Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum




Benign hereditary chorea is a dominantly inherited, childhood-onset hyperkinetic movement disorder characterized by non-progressive chorea and variable degrees of thyroid and respiratory involvement. Loss-of-function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals.


Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis.


Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1y 6mo–18y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of ‘brain–lung–thyroid syndrome’ symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive–compulsive disorder.


Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain–lung–thyroid syndrome. The extended phenotype may include obsessive–compulsive disorder and skeletal abnormalities.


Benign hereditary chorea


Obsessive–compulsive disorder

Benign hereditary chorea (BHC; OMIM 118700) is a rare (estimated incidence 1 in 2 000 000), childhood-onset movement disorder that is characterized by non-progressive chorea without marked cognitive impairment. Linkage analysis and positional cloning have identified NKX2.1 as the causative gene,[1] located on chromosome 14q13 (also known as TITF1, TTF-1, TEBP, and NKX2A). More than 30 different mutations of this gene have been identified to date including whole-gene deletions as well as splice-site, frameshift, nonsense, and missense mutations.[2]

NKX2.1 is a member of the natural killer (NK) gene family of highly conserved homeodomain-containing transcription factors. The majority of pathogenic mutations truncate the resultant protein either before or within the DNA-binding homeobox domain encoded in exon 3, thereby affecting the DNA-binding properties of the protein. Haploinsufficiency of the NKX2.1 protein is thought to give rise to the BHC phenotype.[3, 4]

NKX2.1 is involved in the embryogenesis of brain, lung and thyroid tissue. Before the identification of NKX2.1 mutations in BHC, NKX2.1 variants had been described in patients with variable combinations of congenital hypothyroidism, pulmonary dysfunction, and chorea[3, 5] (more recently referred to as ‘brain–lung–thyroid’ syndrome[6]). Significant inter- and intrafamilial phenotypic variation has been described, with regard not only to thyroid and lung involvement but also neurological and systemic characteristics.[2, 7] Other neurological signs include intention tremor,[8] axial dystonia,[9] dysarthria,[9] and gait disturbance.[10] Hypodontia,[11] short stature, and webbed neck[12] have also been identified in patients with BHC.

This study identified 10 probands with NKX2.1 mutations: nine novel coding mutations, including two whole-gene deletions, and one previously reported mutation.[13] We have also highlighted several previously unrecognized clinical and psychiatric characteristics, thereby expanding the phenotypic spectrum associated with NKX2.1 mutations. Finally, we discuss the types and efficacy of treatment strategies employed.


Patients with suspected BHC and others with known NKX2.1 mutations were identified from paediatric movement disorder clinics throughout the UK and Ireland, including neurology centres in Cardiff, Birmingham, London, Dublin, and Liverpool. These individuals were recruited by email contact through the British Paediatric Neurology Association members' forum.

Clinical assessment

All individuals were assessed by either adult or paediatric movement disorder specialists and a videotaped clinical examination was performed where possible. Systematic clinical information was gathered either at the time of clinical consultation or by retrospective review of the clinical notes. Data collected included a detailed family history, developmental history, signs and symptoms suggestive of neuromuscular involvement in early childhood, the age at onset of chorea, the presence of additional movement disorders, cognition and performance in education, functional disability, the presence of respiratory and other medical symptoms, thyroid function testing, and past and present medications and their efficacy.

Genetic evaluation

Blood samples were collected from all individuals after informed consent was obtained from the patient or assent was obtained from their parent/guardian. DNA was isolated from peripheral blood lymphocytes using standard protocols. All samples underwent direct sequencing of the three exons of the NKX2.1 gene using standard techniques (primers available on request). Seven individuals with NKX2.1 mutations were identified in diagnostic laboratories, the majority by direct sequencing (n=5) and a smaller number by multiplex ligation probe-dependent amplification and comparative genomic hybridization array techniques (n=2). Three individuals with mutations were identified by direct sequencing in a research laboratory (Cardiff, UK).


