
==== Front
J Neural Transm (Vienna)
J Neural Transm (Vienna)
Journal of Neural Transmission
0300-9564
1435-1463
Springer Vienna Vienna

38916623
2800
10.1007/s00702-024-02800-3
Neurology and Preclinical Neurological Studies - Review Article
Differential diagnosis of Huntington’s disease− neurological aspects of NKX2-1-related disorders
http://orcid.org/0009-0005-2157-4905
Skwara Julia 1
Nowicki Maciej 1
Sharif Lucia 1
http://orcid.org/0000-0003-4197-8518
Milanowski Łukasz lukasz.milanowski@wum.edu.pl

2
Dulski Jarosław 34
Elert-Dobkowska Ewelina 5
Skrzypek Katarzyna 6
Hoffman-Zacharska Dorota 6
Koziorowski Dariusz 2
Sławek Jarosław 37
1 https://ror.org/04p2y4s44 grid.13339.3b 0000 0001 1328 7408 Student’s Scientific Group, Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland
2 https://ror.org/04p2y4s44 grid.13339.3b 0000 0001 1328 7408 Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, Ludwika Kondratowicza 8, Warsaw, 03-242 Poland
3 Department of Neurology and Stroke, St. Adalbert Hospital, Gdańsk, Poland
4 https://ror.org/02qp3tb03 grid.66875.3a 0000 0004 0459 167X Department of Neurology, Mayo Clinic, Jacksonville, FL USA
5 https://ror.org/0468k6j36 grid.418955.4 0000 0001 2237 2890 Department of Genetics, Institute Psychiatry and Neurology, Warsaw, Poland
6 grid.418838.e 0000 0004 0621 4763 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
7 grid.11451.30 0000 0001 0531 3426 Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, Gdańsk, Poland
25 6 2024
25 6 2024
2024
131 9 10131024
15 3 2024
12 6 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington’s disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Keywords

Benign hereditary chorea
Brain-lung-thyroid syndrome
Dystonia
Huntington’s disease
NKX2-1
NKX2-1-related disorders
http://dx.doi.org/10.13039/501100004166 Warszawski Uniwersytet Medyczny NZP/NM1/18 Sharif Lucia issue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2024
==== Body
pmcIntroduction

Chorea can be a symptom of a variety of diseases, including hereditary neurological disorders, and their list is constantly increasing due to the availability of advanced molecular diagnostic techniques. The discovery of new genes, followed by the investigation of further cases with partially described phenotypes, often leads to the recognition of additional aspects of the disorders. Chorea is the major phenotypic aspect of Huntington’s disease (HD) (OMIM #143,100) as well as other Huntington-like syndromes and benign hereditary chorea (BHC) – a clinical manifestation of the NKX2-1-related disorders.

BHC is a rare autosomal dominant disorder. It was linked to chromosome 14q13 and a mutation in the NKX2-1 gene (OMIM *600,635) was identified as a causative factor ending the controversy about the existence of BHC as a separate entity (Fernandez et al. 2001; Kleiner-Fisman et al. 2003). BHC usually has a childhood-onset, nonprogressive, with involuntary jerk-like movements, and sometimes with a tendency to improve in adulthood.

However, it is not always benign and the spectrum of manifestations is wide and complex. Neurological symptoms may manifest as chorea, choreoathetosis, developmental delay, cognitive deficits, hypotonia, myoclonus, ataxia, drop attacks, dystonia, and psychiatric disorders. Pulmonary dysfunction, which include respiratory distress syndrome and interstitial lung disease are the second most common manifestation (Gras et al. 2012). Patients might also present with congenital or compensated hypothyroidism due to thyroid dysfunction (Fig. 1).

Fig. 1 Phenotypes of NKX2-1-related disorders. It may manifest in one organ, or any combination, with all three being the “brain-lung-thyroid” syndrome. Created with BioRender.com

The NKX2-1-related disorders are diagnosed by identifying a heterozygous pathogenic variant in the NKX2-1 gene (Patel and Jankovic 2014 [updated 2023]). Both sporadic and familial forms have been reported. According to OMIM, both BHC (OMIM #118,700), chorea, congenital hypothyroidism with or without pulmonary dysfunction (CAHTP, OMIM #610,978); and susceptibility to nonmedullary thyroid cancer-1 (NMTC1, OMIM #188,550), are related to mutations in the NKX2-1 gene.

In the Human Gene Mutation Database (HGMD Professional v.2024.1, 04.2024) 187 pathogenic/likely pathogenic mutations have been described. Mutations are dominant and haploinsufficiency due to loss of function is accepted as a mechanism of disease causation.

The NKX2-1 gene encodes Homeobox protein Nkx-2.1 (alternatively named Thyroid transcription factor 1, TTF-1; UniProt, https://www.uniprot.org/uniprotkb/P43699) which is expressed during early development of thyroid, lung, and forebrain regions, particularly the basal ganglia and hypothalamus. The most frequently reported symptoms are related to the central nervous system, lungs, and thyroid gland, hence the clinical term NKX2-1-related disorders - “brain-lung-thyroid syndrome”. According to the available data, among individuals affected with NKX2-1-related disorders, 50% had the full brain-lung-thyroid syndrome, 30% brain and thyroid involvement, and 13% chorea only (Carré et al. 2009; Parnes et al. 2019).

The Nkx2-1 protein expression is modulated by various regulatory factors. What is more, this protein as nuclear transcription factor is involved in the regulation of expression of other genes necessary in the lung, thyroid and nervous system.

The TIF-1 protein cooperates with a lot of hormones and cytokines, such as thyroid stimulating hormone (TSH), nuclear factor (NFI) (Nakazato et al. 2000), hepatocyte nuclear factor-3 (HNF-3β) (Ikeda et al. 1996), SMAD family member 2 (Smad2) (Li et al. 2013), forkhead box protein A1 (FOXA1) (Minoo et al. 2007), forkhead box protein P2 (FOXP2) (Zhou et al. 2008), GATA-binding factor 6 (GATA6) (Yin et al. 2006) and TTF1 itself (Oguchi and Kimura 1998). TSH when binding to its thyroid stimulating hormone receptor (TSHR) activates the cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) pathway, which enhances the NKX2-1 expression as well as its activity (Guan et al. 2021) (Fig. 2).

Fig. 2 Upstream and downstream targets of NKX2-1. * activation in cooperation with PAX8. ** inhibits NKX2-1 in inflammation. SP, surfactant protein; CCSP, clara cell secretory protein; BMP-4, bone morphogenic protein 4; URP-1, uteroglobin related protein 1; NestBS, nestin binding site; ABCA, ATP-binding cassette sub-family A; RET, rearranged during transfection gene; SCGB3A2, secretoglobin 3A2. Based on Atlas of Genetics and Cytogenetics in Oncology and Haematology (Wilbertz et al. 2010). Created with BioRender.com

This paper describes two Polish families with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8) and gathers data about other previously reported cases of patients with NKX2-1 mutation that presented neurological disorders. The report pays particular attention to a rare case of familial co-occurrence of HD and NKX2-1-related disorders, which could be distinguished based on molecular tests.

Materials and methods

Clinical and genetic analysis

One family member from Family A and three from Family B of Polish origin were recruited from the Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk and Neurology Dpt., St. Adalbert Hospital in Gdansk (Family A) Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, in Warsaw (Family B), Poland.

The clinical diagnosis was established by two experienced movement disorders specialists (DK and JS) and blood samples were collected from the patients. Whole exome sequencing - WES (SureSelect Human All Exon v6 enrichment, Illumina NovaSeq 6000 platform, annotations according to Department of Medical Genetics, Institute of Mother and Child pipeline, VEP2.7) was performed for probands from Family B. The cosegregation of nominated variants was confirmed with Sanger sequencing in the two affected family B members (proband’s mother and brother). In proband from Family A direct Sanger sequencing of the NKX2-1 gene (exons, exons/introus boundaries) was performed.

HTT (CAG)n repeat numbers were analysed using the standard procedure (Warner et al. 1993). PCR was performed with fluorescently labelled primers and 4% polyacrylamide gel electrophoresis on an ABI Prism 377 plate sequencer (Applied Biosystems).

NKX2-1 variants reporting

There are two highly conserved NKX2-1 transcripts. The longer mRNA-isoform 1 NM_001079668 contains exons 1, 2, and 3, whereas mRNA-isoform 2 NM_003317 contains only exons 2 and 3. Isoform 2 is the predominant and isoform 1 represents the minor transcript. However, because the most pathogenic variants in NKX2-1 have been reported in this transcript the described variants are reported in relation to GRCh38 NM_001079668.3 MANE Select reference sequence (https://www.ncbi.nlm.nih.gov/nuccore/NM_001079668.3) and according to HGVS nomenclature recommendation v.21.0.2 (https://hgvs-nomenclature.org/stable/).

