and carbidopa (50/12.5 mg thrice daily), with mild improvement in chorea.

BHC was first reported in 1967 among 32 members of a fivegeneration African-American family in the United States, whose dominant features included chorea and motor delay [4]. The phenotypic spectrum has gradually expanded to include myoclonus, dystonia, ataxia, tics, falls, drop attacks, and tremors. Variants in the NKX2-1 gene were identified as the underlying cause in 2000 [5]. Extraneurological involvement (pulmonary/thyroid abnormalities) and a plethora of associated features, including short stature, joint hypermobility, and sensorineural hearing loss, were also identified [1]. Classically, chorea in BHC has an onset in early childhood, as observed in our patient, and tends to remain stable or improve in adolescence or early adulthood.

The combination of brain and thyroid involvement, as in our case, is observed in up to 50% of patients [1]. Thyroid involvement may manifest as congenital hypothyroidism [2] or compensated hypothyroidism in childhood or even adulthood [6]. Our patient had well-controlled hypothyroidism with onset in early childhood and motor delay. This presentation contrasted with that of the patient with the same variant reported by Li et al. [2], who had congenital hypothyroidism and marked motor and language developmental delay. One-third of patients have the typical triad of “brain-lung-thyroid” involvement. Respiratory involvement may include neonatal respiratory distress syndrome, recurrent chest infections, obstructive airway disease, and interstitial lung disease [7]. Our patient had a history of recurrent childhood infections, although his lungs were normal upon evaluation. A differential for childhood-onset chorea with hypothyroidism includes Allan-Herndon-Dudley syndrome due to SLC16A2 mutation, which encodes for monocarboxylate transporter 8. This is a rare, X-linked disorder associated with dysmorphism [8]. Apart from chorea, neurological features included spastic paraplegia, dystonia and paroxysmal dyskinesia.

Mutations in the NKX2-1 (previously called Thyroid transcription factor 1, TITF1) gene cause pleiotropic manifestations, as NKX2-1 is essential for the development of the basal ganglia, thyroid and lungs [7,9,10]. Sometimes, given a particular locus, variable clinical expression is noted, for example, at the 238 amino acid position, a change from tryptophan > leucine/serine is associated with BHC, tryptophan > cysteine is linked to thyroid dysgenesis, and the tryptophan > stop codon is linked to “brainthyroid– lung” syndrome. Overall, the mutation observed in our patient was a missense change at position 236, in which lysine was changed to glutamine, which might have affected the DNA binding efficiency of NKX2-1, thus hampering its promoter binding activity to its targets. The other observed truncating variant in KMT2C is also of interest in view of the clinical phenotype; however, the presence of this variant in one parent ruled out a clear penetrating nature of the variation. No ethical differences or genotype-phenotype correlations have yet been noted in NKX2-1 disorders, although significant inter- and intrafamilial phenotypic heterogeneity has been observed. However, data from Southeast Asia are lacking, and hence, there are no studies on ethical differences in the current literature.

We report the first Indian patient with BHC who manifested two features of the classical BHC triad due to a de novo variant in the NKX2-1 gene.

Supplementary Materials

Notes

Ethics Statement

The study was approved by the Institutional Review Board of the All India Institute of Medical Sciences (File number: IEC-273/16.05.2023, RP 10.23/ OP 20/12.01.2024). Informed consent was obtained from the parents.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Divyani Garg, Mohammed Faruq. Data curation: Divyani Garg, Ayush Agarwal, Mohammed Faruq. Investigation: Divyani Garg. Supervision: Achal Kumar Srivastava. Validation: Divyani Garg. Visualization: Divyani Garg, Ayush Agarwal, Mohammed Faruq. Writing—original draft: Divyani Garg. Writing—review & editing: Ayush Agarwal, Mohammed Faruq, Achal Kumar Srivastava.

Acknowledgments

The authors wish to thank the patient and his family for their cooperation.

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