Ten patients were identified with NKX2.1 mutations, nine of which are novel, including two contiguous gene deletions. One mutation has been reported previously by one of the authors of this paper.[13] Of these 10 mutations, three were missense mutations, four were nonsense mutations, one was a frameshift mutation, and two were whole-gene deletions (Fig. 1). The first whole-gene deletion was 0.36 Mb in size (Chr 14:36,924,171-37,283,221) and the second extended to 4.7 Mb (Chr 14:35,581,654-40,301,792), both involving NKX2.1. Only three individuals had a positive family history of a movement disorder consistent with autosomal dominant inheritance (Fig. 2). Genetic analysis confirmed maternal inheritance of the mutation in individual 3 but unfortunately DNA was not available from other affected family members in the two remaining kindreds. In the remaining seven individuals, mutations appeared sporadic without any family history of a movement disorder, suggesting the occurrence of a de novo mutation, although genetic confirmation was possible in only a single family. All novel variants were considered pathogenic based on their absence in the comparison group (dbSNP []) and the 1000 Genomes Project ( databases, as well as protein changes predicted by Polyphen 2 and SIFT software tools. Using these tools, all variants were predicted to be pathogenic with the exception of individual 10 (see Appendix S1, online supporting information). Here the variant was not present in the comparison group, but in the absence of functional work its pathogenicity remains undetermined based on conservation and predicted protein change analysis.

Figure 1.

Schematic representation of NKX2.1 gene marked with mutations identified in this cohort. Numbers indicate the nucleotide change and the predicted protein. Missense mutations (black) are indicated above the gene and whole-gene deletions (blue), nonsense mutations (red), and frameshift mutations (green) are indicated below. The whole-gene deletion coordinates and genes involved of individuals 1 and 4 are as follows: individual 1 – Chr 14:36,924,171-37,283,221; SFTA3, NKX2.1, BX161496, NKX2.8, PAX9, SLC25A21; individual 4 – Chr 14:35,581,654-40,301,792; SPP54, FAM177A1, PPP2R3C, AK128559, KIAA0391, PSMA6, NFKBIA, RALGAPA1, INSM2, BRMS1L, LINC00609, PTCSC3, MBIP, DPPA3, SFTA3, NKX2.1, BX161496, NKX2.8, PAX9, SLC25A21, MIR4503, MIPOL1, FOXA1, C14orf25, TTC6, AK125955, SSTR1, CLEC14A, LINC00639, SEC23A, GEMIN2, TRAPPC6B, PNN, MIA2, CTAGE5, FBX033.

Figure 2.

Pedigrees of individuals with a positive family history for NKX2.1 mutations.

Almost two-thirds of our cohort was female with an onset of neurological symptoms mainly in infancy and early childhood (age range 17mo–13y 6mo, median 3y). The majority of individuals (eight out of 10) had initial features of limb and trunk hypotonia, with subsequent development of variable additional features including myoclonus (five out of 10), dystonia (six out of 10), ataxia (three out of 10), and upper limb tremor (one out of 10). All individuals had evidence of chorea involving either the upper or lower limbs or both. There were two individuals in whom additional, larger amplitude truncal chorea was observed and two individuals in whom facial chorea was observed. Limb involvement in five individuals took the form of fine, low-amplitude movements of the hands and fingers. These features are described in further detail in the accompanying video (Videos S1 and S2, online supporting information). Motor developmental delay was reported in six individuals, three of whom also had symptoms of dystonia. Four individuals had speech involvement, in the form of dysarthria. In all individuals, cerebral imaging was reported as being within normal limits.

One-third of individuals had comorbid hypothyroidism, three with congenital onset and one with subclinical hypothyroidism. Respiratory involvement was evident in 4 out of the 10 individuals. Recurrent lower respiratory tract infection and infant respiratory distress syndrome were each reported in two individuals. In one of the individuals who showed evidence of respiratory involvement, this took the form of four lower respiratory tract infections during the first year of life, each of which required antibiotic therapy, and on two occasions resulted in hospital admission. This patient has also subsequently been treated with a salbutamol inhaler owing to recurrent coughing, although this has now been discontinued. Those diagnosed with infant respiratory distress syndrome all required ventilator support during the neonatal period. The full triad of symptoms were present in just over one-quarter of all individuals (three out of 10).