Data analysis

PubMed database was searched using the following keywords; “benign hereditary chorea”, “TTF-1”, “brain-lung-thyroid syndrome”, “NKX2-1”, “chorea”, “choreoathetosis”, “ataxia”, “dystonia”, “neurology”, and “myoclonus”. A total of 49 articles were selected and included in this analysis.

Results

Presentation of cases

Family A

Proband (III-3) is a male patient who was diagnosed with infant hypotonia and delayed psychomotor development (Video 1). He could sit and walk at 2 and 5 years, respectively, and presented with mild cognitive impairment. At 5 years of age, he developed nonprogressive, generalized, mild chorea and dystonia followed by ataxia. He was also diagnosed with apathy and depression, hypothyroidism, and recurrent respiratory tract infections complicated by pneumothorax. He was initially treated with sulpiride, tiapride, and pridinol. However, these were discontinued due to their side effects. A trial with L-Dopa to exclude levodopa responsive dystonia was ineffective. He benefitted only from clonazepam. Brain MRI showed frontotemporal and cerebellar atrophy. He is still independent in his daily activities. The proband had two older brothers; the oldest (III-1) was diagnosed with a congenital heart defect and hypothyroidism and died when he was 6 months old, whereas the second brother (III-2) presented with chorea when he was 3 years old accompanied by hypothyroidism. There was a positive family history of similar symptoms on both the maternal and paternal side of the family. The proband’s father (II-1) showed generalized chorea with childhood-onset, developed alcoholism in adulthood, and died of colorectal cancer. The proband’s mother was healthy; however, her three siblings (II-2-4) presented with chorea and were diagnosed with HD, as well as proband’s grandmother (I-1) and her siblings (I-2-4). The molecular analysis of the HTT in subjects II-2 and II-3 revealed the presence of (CAG)n repeats in the pathogenic range (genotypes: 47/19 and 49/15) and these results confirmed clinical diagnosis. The analysis of HTT gene (CAG)n expansion was also performed for proband’s mother II-1 (carrier status) and father II-1’ (diagnostic test) and the results were negative (Fig. 3). Wilson disease was molecularly excluded for the proband. Subsequently, the analysis of NKX2-1 gene revealed a presence of heterozygous substitution c.623G > T causing the missense variant p.(Trp208Leu), classified as pathogenic (Table 1). The identified variant, was already known and described in databases as pathogenic (HGMD 2024.1; accession: CM020775) causative for BHC (Breedveld et al. 2002) and pathogenic/likely pathogenic (ClinVar ID:8974 accession: VCV000008974.8) causative for BHC/Brain-lung-thyroid syndrome.

Fig. 3 Pedigree of two described families carrying the NKX2-1 mutations Family A (p.Thr208Leu) and Family B (p.Cys117Alafs*8).

Table 1 NKX2-1 variants characteristic

Fam	c.DNA
NM_001-79668.3	Protein
NP_001073136.1	ACMG criteria	CADD	Missense prediction	gnomAD frequency
(v.3.1.2)	Final pathogenicity
Classification*	Ref.	
MutTaster	PolyPhen2 (HumVar)	
A	c.623G > T	p.(Trp208Leu)	P	29.7	Deleterious	Probably Damaging	0	Pathogenic	Breedveld (2002)	
B	c.348del	p.(Cys117Alafs*8)	LP	38.0	-	-	0	Pathogenic	-	
P – pathogenic. LP – likely pathogenic

* interpretation of pathogenicity based on all analyzed criteria

During the 20-year follow-up, the proband’s symptoms did not progress and he remains independent in the activities of daily living at the age of 42.

Family B

A 29-year-old proband (III-1) presented with generalized dystonia affecting the face, neck, trunk, limbs (more affected on the left side than the right side), and slight dysarthria. There was no improvement after alcohol usage. He was born at term from an uneventful pregnancy. The involuntary movements began in early childhood and were first recognized as myoclonus. Developmental delay was observed in this patient in his. He was diagnosed with mild mental impairment. (He also suffered from hypothyroidism and depression. He was first admitted to the Department of Neurology when he was 18 years old. MRI was impossible to perform. His younger brother (III-2) had right limb dystonia and hypothyroidism. His mother (II-1) had cervical dystonia from early childhood with lower limb chorea and hypothyroidism. Analysis of the TOR1A, THAP1, and SGCE genes excluded dystonia type 1, 6 (DYT1, DYT6) and myoclonus dystonia (DYT11). WES revealed the presence of heterozygous deletion c.348delC, causing the frameshift variant p.(Cys117Alafs*8). This variant is new and has not been described previously. Because the mutation is a truncating variant in a gene where loss of function (LOF) is the mutational mechanism, and due to its cosegregation with the disease phenotype in the family (Fig. 3), this variant was recognized as likely pathogenic according to ACMG guidelines. Consequently, it was classified as pathogenic (Table 1). To exclude levodopa-responsive dystonia, the proband’s treatment was started with levodopa 300 mg with no improvement in the involuntary movements. His dystonia was treated with botulinum toxin injections and finally with globus pallidus DBS when he was 23 years old with a good response (Online Resource 1). This was the first DBS treatment of a NKX2-1-related dystonia.

NKX2-1- related disorders – literature review

The literature search identified 49 publications that described 195 patients with confirmed NKX2-1 gene mutations (Krude et al. 2002; Kawano et al. 2003; Doyle et al. 2004; Willemsen et al. 2005; Asmus et al. 2005, 2007; Costa et al. 2005; Moya et al. 2006; Glik et al. 2008; Provenzano et al. 2008, 2016; Nagasaki et al. 2008; Ferrara et al. 2008, 2012; Carré et al. 2009; Salvatore et al. 2010; Armstrong et al. 2011; Gras et al. 2012; Fons et al. 2012; Teissier et al. 2012; Konishi et al. 2013; Peall et al. 2014; McMichael et al. 2013; Nettore et al. 2013; Shetty et al. 2014; Thorwarth et al. 2014; Veneziano et al. 2014; Rosati et al. 2015; Williamson et al. 2014; de Gusmao et al. 2016; Monti et al. 2015; Tozawa et al. 2016; Koht et al. 2016; Shiohama et al. 2018; Gauquelin et al. 2017; Blumkin et al. 2018; Tübing et al. 2018; Parnes et al. 2019; Basu et al. 2018; Villafuerte et al. 2018; Iodice et al. 2019; Balicza et al. 2018; Gonçalves et al. 2019; Milone et al. 2019; Prasad et al. 2019; Graziola et al. 2021; Liao et al. 2021; Thust et al. 2022; Lamiral et al. 2020). The two probands were also added to this review study (Table 2).

Table 2 Clinical characteristics of our two probands and percentage analysis of all affected individuals found in the literature (including probands). n = 197

Clinical feature	Proband 1	Proband 2	% of affected individuals	
Chorea and choreiform movements	+	-	84.3%	
Delayed motor development (milestones)	+	+	81.2%	
Hypotonia	+	-	47.7%	
Dysarthria	+	+	25.4%	
Cognitive delay and learning difficulties	+	+	24.9%	
Dystonia	+	+	23.9%	
Ataxia	+	-	23.4%	
Myoclonus	-	+	14.7%	
Choreoathetosis	-	-	10.2%	
Abnormalities in MRI	+	n/a	20.2%*	
Thyroid manifestation	+	+	67%	
Lung manifestation	+	-	48.2%	
* out of 104 patients who had an available MRI

Most of the analyzed patients (81.2%) had delayed motor milestones and a significant group (24.9%) had cognitive impairment. Only 3% of the described patients had an intellectual disability. Chorea and choreiform movements occurred in 84.3% of the patients, making it the most common symptom of NKX2-1-related disorders, which is why it is described in the literature as benign hereditary chorea. However, there are other neurological features that the patient can present, which makes the term “benign hereditary chorea” quite inaccurate since symptoms such as hypotonia (47.7%), dysarthria (25.4%), dystonia (23.9%), ataxia (23.4%), myoclonus (14.7%), and choreoathetosis (10.2%) can occur, sometimes in one patient.

In some cases, ataxia and ataxic gait were the symptoms preceding actual choreiform movements during infancy and childhood. There are examples of patients in which ataxia completely ended and was replaced by chorea (McMichael et al. 2013).

Moreover, there is an example in the literature of a 49-year-old patient with the NKX2-1 mutation who presented with ataxic gait, but chorea had still not occurred. Therefore, NKX2-1-related disorders could be mistaken for ataxic cerebral palsy (McMichael et al. 2013).