None of the patients within our cohort had marked cognitive impairment during routine clinical examination and all were, or are, currently in mainstream education. However, no detailed assessments were performed of cognitive function, and therefore mild impairments may have gone undetected. A single individual had severe symptoms of obsessive–compulsive disorder (OCD), taking the form of complex object-touching rituals driven by recurrent, intrusive thoughts of the risk of harm to family members. None was found to have evidence of attention-deficit–hyperactivity disorder (ADHD). A full summary of the clinical details can be seen in Table 1.

Table 1. Summary of clinical characteristics
  1. a

    Novel mutation. WGD, whole-gene deletion.

SexFemaleMaleFemaleMaleMaleFemaleFemaleFemaleFemaleMale4:6 (male:female)
Age at examination, y111.5361218164514Median 8.5 (range 1.5-18)
Mutation typeWGDNonsenseNonsenseWGDMissenseFrameshiftNonsenseNonsenseMissenseMissense 
Nucleotide change NM_001079668c.612delCac.428G>Aac.872C>Tac.1204T>Aac.1161C>Gac.432C>Ac.1022C>Tac.520G>Ta
Effect on protein NM_001079668p.Y204Xp.W143Xp.P291Lp.X402RextX63p.Y387Xp.Y144Xp.A341Vp.G174C
Nucleotide change NM_003317c.522delCc.338G>Ac.782C>Tc.1114T>Ac.1071C>Gc.342C>Ac.932C>Tc.430G>T
Effect on protein NM_003317p.Y174Xp.W113Xp.P261Lp.X372RextX63p.Y357Xp.Y114Xp.A311Vp.G144C
Family historyNoYesYesNoNoYesNoNoNoNon=3
Neurological features (motor)
Muscle tone in infancyHypotoniaHypotoniaHypertoniaHypotoniaHypotoniaHypotoniaHypotoniaHypotoniaNormalHypotoniaHypotonia, n=8
Age at onset of chorea7y1y3y6y3y1y2y17moUncertain13y 6moMedian age=3y
Tics (motor/vocal)NoNoNoNoNoNoNoNoNoNon=0
Developmental delayYesNoYesYesYesYesYesNoNoNon=6
Psychological/psychiatric features
Cognitive impairmentNoNoNoNoNoNoNoNoNoNon=0
Attention-deficit–hyperactivity disorderNoNoNoNoNoNoNoNoNoNon=0
Obsessive–compulsive disorderNoNoNoNoNoNoYesNoNoNon=0
Thyroid dysfunction
Congenital hypothyroidismNoYesYesYesNoNoNoNoNoNon=3
Subclinical hypothyroidismNoNoNoNoNoNoNoNoNoYesn=1
Respiratory dysfunction
Infant/neonatal respiratory distressNoNoYesNoYesNoNoNoNoNon=2
Recurrent lower respiratory infectionsNoYesNoYesNoNoNoNoNoNon=2
Additional clinical characteristicsGrowth hormone deficiency, visual impairmentPes cavus, kyphoscoliosisDuplex kidney, lichen planus

Additional clinical features were noted in three individuals. Individual 4 had evidence of growth hormone deficiency and visual disturbance owing to bilateral hypermetropia and right-sided esotropia. Individual 5 had pes cavus and kyphosis. Individual 7 had recurrent urinary difficulties in early childhood and was later diagnosed with a duplex kidney; she also had lichen sclerosis.

Pharmacological treatment was started in six individuals, in whom the movement disorder was felt to be severe enough to warrant treatment. Of those treated, none experienced a complete resolution of his or her chorea. Treatment with trihexyphenidyl and clonazepam provided patient-reported improvement in a single individual each, whereas treatment with tetrabenazine, levodopa (to a maximum of 375mg/d), sodium valproate, and sulpiride provided no improvement in chorea. Interestingly, treatment with trihexyphenidyl in individual 7 resulted in an improvement to her OCD symptoms. A full summary of treatment responses can be seen in Table 2.