8% of analyzed patients had attention-deficit hyperactivity disorder (ADHD), a notably high percentage that merits consideration of the potential interrelationship with the NKX2-1 mutation. Several neuropsychiatric symptoms and disorders occurred in these analyzed cases, such as depression(Liao et al. 2021; Balicza et al. 2018; Salvatore et al. 2010; Ferrara et al. 2012), psychosis (Glik et al. 2008; Salvatore et al. 2010; Ferrara et al. 2012), schizophrenia (Glik et al. 2008), autism spectrum disorder (Milone et al. 2019; Shetty et al. 2014), anxiety (Balicza et al. 2018; Basu et al. 2018), obsessive-compulsive disorder (Peall et al. 2014; Parnes et al. 2019), conduct disorder (Liao et al. 2021) and disruptive behavior disorder (Liao et al. 2021).

Some individuals (3.6%) had a history of seizures (epileptic or non-epileptic). Loss of NKX2-1 gene function in a mouse model during early neurogenesis causes seizures and hyperkinetic movements, resulting from a reduction of GABAergic cortical interneurons (Ferrara et al. 2012).

Other rare symptoms described in individual cases include apraxia (Veneziano et al. 2014; Thust et al. 2022; Salvatore et al. 2010), spasticity (Costa et al. 2005; Balicza et al. 2018; Liao et al. 2021), tics (Rosati et al. 2015; Gras et al. 2012; Koht et al. 2016), dysdiadochokinesis (Veneziano et al. 2014; Thust et al. 2022), dysmetria (Tübing et al. 2018; Provenzano et al. 2016; Gonçalves et al. 2019), stuttering (Costa et al. 2005; Ferrara et al. 2012; Koht et al. 2016), tremor (Liao et al. 2021; Williamson et al. 2014; Peall et al. 2014; Glik et al. 2008; Gras et al. 2012), nystagmus (Provenzano et al. 2016; Liao et al. 2021), dyslexia (Balicza et al. 2018) and restless leg syndrome (Iodice et al. 2019). Further studies are required to determine the linkage between these symptoms and NKX2-1 pathogenic variants.

Thyroid manifestation

67% of patients had a thyroid manifestation of the disorder, such as congenital hypothyroidism, subclinical hypothyroidism, or thyroid dysgenesis.

Lung manifestation

More than 48% of patients had a lung manifestation of the disorder, such as neonatal respiratory distress syndrome, asthma, frequent respiratory infections, or lung cancer.

MRI

In most analyzed cases, magnetic resonance imaging (MRI) of the brain showed no abnormalities. However, 20.2% of patients who had an MRI had structural brain anomalies, such as cavum septum pellucidum (Balicza et al. 2018); hypoplastic pallidum (Krude et al. 2002); agenesis of the corpus callosum (Carré et al. 2009); ventricular dilatation (Salvatore et al. 2010); hippocampal dysmorphism (Iodice et al. 2019); Chiari malformation type 1 (Gonçalves et al. 2019); or mild cerebellar atrophy (Provenzano et al. 2016; Costa et al. 2005). Pituitary anomalies occurred in 61.9% of patients that had an abnormal MRI, such as abnormal sella turcica (Krude et al. 2002); empty sella (Balicza et al. 2018; Salvatore et al. 2010); pituitary cysts (Thust et al. 2022; Krude et al. 2002; Veneziano et al. 2014); anterior displacement of pituitary stalk and gland (Thust et al. 2022); or decreased size of the pituitary gland (Prasad et al. 2019; Iodice et al. 2019).

Other non-neurological manifestations

Single articles describe various symptoms that occur in patients with NKX2-1 gene mutation: erectile dysfunction (Balicza et al. 2018); immunodeficiency (Villafuerte et al. 2018); ligamentous laxity (Villafuerte et al. 2018; Peall et al. 2014; Parnes et al. 2019); pes cavus (Costa et al. 2005; Peall et al. 2014); genitourinary abnormalities (Ferrara et al. 2008; Salvatore et al. 2010); congenital heart defect (Thorwarth et al. 2014); or hypodontia (Villafuerte et al. 2018). Further studies are required to determine the significance of these findings.

Differential diagnosis

In some cases, primarily diagnosed with BHC, the HD, myoclonic dystonia, hereditary essential myoclonus or tics were found (Schrag et al. 2000). Chorea minima, physiologic chorea of infancy, idiopathic chorea or oro-bucco-lingual dyskinesia should be considered in the differential diagnosis in individuals with chorea characterized as childhood-onset and nonprogressive. Disorders such as ADCY5-associated disease; tumor-related chorea; Wilson disease; developmental chorea; Lesch-Nyhan syndrome; cerebral palsy or others where chorea is associated with progressive neurological and cognitive dysfunction can be differentiated from those related to NKX2-1 mutations (Patel and Jankovic 2014 [updated 2023]).

Huntington’s disease

Choreiform movements in HD progress, in contrast to BHC, where they are described as nonprogressive. HD leads to marked cognitive dysfunction whereas in BHC, the patients’ cognition remains normal or only slightly impaired (Kleiner-Fisman 2011) (Table 3).

Table 3 Chorea – differential diagnosis. Based on a review article by Termsarasab (2019)

	Disorder	Onset of chorea*	Cause/pattern	Duration	
Hereditary causes of chorea	Huntington disease	Adult	HTT gene mutation

Autosomal dominant

	chronic	
Huntington disease like-2 (HDL-2)	Adult	JPH3 gene mutation

Autosomal dominant

	
Chorea-acanthocytosis	Adult	VPS13A

Autosomal recessive

	
C9orf72 disease	Adult	C9orf72 gene mutation

Autosomal dominant

	
Wilson disease	childhood	ATP7B gene mutation

Autosomal recessive

	
Lesch-Nyhan syndrome	childhood	HPRT1 gene mutation

X-linked recessive

	
NKX2-1-related disorders	childhood	NKX2-1 gene mutation

Autosomal dominant

	
ADCY5-related dyskinesia	childhood	ADCY5 gene mutation

Autosomal dominant

	
Acquired causes of chorea	endocrine/metabolic	sporadic	e.g. hypoglycemia

hyperthyroidism

	acute/subacute	
tumor-related chorea	structural lesion	
drug-induced	e.g. levodopa, lithium, amphetamine	
infectious	e.g. HIV, toxoplasmosis	
Sydenham chorea	childhood	autoimmune

(group A beta-haemolytic Streptococcus infection)

	
	Cerebral palsy	childhood	combination of genetic and neurometabolic causes	chronic	
*- standard onset

Myoclonic dystonia

Rapid, lightning-like myoclonic jerks, which tend to be provoked by compound intentional movements, are the main manifestation of myoclonic dystonia with SGCE mutations. Such symptoms appear only in patients with this mutation. On the other hand, choreiform movements, characteristic of NKX2-1 mutation carriers, are absent in SGCE mutation carriers (Asmus et al. 2007).

Treatment of neurological manifestations - summary of descriptions from previous reports

Tetrabenazine is recommended as a first-line pharmacological treatment for chorea (Patel and Jankovic 2014 [updated 2023]), starting with a low dose (0.5 mg/kg/day in children and 37.5 mg/day in adults divided into 2–3 doses). For pediatric patients, it was reported that increasing doses by 0.5 mg/kg at weekly intervals, depending on tolerability, up to a maximum of 4.5 mg/kg/day, without exceeding 100–150 mg/day, can be beneficial (Gras et al. 2012). Levodopa was reported in 9 cases as a successful treatment for involuntary movements (Farrenburg and Gupta 2020). The disruption of the NKX2-1 gene causes abnormal migration of dopaminergic neurons in animal models (Kawano et al. 2003; Butt et al. 2008), which could explain the benefits of levodopa pharmacotherapy. Methylphenidate could significantly improve speech, motor skills, and gait in patients with coexisting ADHD diagnosis, even within 30 min after receiving a daily dose (Gauquelin et al. 2017). Another case described a young male with NKX2-1 mutation and ADHD diagnosis who presented with generalized chorea. Methylphenidate considerably improved his symptoms (Tübing et al. 2018). In certain instances, multiple medications were used in combination or sequentially. The most common combinations included tetrabenazine with L-dopa, L-dopa with methylphenidate, and L-dopa with carbamazepine (Nou-Fontanet et al. 2023).

It was reported that l-thyroxine monotherapy improved stability and effectively managed drop attacks in a childhood-onset case of BHC. (Shiohama et al. 2018) Moreover, when l-thyroxine was suspended for a month, the drop attacks recurred despite the maintained euthyroidism in this patient. However, l-thyroxine did not improve the patient’s chorea (Shiohama et al. 2018). Another symptom responsive to treatment is dystonia. Proband (III-1) was effectively treated with botulinum toxin injections and DBS. It was also reported that myoclonus responded positively to levetiracetam in patients treated with small doses (Balicza et al. 2018) (Table 4).

Table 4 Summary of therapeutic options for the NKX2-1-related disorders

Manifestation	Methods of treatment	Description	References	
Chorea	Tetrabenazine	0.5 mg/kg/day for children and 37.5 mg/day in adults	(Patel and Jankovic 2014 [updated 2023])	
Levodopa	2–6 mg/kg/day	(Farrenburg and Gupta 2020)	
Methylphenidate	20–72 mg/day	(Gauquelin et al. 2017), (Tübing et al. 2018)	
Drop attacks	L-thyroxine	1–2 µg/kg/day	(Shiohama et al. 2018)	
Dystonia	DBS	globus pallidus deep brain stimulation	This study	
Botulinum toxin	regular injections	(Balicza et al. 2018)	
Myoclonus	Levetiracetam	2 × 12,5 mg	(Balicza et al. 2018)	

Nou-Fontanet et al. (2023) summarized the usage of other medications (e.g. amantadine, beta-blockers, diazepam, olanzapine) that were described in isolated reports of patients with NKX2-1-related disorders. Additional research is necessary to assess the importance of these findings.

Prognosis

Chorea tends to progress throughout puberty, then stabilizes in adulthood or even reducesin severity (Gras et al. 2012). Moreover, patients with NKX2-1-related disorders are expected to have a normal life expectancy (Fernandez et al. 2001). Our first proband’s follow-up revealed a stable disease course and unaffected life functioning.

Discussion

NKX2-1 gene mutations result in various and diverse phenotypes. Most analyzed cases presented the symptoms in infancy or early childhood, usually connected with delayed motor development, frequent falls, movement disorders, and compensated hypothyroidism. Therefore, NKX2-1-related disorders should be considered in the differential diagnosis of infants with such symptoms and family history. Lack of chorea does not always exclude the diagnosis of NKX2-1-related disorders, so the term “benign hereditary chorea” is not always accurate and should be avoided. Hereditary dystonias have one of the most complicated classifications. Some of them have distinct phenotypes, but overlap can always occur. In some cases, exact genetic diagnosis is important and may play a role in dystonia treatment (Weisheit et al. 2018).

The wide impact of the pathogenic NKX2-1 variants on human development and neurological, endocrinological, and pulmonary diseases demonstrates the ongoing scientific challenges and issues. Despite discovering this gene locus and analyzing its regions, many details and processes regarding the pathogenesis and regulatory mechanisms of NKX2-1-related disorders remain unknown. A recent study showed that NKX2-1 is expressed in certain types of lung adenocarcinoma resulting in unfavorable prognosis. Knockdown of NKX2-1 causes suppression of cancer cell proliferation and, as a result, may be used as a molecular target in the treatment of lung adenocarcinoma (Matsubara et al. 2020). This is one example of the opportunities that targeted treatment might offer.

As described above, there is a wide spectrum of neurological cases with NKX2-1 gene mutations, demonstrating a need for a thorough differential diagnosis in patients with chorea. Even HD and NKX2-1-related disorder are rare, and it seems unlikely that they occur in one family, but it is possible, as presented in this case. This case illustrates that a positive family history for HD does not exclude other causes of chorea as a possible diagnosis, including an NKX2-1-related disorder. Reporting novel mutations and cases of various phenotypes has an important potential value in fully understanding genetic diseases. The diversity among cases of NKX2-1 patients and other neurogenetic disorders demonstrates the necessity of genetic testing to provide patients with molecularly targeted treatment in the future era of personalized medicine.

This study has several limitations. As described in the literature review section of the article, 81,2% of the analyzed patients had delayed motor milestones. Thus, they presumably presented with childhood-onset manifestations of the disease. However, it is a highly heterogeneous disorder that is a diagnostic challenge for clinicians, as well as a difficulty in determining whether all of the patients’ symptoms result from the NKX2-1 gene mutation. Additionally, the report only includes data based on two families, and the true coincidence of the symptoms may be missed. Moreover, the pathogenicity of the newly reported variant was not confirmed in the functional analysis. The follow-up with some of the family members was missed. However, the report highlights the challenging diagnosis of genetic choreas in clinical practice.

Acknowledgements

The authors have no acknowledgments to report.

Funding

This study was supported by the Medical University of Warsaw under grant number NZP/NM1/18.

Data availability

Data available on request due to restrictions e.g. privacy or ethical. The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the patients’ privacy.

Declarations

Ethical approval

The study was approved by the ethical review board KB/56/2018.

Informed consent

All tested individuals consented to genetic testing in terms of analysis of the selected genes and WES (probands), and a specific mutation in the NKX2-1 gene (Family B members). Written informed consent has been obtained from the patient(s) for the publication of the videos.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