Table 2. Summary of medical therapies
  1. Doses are given as maximal daily doses achieved. aTreatment was stopped as a result of side-effects. bNo change to movement disorders. cModerate improvement of the movement disorder.

Treatment intervention givenNoYesYesNoYesYesYesNoYesNo
Treatment (maximum dose and response)
Sodium valproate360mgb


This study of 10 probands represents one of the largest paediatric series of BHC associated with NKX2.1 mutations. In addition to many of the motor characteristics already found in previous reports,[14, 15] we also identified several unique additional genetic, psychiatric, and clinical findings.

Consistent with previous studies, a female preponderance of individuals was observed in this cohort.[14] It is possible that additional genetic or environmental mechanisms influencing sex preponderance may be related to disease expression and further larger scale family studies will be needed.[1] A positive family history was observed in only three probands (out of 10, see Fig. 2), similar to the five cases reported in a recent series of 13 probands.[14] It is possible that there is reduced penetrance of NKX2.1 mutations or that de novo mutations are common. However, we did not have the opportunity to examine or genotype multiple family members so this remains uncertain.

In keeping with previous publications, median age at onset of chorea was 3 years with no individuals developing symptoms after 13 years and 6 months of age.[16] Muscle hypotonia, manifesting as delayed motor milestones, was the initial symptom in all except two of our participants, again suggesting that this may be an important diagnostic feature.[14, 17] Dystonia and myoclonus were the most common additional neurological signs, both of which frequently became more disabling than the chorea and contributed to delayed motor development.[12, 13]

Our cohort represents the second largest case series of NKX2.1 mutation-positive individuals with BHC. Despite a number of individual case reports and small (fewer than five individuals) case series, only one larger cohort has been reported to date.[14] This included 28 individuals, of whom 13 were probands, each with a different mutation. As discussed above, a number of features identified in this group were also observed in our cohort, including initial hypotonia and delayed motor development. A number of their individuals were also observed to have myoclonus (eight out of 28) and dystonia (seven out of 28) and, unlike our patients, three individuals also had vocal tics. It was also reported in the French cohort that chorea in all individuals improved in adolescence or early adulthood, remaining stable thereafter with myoclonus becoming the predominant disabling feature in some. In our cohort, only three individuals have reached adolescence or early adulthood; in two individuals, the chorea has stabilized and myoclonus is now the more disabling movement disorder, whereas the other individual experienced quite marked deterioration of choreoathetosis during adolescence. The remainder and majority of the cohort are yet to reach adolescence and, therefore, although we might anticipate a similar pattern of chorea stabilization in the majority, further follow-up study at regular intervals will be required over the next decade.

Thyroid transcription factor 1 protein also plays an important role in thyroid and lung organogenesis.[18] Previous reviews have suggested that approximately half of all individuals with NKX2.1 mutations have the full triad of brain, lung, and thyroid involvement.[2, 16] However, in our series only three out of 10 individuals had involvement of all three organs, despite comprehensive investigation. This observation is likely to represent a recruitment bias, as probands in our cohort were identified exclusively from neurology clinics. Respiratory involvement was present in just under half (four out of 10) of our individuals, corresponding to the 28/48[2] and 25/46[16] reported in previous reviews. These findings emphasize that, although additional lung and thyroid involvement may be a useful diagnostic marker and important to recognize because of potential therapeutic implications, the absence of these features should not preclude the diagnosis of BHC and NKX2.1 mutational screening.