Armstrong MJ Shah BB Chen R Angel MJ Lang AE Expanding the phenomenology of benign hereditary chorea: evolution from chorea to myoclonus and dystonia Mov Disord 2011 26 12 2296 2297 10.1002/mds.23822 21714005
Armstrong MJ, Shah BB, Chen R, Angel MJ, Lang AE (2011) Expanding the phenomenology of benign hereditary chorea: evolution from chorea to myoclonus and dystonia. Mov Disord 26(12):2296–2297. 10.1002/mds.2382221714005 10.1002/mds.23822
Asmus F Horber V Pohlenz J Schwabe D Zimprich A Munz M Schöning M Gasser T A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa Neurology 2005 64 11 1952 1954 10.1212/01.Wnl.0000164000.75046.Cc 15955952
Asmus F, Horber V, Pohlenz J, Schwabe D, Zimprich A, Munz M, Schöning M, Gasser T (2005) A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 64(11):1952–1954. 10.1212/01.Wnl.0000164000.75046.Cc15955952 10.1212/01.Wnl.0000164000.75046.Cc
Asmus F Devlin A Munz M Zimprich A Gasser T Chinnery PF Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia Mov Disord 2007 22 14 2104 2109 10.1002/mds.21692 17702043
Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, Chinnery PF (2007) Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord 22(14):2104–2109. 10.1002/mds.2169217702043 10.1002/mds.21692
Balicza P Grosz Z Molnár V Illés A Csabán D Gézsi A Dézsi L Zádori D Vécsei L Molnár MJ NKX2-1 New Mutation Associated with Myoclonus, Dystonia, and Pituitary involvement Front Genet 2018 9 335 10.3389/fgene.2018.00335 30186310
Balicza P, Grosz Z, Molnár V, Illés A, Csabán D, Gézsi A, Dézsi L, Zádori D, Vécsei L, Molnár MJ (2018) NKX2-1 New Mutation Associated with Myoclonus, Dystonia, and Pituitary involvement. Front Genet 9:335. 10.3389/fgene.2018.0033530186310 10.3389/fgene.2018.00335
Basu MR Espay AJ Wakefield EG Wu SW Clinical reasoning: importance of clinical phenomenology in the era of genetic testing Neurology 2018 90 6 e534 e537 10.1212/wnl.0000000000004930 29438030
Basu MR, Espay AJ, Wakefield EG, Wu SW (2018) Clinical reasoning: importance of clinical phenomenology in the era of genetic testing. Neurology 90(6):e534–e537. 10.1212/wnl.000000000000493029438030 10.1212/wnl.0000000000004930
Blumkin L Lerman-Sagie T Westenberger A Ben-Pazi H Zerem A Yosovich K Lev D Multiple causes of Pediatric Early Onset Chorea-Clinical and Genetic Approach Neuropediatrics 2018 49 4 246 255 10.1055/s-0038-1645884 29801190
Blumkin L, Lerman-Sagie T, Westenberger A, Ben-Pazi H, Zerem A, Yosovich K, Lev D (2018) Multiple causes of Pediatric Early Onset Chorea-Clinical and Genetic Approach. Neuropediatrics 49(4):246–255. 10.1055/s-0038-164588429801190 10.1055/s-0038-1645884
Breedveld GJ van Dongen JW Danesino C Guala A Percy AK Dure LS Harper P Lazarou LP van der Linde H Joosse M Grüters A MacDonald ME de Vries BB Arts WF Oostra BA Krude H Heutink P Mutations in TITF-1 are associated with benign hereditary chorea Hum Mol Genet 2002 11 8 971 979 10.1093/hmg/11.8.971 11971878
Breedveld GJ, van Dongen JW, Danesino C, Guala A, Percy AK, Dure LS, Harper P, Lazarou LP, van der Linde H, Joosse M, Grüters A, MacDonald ME, de Vries BB, Arts WF, Oostra BA, Krude H, Heutink P (2002) Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 11(8):971–979. 10.1093/hmg/11.8.97111971878 10.1093/hmg/11.8.971
Butt SJ Sousa VH Fuccillo MV Hjerling-Leffler J Miyoshi G Kimura S Fishell G The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes Neuron 2008 59 5 722 732 10.1016/j.neuron.2008.07.031 18786356
Butt SJ, Sousa VH, Fuccillo MV, Hjerling-Leffler J, Miyoshi G, Kimura S, Fishell G (2008) The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron 59(5):722–732. 10.1016/j.neuron.2008.07.03118786356 10.1016/j.neuron.2008.07.031
Carré A Szinnai G Castanet M Sura-Trueba S Tron E Broutin-L’Hermite I Barat P Goizet C Lacombe D Moutard ML Raybaud C Raynaud-Ravni C Romana S Ythier H Léger J Polak M Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case Hum Mol Genet 2009 18 12 2266 2276 10.1093/hmg/ddp162 19336474
Carré A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L’Hermite I, Barat P, Goizet C, Lacombe D, Moutard ML, Raybaud C, Raynaud-Ravni C, Romana S, Ythier H, Léger J, Polak M (2009) Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet 18(12):2266–2276. 10.1093/hmg/ddp16219336474 10.1093/hmg/ddp162
Costa MC Costa C Silva AP Evangelista P Santos L Ferro A Sequeiros J Maciel P Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea Neurogenetics 2005 6 4 209 215 10.1007/s10048-005-0013-1 16220345
Costa MC, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, Sequeiros J, Maciel P (2005) Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 6(4):209–215. 10.1007/s10048-005-0013-116220345 10.1007/s10048-005-0013-1
de Gusmao CM Kok F Casella EB Waugh JL Benign hereditary chorea related to NKX2-1 with ataxia and dystonia Neurol Genet 2016 2 1 e40 10.1212/nxg.0000000000000040 27066577
de Gusmao CM, Kok F, Casella EB, Waugh JL (2016) Benign hereditary chorea related to NKX2-1 with ataxia and dystonia. Neurol Genet 2(1):e40. 10.1212/nxg.000000000000004027066577 10.1212/nxg.0000000000000040
Doyle DA Gonzalez I Thomas B Scavina M Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1 J Pediatr 2004 145 2 190 193 10.1016/j.jpeds.2004.04.011 15289765
Doyle DA, Gonzalez I, Thomas B, Scavina M (2004) Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr 145(2):190–193. 10.1016/j.jpeds.2004.04.01115289765 10.1016/j.jpeds.2004.04.011
Farrenburg M Gupta HV Levodopa-Responsive Chorea: a review Ann Indian Acad Neurol 2020 23 2 211 214 10.4103/aian.AIAN_221_19 32189864
Farrenburg M, Gupta HV (2020) Levodopa-Responsive Chorea: a review. Ann Indian Acad Neurol 23(2):211–214. 10.4103/aian.AIAN_221_1932189864 10.4103/aian.AIAN_221_19
Fernandez M Raskind W Matsushita M Wolff J Lipe H Bird T Hereditary benign chorea: clinical and genetic features of a distinct disease Neurology 2001 57 1 106 110 10.1212/wnl.57.1.106 11445636
Fernandez M, Raskind W, Matsushita M, Wolff J, Lipe H, Bird T (2001) Hereditary benign chorea: clinical and genetic features of a distinct disease. Neurology 57(1):106–110. 10.1212/wnl.57.1.10611445636 10.1212/wnl.57.1.106
Ferrara AM De Michele G Salvatore E Di Maio L Zampella E Capuano S Del Prete G Rossi G Fenzi G Filla A Macchia PE A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea Thyroid 2008 18 9 1005 1009 10.1089/thy.2008.0085 18788921
Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, Del Prete G, Rossi G, Fenzi G, Filla A, Macchia PE (2008) A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid 18(9):1005–1009. 10.1089/thy.2008.008518788921 10.1089/thy.2008.0085
Ferrara JM Adam OR Kirwin SM Houghton DJ Shepherd C Vinette KM Litvan I Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation J Child Neurol 2012 27 1 68 73 10.1177/0883073811413584 21813802
Ferrara JM, Adam OR, Kirwin SM, Houghton DJ, Shepherd C, Vinette KM, Litvan I (2012) Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. J Child Neurol 27(1):68–73. 10.1177/088307381141358421813802 10.1177/0883073811413584
Fons C Rizzu P Garcia-Cazorla A Martorell L Ormazabal A Artuch R Campistol J Fernandez-Alvarez E TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment Brain Dev 2012 34 3 255 257 10.1016/j.braindev.2011.04.007 21555194
Fons C, Rizzu P, Garcia-Cazorla A, Martorell L, Ormazabal A, Artuch R, Campistol J, Fernandez-Alvarez E (2012) TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment. Brain Dev 34(3):255–257. 10.1016/j.braindev.2011.04.00721555194 10.1016/j.braindev.2011.04.007
Gauquelin L Tran LT Chouinard S Bernard G The Movement disorder of brain-lung-thyroid syndrome can be responsive to Methylphenidate Tremor Other Hyperkinet Mov (N Y) 2017 7 508 10.7916/d84x5m9z 29109906
Gauquelin L, Tran LT, Chouinard S, Bernard G (2017) The Movement disorder of brain-lung-thyroid syndrome can be responsive to Methylphenidate. Tremor Other Hyperkinet Mov (N Y) 7:508. 10.7916/d84x5m9z29109906 10.7916/d84x5m9z
Glik A Vuillaume I Devos D Inzelberg R Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation Mov Disord 2008 23 12 1744 1747 10.1002/mds.22215 18661567
Glik A, Vuillaume I, Devos D, Inzelberg R (2008) Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord 23(12):1744–1747. 10.1002/mds.2221518661567 10.1002/mds.22215
Gonçalves D Lourenço L Guardiano M Castro-Correia C Sampaio M Leão M Chiari Malformation Type I in a patient with a Novel NKX2-1 mutation J Pediatr Neurosci 2019 14 3 169 172 10.4103/jpn.JPN_108_18 31649781
Gonçalves D, Lourenço L, Guardiano M, Castro-Correia C, Sampaio M, Leão M (2019) Chiari Malformation Type I in a patient with a Novel NKX2-1 mutation. J Pediatr Neurosci 14(3):169–172. 10.4103/jpn.JPN_108_1831649781 10.4103/jpn.JPN_108_18
Gras D Jonard L Roze E Chantot-Bastaraud S Koht J Motte J Rodriguez D Louha M Caubel I Kemlin I Lion-François L Goizet C Guillot L Moutard ML Epaud R Héron B Charles P Tallot M Camuzat A Durr A Polak M Devos D Sanlaville D Vuillaume I de Billette T Vidailhet M Doummar D Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene J Neurol Neurosurg Psychiatry 2012 83 10 956 962 10.1136/jnnp-2012-302505 22832740
Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, Rodriguez D, Louha M, Caubel I, Kemlin I, Lion-François L, Goizet C, Guillot L, Moutard ML, Epaud R, Héron B, Charles P, Tallot M, Camuzat A, Durr A, Polak M, Devos D, Sanlaville D, Vuillaume I, de Billette T, Vidailhet M, Doummar D (2012) Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry 83(10):956–962. 10.1136/jnnp-2012-30250522832740 10.1136/jnnp-2012-302505
Graziola F Garone G Grasso M Schirinzi T Capuano A Working memory, attention and planning abilities in NKX2.1-related chorea Parkinsonism Relat Disord 2021 88 24 27 10.1016/j.parkreldis.2021.05.021 34091414
Graziola F, Garone G, Grasso M, Schirinzi T, Capuano A (2021) Working memory, attention and planning abilities in NKX2.1-related chorea. Parkinsonism Relat Disord 88:24–27. 10.1016/j.parkreldis.2021.05.02134091414 10.1016/j.parkreldis.2021.05.021
Guan L, Zhao X, Tang L, Chen J, Zhao J, Guo M, Chen C, Zhou Y, Xu L (2021) Thyroid transcription Factor-1: structure, expression, function and its relationship with Disease. Biomed Res Int 2021(9957209). 10.1155/2021/9957209
Ikeda K Shaw-White JR Wert SE Whitsett JA Hepatocyte nuclear factor 3 activates transcription of thyroid transcription factor 1 in respiratory epithelial cells Mol Cell Biol 1996 16 7 3626 3636 10.1128/MCB.16.7.3626 8668179
Ikeda K, Shaw-White JR, Wert SE, Whitsett JA (1996) Hepatocyte nuclear factor 3 activates transcription of thyroid transcription factor 1 in respiratory epithelial cells. Mol Cell Biol 16(7):3626–3636. 10.1128/MCB.16.7.36268668179 10.1128/MCB.16.7.3626
Iodice A Carecchio M Zorzi G Garavaglia B Spagnoli C Salerno GG Frattini D Mencacci NE Invernizzi F Veneziano L Mantuano E Angriman M Fusco C Restless legs syndrome in NKX2-1-related chorea: an expansion of the disease spectrum Brain Dev 2019 41 3 250 256 10.1016/j.braindev.2018.10.001 30352709
Iodice A, Carecchio M, Zorzi G, Garavaglia B, Spagnoli C, Salerno GG, Frattini D, Mencacci NE, Invernizzi F, Veneziano L, Mantuano E, Angriman M, Fusco C (2019) Restless legs syndrome in NKX2-1-related chorea: an expansion of the disease spectrum. Brain Dev 41(3):250–256. 10.1016/j.braindev.2018.10.00130352709 10.1016/j.braindev.2018.10.001
Kawano H Horie M Honma S Kawamura K Takeuchi K Kimura S Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1 Exp Neurol 2003 182 1 103 112 10.1016/s0014-4886(03)00030-x 12821380
Kawano H, Horie M, Honma S, Kawamura K, Takeuchi K, Kimura S (2003) Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1. Exp Neurol 182(1):103–112. 10.1016/s0014-4886(03)00030-x12821380 10.1016/s0014-4886(03)00030-x
Kleiner-Fisman G (2011) Chap. 12 - benign hereditary chorea. In: Weiner WJ, Tolosa E (eds) Handbook of clinical neurology, vol 100. Elsevier, pp 199–212. doi:10.1016/B978-0-444-52014-2.00012-4
Kleiner-Fisman G Rogaeva E Halliday W Houle S Kawarai T Sato C Medeiros H St George-Hyslop PH Lang AE Benign hereditary chorea: clinical, genetic, and pathological findings Ann Neurol 2003 54 2 244 247 10.1002/ana.10637 12891678
Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, Medeiros H, St George-Hyslop PH, Lang AE (2003) Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 54(2):244–247. 10.1002/ana.1063712891678 10.1002/ana.10637
Koht J Løstegaard SO Wedding I Vidailhet M Louha M Tallaksen CM Benign hereditary chorea, not only chorea: a family case presentation Cerebellum Ataxias 2016 3 3 10.1186/s40673-016-0041-7 26839702
Koht J, Løstegaard SO, Wedding I, Vidailhet M, Louha M, Tallaksen CM (2016) Benign hereditary chorea, not only chorea: a family case presentation. Cerebellum Ataxias 3:3. 10.1186/s40673-016-0041-726839702 10.1186/s40673-016-0041-7
Konishi T Kono S Fujimoto M Terada T Matsushita K Ouchi Y Miyajima H Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation J Neurol 2013 260 1 207 213 10.1007/s00415-012-6618-z 22825795
Konishi T, Kono S, Fujimoto M, Terada T, Matsushita K, Ouchi Y, Miyajima H (2013) Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation. J Neurol 260(1):207–213. 10.1007/s00415-012-6618-z22825795 10.1007/s00415-012-6618-z
Krude H Schütz B Biebermann H von Moers A Schnabel D Neitzel H Tönnies H Weise D Lafferty A Schwarz S DeFelice M von Deimling A van Landeghem F DiLauro R Grüters A Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency J Clin Invest 2002 109 4 475 480 10.1172/jci14341 11854319
Krude H, Schütz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tönnies H, Weise D, Lafferty A, Schwarz S, DeFelice M, von Deimling A, van Landeghem F, DiLauro R, Grüters A (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109(4):475–480. 10.1172/jci1434111854319 10.1172/jci14341
Lamiral A El Chehadeh S Chelly J Anheim M Laugel V Tranchant C Benign hereditary chorea: from benign to serious Rev Neurol (Paris) 2020 176 4 295 296 10.1016/j.neurol.2019.07.026 31983472
Lamiral A, El Chehadeh S, Chelly J, Anheim M, Laugel V, Tranchant C (2020) Benign hereditary chorea: from benign to serious. Rev Neurol (Paris) 176(4):295–296. 10.1016/j.neurol.2019.07.02631983472 10.1016/j.neurol.2019.07.026
Li Y Eggermont K Vanslembrouck V Verfaillie CM NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell Stem Cells Dev 2013 22 9 1433 1442 10.1089/scd.2012.0620 23259454
Li Y, Eggermont K, Vanslembrouck V, Verfaillie CM (2013) NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell. Stem Cells Dev 22(9):1433–1442. 10.1089/scd.2012.062023259454 10.1089/scd.2012.0620
Liao J Coffman KA Locker J Padiath QS Nmezi B Filipink RA Hu J Sathanoori M Madan-Khetarpal S McGuire M Schreiber A Moran R Friedman N Hoffner L Rajkovic A Yatsenko SA Surti U Deletion of conserved non-coding sequences downstream from NKX2-1: a novel disease-causing mechanism for benign hereditary chorea Mol Genet Genomic Med 2021 9 4 e1647 10.1002/mgg3.1647 33666368
Liao J, Coffman KA, Locker J, Padiath QS, Nmezi B, Filipink RA, Hu J, Sathanoori M, Madan-Khetarpal S, McGuire M, Schreiber A, Moran R, Friedman N, Hoffner L, Rajkovic A, Yatsenko SA, Surti U (2021) Deletion of conserved non-coding sequences downstream from NKX2-1: a novel disease-causing mechanism for benign hereditary chorea. Mol Genet Genomic Med 9(4):e1647. 10.1002/mgg3.164733666368 10.1002/mgg3.1647
Matsubara D Yoshimoto T Soda M Amano Y Kihara A Funaki T Ito T Sakuma Y Shibano T Endo S Hagiwara K Ishikawa S Fukayama M Murakami Y Mano H Niki T Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas Cancer Sci 2020 111 6 2183 2195 10.1111/cas.14403 32237253
Matsubara D, Yoshimoto T, Soda M, Amano Y, Kihara A, Funaki T, Ito T, Sakuma Y, Shibano T, Endo S, Hagiwara K, Ishikawa S, Fukayama M, Murakami Y, Mano H, Niki T (2020) Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas. Cancer Sci 111(6):2183–2195. 10.1111/cas.1440332237253 10.1111/cas.14403
McMichael G Haan E Gardner A Yap TY Thompson S Ouvrier R Dale RC Gecz J Maclennan AH NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy Eur J Med Genet 2013 56 9 506 509 10.1016/j.ejmg.2013.07.003 23911641
McMichael G, Haan E, Gardner A, Yap TY, Thompson S, Ouvrier R, Dale RC, Gecz J, Maclennan AH (2013) NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy. Eur J Med Genet 56(9):506–509. 10.1016/j.ejmg.2013.07.00323911641 10.1016/j.ejmg.2013.07.003
Milone R Masson R Di Cosmo C Tonacchera M Bertini V Guzzetta A Battini R A not so Benign Family Pedigree with Hereditary Chorea: a broader phenotypic expression or additional picture? Child Neurol Open 2019 6 2329048x19828881 10.1177/2329048x19828881 30793011