A single individual in this series was observed to have coexistent psychological features in the form of OCD, developed during her mid-teens. Although OCD has not previously been described in patients with NKX2.1 mutations, an excess of OCD, particularly compulsivity, has recently been reported in a large cohort of SGCE (sarcoglycan, epsilon) mutation-positive patients with myoclonus dystonia.[19] The background population rate of OCD is approximately 4%,[20] and therefore this finding may be incidental. However, given the similar motor signs observed both in patients with BHC and in patients with myoclonus dystonia, it is conceivable that there may be some overlap in psychiatric comorbidity.[17] Furthermore, systematic assessment of larger BHC cohorts will aid in determining these findings. Comorbid psychiatric symptoms of depression[21] were reported in patients with BHC before the availability of NKX2.1 genetic testing. Since then, a number of genetically confirmed individuals were reported to have psychosis[7, 12, 22] and a recent large study by Gras et al.[14] found seven out of 28 of their cohort to have symptoms of ADHD. None of the individuals with in our study was found to have either psychosis or ADHD; however, this was based upon clinical assessment rather than structured interview so subtle symptoms may have resulted in under diagnosis.

Associated clinical characteristics have been reported in a number of individuals with NKX2.1 mutations. These have included hypodontia,[11] short stature and webbed neck,[12] patent foramen ovale,[23] microcephaly, dysmorphic features, and malabsorption.[16] These more severe phenotypes have been thought to be related to whole-gene deletions or those that lead to early truncation of the resultant protein. Two whole-gene deletions were identified within our cohort, one with growth hormone deficiency and visual impairment and the other with no additional features. No genes thought to be involved in growth hormone regulation were involved in our cohort, and a single case of growth hormone deficiency in the context of an NKX2.1 mutation has been observed previously.[16] Two individuals, one with a missense mutation and the other a nonsense mutation, also had evidence of pes cavus, kyphosis, duplex kidney, and lichen sclerosis. A single individual with urinary tract malformation in a gene-positive individual has been described.[7] These and the other possible associated clinical features may be incidental and unrelated to the NKX2.1 mutation.

Findings from this cohort do not suggest that severity of clinical phenotype is associated with mutation type; in particular those with contiguous gene deletions do not appear to be more severely affected than those with point mutations. The larger contiguous gene deletion reported in individual 4 is similar in chromosomal location to one previously reported, although slightly smaller.[24] This individual was reported to have a more severe phenotype including developmental delay, mild intellectual disability, ligament laxity, oligodontia, and gait disturbance. These individuals may indicate that this is a region susceptible to chromosomal rearrangement and that those genes involved only in the individual with the larger deletion may be responsible for the additional phenotypic characteristics. It does remain possible, however, that clinical phenotype is influenced to a greater extent by as yet undetermined environmental and epigenetic factors.

Finally, the individuals in our series have been treated with a variety of oral therapies, none of which has provided significant improvement in their chorea. Previous studies have reported improvement with levodopa,[4] ropinirole,[2] and tetrabenazine,[14] a partial response to propranolol,[2] and worsening of symptoms with haloperidol.[25] The lack of response in our cohort may be explained by the use of lower doses because of the development of intolerable side-effects.


We report one of the largest case series of paediatric patients with BHC, the majority with novel mutations in the NKX2.1 gene. In addition to previously reported motor characteristics, we identified additional clinical characteristics including pes cavus, kyphosis, and severe OCD as psychiatric comorbidities. The majority of patients presented with marked hypotonia and associated motor developmental delay, indicating that NKX2.1-related BHC may mimic a neuromuscular disorder before more typical symptoms evolve. A number of treatment strategies were employed within our cohort, none of which provided significant improvement to the signs and symptoms of chorea. Despite improved understanding of the role of the thyroid transcription factor 1 protein in the brain and other organs, further work is required to understand the full impact of the NKX2.1 mutant state on the normal development and function of these tissues and whether early intervention with novel therapies could limit or improve clinical symptoms.


We thank the patients and their families for their participation. KP was funded by the Ipsen fund and the Welsh Clinical Academic Track programme. JPL has received grants from Guy's and St Thomas' Charity new services and innovation fund, The Dystonia Society UK, and Action Medical Research. HM is funded by the Medical Research Council, Parkinson's UK, Welsh Government, and the Ipsen Fund. MK is funded by Great Ormond Street Hospital Children's Charity, Action Medical Research, and a Wellcome Trust Intermediate Clinical Fellowship. The authors have stated that they had no interests which might be perceived as posing a conflict or bias.