Milone R, Masson R, Di Cosmo C, Tonacchera M, Bertini V, Guzzetta A, Battini R (2019) A not so Benign Family Pedigree with Hereditary Chorea: a broader phenotypic expression or additional picture? Child Neurol Open 6:2329048x19828881. 10.1177/2329048x1982888130793011 10.1177/2329048x19828881
Minoo P Hu L Xing Y Zhu NL Chen H Li M Borok Z Li C Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells Mol Cell Biol 2007 27 6 2155 2165 10.1128/mcb.01133-06 17220277
Minoo P, Hu L, Xing Y, Zhu NL, Chen H, Li M, Borok Z, Li C (2007) Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Mol Cell Biol 27(6):2155–2165. 10.1128/mcb.01133-0617220277 10.1128/mcb.01133-06
Monti S Nicoletti A Cantasano A Krude H Cassio A NKX2.1-Related disorders: a novel mutation with mild clinical presentation Ital J Pediatr 2015 41 45 10.1186/s13052-015-0150-6 26103969
Monti S, Nicoletti A, Cantasano A, Krude H, Cassio A (2015) NKX2.1-Related disorders: a novel mutation with mild clinical presentation. Ital J Pediatr 41:45. 10.1186/s13052-015-0150-626103969 10.1186/s13052-015-0150-6
Moya CM Perez de Nanclares G Castaño L Potau N Bilbao JR Carrascosa A Bargadá M Coya R Martul P Vicens-Calvet E Santisteban P Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress J Clin Endocrinol Metab 2006 91 5 1832 1841 10.1210/jc.2005-1497 16507635
Moya CM, Perez de Nanclares G, Castaño L, Potau N, Bilbao JR, Carrascosa A, Bargadá M, Coya R, Martul P, Vicens-Calvet E, Santisteban P (2006) Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress. J Clin Endocrinol Metab 91(5):1832–1841. 10.1210/jc.2005-149716507635 10.1210/jc.2005-1497
Nagasaki K Narumi S Asami T Kikuchi T Hasegawa T Uchiyama M Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin Endocr J 2008 55 5 875 878 10.1507/endocrj.k08e-124 18506088
Nagasaki K, Narumi S, Asami T, Kikuchi T, Hasegawa T, Uchiyama M (2008) Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. Endocr J 55(5):875–878. 10.1507/endocrj.k08e-12418506088 10.1507/endocrj.k08e-124
Nakazato M Chung HK Ulianich L Grassadonia A Suzuki K Kohn LD Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression Mol Cell Biol 2000 20 22 8499 8512 10.1128/mcb.20.22.8499-8512.2000 11046146
Nakazato M, Chung HK, Ulianich L, Grassadonia A, Suzuki K, Kohn LD (2000) Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression. Mol Cell Biol 20(22):8499–8512. 10.1128/mcb.20.22.8499-8512.200011046146 10.1128/mcb.20.22.8499-8512.2000
Nettore IC Mirra P Ferrara AM Sibilio A Pagliara V Kay CS Lorenzoni PJ Werneck LC Bruck I Dos Santos LH Beguinot F Salvatore D Ungaro P Fenzi G Scola RH Macchia PE Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature Thyroid 2013 23 6 675 682 10.1089/thy.2012.0267 23379327
Nettore IC, Mirra P, Ferrara AM, Sibilio A, Pagliara V, Kay CS, Lorenzoni PJ, Werneck LC, Bruck I, Dos Santos LH, Beguinot F, Salvatore D, Ungaro P, Fenzi G, Scola RH, Macchia PE (2013) Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature. Thyroid 23(6):675–682. 10.1089/thy.2012.026723379327 10.1089/thy.2012.0267
Nou-Fontanet L Martín-Gómez C Isabel-Gómez R Bachoud-Lévi AC Zorzi G Capuano A Blasco-Amaro JA Ortigoza-Escobar JD Systematic review of drug therapy for chorea in NXK2-1-related disorders: efficacy and safety evidence from case studies and series Eur J Neurol 2023 30 12 3928 3948 10.1111/ene.16038 37694681
Nou-Fontanet L, Martín-Gómez C, Isabel-Gómez R, Bachoud-Lévi AC, Zorzi G, Capuano A, Blasco-Amaro JA, Ortigoza-Escobar JD (2023) Systematic review of drug therapy for chorea in NXK2-1-related disorders: efficacy and safety evidence from case studies and series. Eur J Neurol 30(12):3928–3948. 10.1111/ene.1603837694681 10.1111/ene.16038
Oguchi H Kimura S Multiple transcripts encoded by the thyroid-specific enhancer-binding protein (T/EBP)/thyroid-specific transcription factor-1 (TTF-1) gene: evidence of autoregulation Endocrinology 1998 139 4 1999 2006 10.1210/endo.139.4.5933 9528987
Oguchi H, Kimura S (1998) Multiple transcripts encoded by the thyroid-specific enhancer-binding protein (T/EBP)/thyroid-specific transcription factor-1 (TTF-1) gene: evidence of autoregulation. Endocrinology 139(4):1999–2006. 10.1210/endo.139.4.59339528987 10.1210/endo.139.4.5933
Parnes M Bashir H Jankovic J Is Benign Hereditary Chorea really Benign? Brain-lung-thyroid syndrome caused by NKX2-1 mutations Mov Disord Clin Pract 2019 6 1 34 39 10.1002/mdc3.12690 30746413
Parnes M, Bashir H, Jankovic J (2019) Is Benign Hereditary Chorea really Benign? Brain-lung-thyroid syndrome caused by NKX2-1 mutations. Mov Disord Clin Pract 6(1):34–39. 10.1002/mdc3.1269030746413 10.1002/mdc3.12690
Patel NJ Jankovic J Adam MP Feldman J Mirzaa GM [updated 2023]) NKX2-1-Related disorders GeneReviews(®) [Internet] 2014 Seattle University of Washington
Patel NJ, Jankovic J (2014) [updated 2023]) NKX2-1-Related disorders. In: Adam MP, Feldman J, Mirzaa GM et al (eds) GeneReviews(®) [Internet]. University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved., Seattle (WA)
Peall KJ Lumsden D Kneen R Madhu R Peake D Gibbon F Lewis H Hedderly T Meyer E Robb SA Lynch B King MD Lin JP Morris HR Jungbluth H Kurian MA Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum Dev Med Child Neurol 2014 56 7 642 648 10.1111/dmcn.12323 24171694
Peall KJ, Lumsden D, Kneen R, Madhu R, Peake D, Gibbon F, Lewis H, Hedderly T, Meyer E, Robb SA, Lynch B, King MD, Lin JP, Morris HR, Jungbluth H, Kurian MA (2014) Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. Dev Med Child Neurol 56(7):642–648. 10.1111/dmcn.1232324171694 10.1111/dmcn.12323
Prasad R Nicholas AK Schoenmakers N Barton J Haploinsufficiency of NKX2-1 in brain-lung-thyroid syndrome with additional multiple pituitary dysfunction Horm Res Paediatr 2019 92 5 340 344 10.1159/000503683 31707387
Prasad R, Nicholas AK, Schoenmakers N, Barton J (2019) Haploinsufficiency of NKX2-1 in brain-lung-thyroid syndrome with additional multiple pituitary dysfunction. Horm Res Paediatr 92(5):340–344. 10.1159/00050368331707387 10.1159/000503683
Provenzano C Veneziano L Appleton R Frontali M Civitareale D Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea J Neurol Sci 2008 264 1 56 62 10.1016/j.jns.2007.06.056 17765926
Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D (2008) Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. J Neurol Sci 264(1):56–62. 10.1016/j.jns.2007.06.05617765926 10.1016/j.jns.2007.06.056
Provenzano C Zamboni M Veneziano L Mantuano E Garavaglia B Zorzi G Pagonabarraga J Giunti P Civitareale D Functional characterization of two novel mutations in TTF-1/NKX2.1 homeodomain in patients with benign hereditary chorea J Neurol Sci 2016 360 78 83 10.1016/j.jns.2015.11.050 26723978
Provenzano C, Zamboni M, Veneziano L, Mantuano E, Garavaglia B, Zorzi G, Pagonabarraga J, Giunti P, Civitareale D (2016) Functional characterization of two novel mutations in TTF-1/NKX2.1 homeodomain in patients with benign hereditary chorea. J Neurol Sci 360:78–83. 10.1016/j.jns.2015.11.05026723978 10.1016/j.jns.2015.11.050
Rosati A Berti B Melani F Cellini E Procopio E Guerrini R Recurrent drop attacks in early childhood as presenting symptom of benign hereditary chorea caused by TITF1 gene mutations Dev Med Child Neurol 2015 57 8 777 779 10.1111/dmcn.12644 25412988
Rosati A, Berti B, Melani F, Cellini E, Procopio E, Guerrini R (2015) Recurrent drop attacks in early childhood as presenting symptom of benign hereditary chorea caused by TITF1 gene mutations. Dev Med Child Neurol 57(8):777–779. 10.1111/dmcn.1264425412988 10.1111/dmcn.12644
Salvatore E Di Maio L Filla A Ferrara AM Rinaldi C Saccà F Peluso S Macchia PE Pappatà S De Michele G Benign hereditary chorea: clinical and neuroimaging features in an Italian family Mov Disord 2010 25 10 1491 1496 10.1002/mds.23065 20544814
Salvatore E, Di Maio L, Filla A, Ferrara AM, Rinaldi C, Saccà F, Peluso S, Macchia PE, Pappatà S, De Michele G (2010) Benign hereditary chorea: clinical and neuroimaging features in an Italian family. Mov Disord 25(10):1491–1496. 10.1002/mds.2306520544814 10.1002/mds.23065
Schrag A Quinn NP Bhatia KP Marsden CD Benign hereditary chorea–entity or syndrome? Mov Disord 2000 15 2 280 288 10.1002/1531-8257(200003)15:2<280::aid-mds1011>3.0.co;2-q 10752577
Schrag A, Quinn NP, Bhatia KP, Marsden CD (2000) Benign hereditary chorea–entity or syndrome? Mov Disord 15(2):280–288. 10.1002/1531-8257(200003)15:2<280::aid-mds1011>3.0.co;2-q10752577 10.1002/1531-8257(200003)15:2<280::aid-mds1011>3.0.co;2-q
Shetty VB Kiraly-Borri C Lamont P Bikker H Choong CS NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients J Pediatr Endocrinol Metab 2014 27 3–4 373 378 10.1515/jpem-2013-0109 24129101
Shetty VB, Kiraly-Borri C, Lamont P, Bikker H, Choong CS (2014) NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. J Pediatr Endocrinol Metab 27(3–4):373–378. 10.1515/jpem-2013-010924129101 10.1515/jpem-2013-0109
Shiohama T Ohashi H Shimizu K Fujii K Oba D Takatani T Kato M Shimojo N l-Thyroxine-responsive drop attacks in childhood benign hereditary chorea: a case report Brain Dev 2018 40 4 353 356 10.1016/j.braindev.2017.12.008 29289388
Shiohama T, Ohashi H, Shimizu K, Fujii K, Oba D, Takatani T, Kato M, Shimojo N (2018) l-Thyroxine-responsive drop attacks in childhood benign hereditary chorea: a case report. Brain Dev 40(4):353–356. 10.1016/j.braindev.2017.12.00829289388 10.1016/j.braindev.2017.12.008
Teissier R Guillot L Carré A Morandini M Stuckens C Ythier H Munnich A Szinnai G de Blic J Clement A Leger J Castanet M Epaud R Polak M Multiplex ligation-dependent probe amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome Horm Res Paediatr 2012 77 3 146 151 10.1159/000337214 22488412
Teissier R, Guillot L, Carré A, Morandini M, Stuckens C, Ythier H, Munnich A, Szinnai G, de Blic J, Clement A, Leger J, Castanet M, Epaud R, Polak M (2012) Multiplex ligation-dependent probe amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome. Horm Res Paediatr 77(3):146–151. 10.1159/00033721422488412 10.1159/000337214
Termsarasab P Chorea Continuum (Minneap Minn) 2019 25 4 1001 1035 10.1212/con.0000000000000763 31356291
Termsarasab P (2019) Chorea. Continuum (Minneap Minn) 25(4):1001–1035. 10.1212/con.000000000000076331356291 10.1212/con.0000000000000763
Thorwarth A Schnittert-Hübener S Schrumpf P Müller I Jyrch S Dame C Biebermann H Kleinau G Katchanov J Schuelke M Ebert G Steininger A Bönnemann C Brockmann K Christen HJ Crock P deZegher F Griese M Hewitt J Ivarsson S Hübner C Kapelari K Plecko B Rating D Stoeva I Ropers HH Grüters A Ullmann R Krude H Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum J Med Genet 2014 51 6 375 387 10.1136/jmedgenet-2013-102248 24714694
Thorwarth A, Schnittert-Hübener S, Schrumpf P, Müller I, Jyrch S, Dame C, Biebermann H, Kleinau G, Katchanov J, Schuelke M, Ebert G, Steininger A, Bönnemann C, Brockmann K, Christen HJ, Crock P, deZegher F, Griese M, Hewitt J, Ivarsson S, Hübner C, Kapelari K, Plecko B, Rating D, Stoeva I, Ropers HH, Grüters A, Ullmann R, Krude H (2014) Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. J Med Genet 51(6):375–387. 10.1136/jmedgenet-2013-10224824714694 10.1136/jmedgenet-2013-102248
Thust S Veneziano L Parkinson MH Bhatia KP Mantuano E Gonzalez-Robles C Davagnanam I Giunti P Altered pituitary morphology as a sign of benign hereditary chorea caused by TITF1/NKX2.1 mutations Neurogenetics 2022 23 2 91 102 10.1007/s10048-021-00680-3 35079915
Thust S, Veneziano L, Parkinson MH, Bhatia KP, Mantuano E, Gonzalez-Robles C, Davagnanam I, Giunti P (2022) Altered pituitary morphology as a sign of benign hereditary chorea caused by TITF1/NKX2.1 mutations. Neurogenetics 23(2):91–102. 10.1007/s10048-021-00680-335079915 10.1007/s10048-021-00680-3
Tozawa T Yokochi K Kono S Konishi T Yamamoto T Nishimura A Chiyonobu T Morimoto M Hosoi H A video report of brain-lung-thyroid syndrome in a Japanese female with a Novel Frameshift mutation of the NKX2-1 gene Child Neurol Open 2016 3 2329048x16665012 10.1177/2329048x16665012 28503612
Tozawa T, Yokochi K, Kono S, Konishi T, Yamamoto T, Nishimura A, Chiyonobu T, Morimoto M, Hosoi H (2016) A video report of brain-lung-thyroid syndrome in a Japanese female with a Novel Frameshift mutation of the NKX2-1 gene. Child Neurol Open 3:2329048x16665012. 10.1177/2329048x1666501228503612 10.1177/2329048x16665012
Tübing J Bohnenpoll J Spiegler J Gillessen-Kaesbach G Bäumer T Max C Sperner J Klein C Münchau A Methylphenidate can improve Chorea in NKX2.1 and ADCY5 mutation-positive Patients-A report of two children Mov Disord Clin Pract 2018 5 3 343 345 10.1002/mdc3.12608 30800710
Tübing J, Bohnenpoll J, Spiegler J, Gillessen-Kaesbach G, Bäumer T, Max C, Sperner J, Klein C, Münchau A (2018) Methylphenidate can improve Chorea in NKX2.1 and ADCY5 mutation-positive Patients-A report of two children. Mov Disord Clin Pract 5(3):343–345. 10.1002/mdc3.1260830800710 10.1002/mdc3.12608
Veneziano L Parkinson MH Mantuano E Frontali M Bhatia KP Giunti P A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature Cerebellum 2014 13 5 588 595 10.1007/s12311-014-0570-7 24930029
Veneziano L, Parkinson MH, Mantuano E, Frontali M, Bhatia KP, Giunti P (2014) A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature. Cerebellum 13(5):588–595. 10.1007/s12311-014-0570-724930029 10.1007/s12311-014-0570-7
Villafuerte B Natera-de-Benito D González A Mori MA Palomares M Nevado J García-Miñaur S Lapunzina P González-Granado LI Allende LM Moreno JC The brain-lung-thyroid syndrome (BLTS): a novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency Eur J Med Genet 2018 61 7 393 398 10.1016/j.ejmg.2018.02.007 29477862
Villafuerte B, Natera-de-Benito D, González A, Mori MA, Palomares M, Nevado J, García-Miñaur S, Lapunzina P, González-Granado LI, Allende LM, Moreno JC (2018) The brain-lung-thyroid syndrome (BLTS): a novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency. Eur J Med Genet 61(7):393–398. 10.1016/j.ejmg.2018.02.00729477862 10.1016/j.ejmg.2018.02.007
Warner JP Barron LH Brock DJ A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington’s disease chromosomes Mol Cell Probes 1993 7 3 235 239 10.1006/mcpr.1993.1034 8366869
Warner JP, Barron LH, Brock DJ (1993) A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington’s disease chromosomes. Mol Cell Probes 7(3):235–239. 10.1006/mcpr.1993.10348366869 10.1006/mcpr.1993.1034
Weisheit CE Pappas SS Dauer WT Inherited dystonias: clinical features and molecular pathways Handb Clin Neurol 2018 147 241 254 10.1016/b978-0-444-63233-3.00016-6 29325615
Weisheit CE, Pappas SS, Dauer WT (2018) Inherited dystonias: clinical features and molecular pathways. Handb Clin Neurol 147:241–254. 10.1016/b978-0-444-63233-3.00016-629325615 10.1016/b978-0-444-63233-3.00016-6
Wilbertz T, Maier S, Perner S (2010) NKX2-1 (NK2 homeobox 1). Atlas Genet Cytogenet Oncol Haematol
Willemsen MA Breedveld GJ Wouda S Otten BJ Yntema JL Lammens M de Vries BB Brain-thyroid-lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene Eur J Pediatr 2005 164 1 28 30 10.1007/s00431-004-1559-x 15517377
Willemsen MA, Breedveld GJ, Wouda S, Otten BJ, Yntema JL, Lammens M, de Vries BB (2005) Brain-thyroid-lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr 164(1):28–30. 10.1007/s00431-004-1559-x15517377 10.1007/s00431-004-1559-x
Williamson S Kirkpatrick M Greene S Goudie D A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome J Child Neurol 2014 29 5 666 669 10.1177/0883073813518243 24453141
Williamson S, Kirkpatrick M, Greene S, Goudie D (2014) A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome. J Child Neurol 29(5):666–669. 10.1177/088307381351824324453141 10.1177/0883073813518243
Yin Z Gonzales L Kolla V Rath N Zhang Y Lu MM Kimura S Ballard PL Beers MF Epstein JA Morrisey EE Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression Am J Physiol Lung Cell Mol Physiol 2006 291 2 L191 199 10.1152/ajplung.00385.2005 16510470
Yin Z, Gonzales L, Kolla V, Rath N, Zhang Y, Lu MM, Kimura S, Ballard PL, Beers MF, Epstein JA, Morrisey EE (2006) Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression. Am J Physiol Lung Cell Mol Physiol 291(2):L191–199. 10.1152/ajplung.00385.200516510470 10.1152/ajplung.00385.2005
Zhou B Zhong Q Minoo P Li C Ann DK Frenkel B Morrisey EE Crandall ED Borok Z Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain Am J Respir Cell Mol Biol 2008 38 6 750 758 10.1165/rcmb.2007-0350OC 18239190
Zhou B, Zhong Q, Minoo P, Li C, Ann DK, Frenkel B, Morrisey EE, Crandall ED, Borok Z (2008) Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain. Am J Respir Cell Mol Biol 38(6):750–758. 10.1165/rcmb.2007-0350OC18239190 10.1165/rcmb.2007-0350OC
