Clinical characteristics.

NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.

Diagnosis/testing.

The diagnosis of an NKX2-1-related disorder is established in a proband by identification of a heterozygous pathogenic variant in NKX2-1.

Management.

Treatment of manifestations: Tetrabenazine in low doses reduces chorea. Levodopa has been reported to improve chorea in four children with substantial improvement in gait symptoms (falls); it can be considered as second line therapy for the treatment of chorea and as first line therapy in children with gait impairment. Pulmonary manifestations are treated in the usual manner for asthma and interstitial lung disease; hypothyroidism is treated with thyroid replacement therapy.

Surveillance:

• For individuals with no or minimal neurologic manifestations: Annual neurologic evaluation.
• For individuals with no or minimal pulmonary manifestations, starting at the time of diagnosis: Annual pulmonary function tests and chest x-ray or CT scan of the chest to screen for pulmonary malignancy.
• For individuals with no or minimal manifestations of thyroid disease, starting at the time of diagnosis: Annual serum thyroid-stimulating hormone and physical examination (including thyroid palpation) to screen for thyroid cancer.

Evaluation of relatives at risk:

• In a family in which the NKX2-1 pathogenic variant has been identified, testing of at-risk relatives prenatally or as soon as possible after birth allows early identification of infants at high risk for congenital hypothyroidism and pulmonary disease to permit early diagnosis and management, particularly to prevent the neurodevelopmental consequences of untreated hypothyroidism.
• In a family with benign hereditary chorea or brain-lung-thyroid syndrome in which a pathogenic variant has not been identified, assessing thyroid function of at-risk infants as soon as possible after birth allows early identification and management of congenital hypothyroidism.

Pregnancy management: Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine the safety for the fetus of the use of any medication she is taking for chorea.

Genetic counseling.

NKX2-1-related disorders are inherited in an autosomal dominant manner. Most individuals with an NKX2-1-related disorder have an affected parent. Each child of an individual with an NKX2-1-related disorder has a 50% chance of inheriting the pathogenic variant. Once the NKX2-1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is a possible option.

Suggestive Findings

NKX2-1-related disorders should be suspected in individuals with EITHER of the following:

• Childhood-onset non-progressive chorea that may or may not be associated with congenital hypothyroidism or respiratory distress syndrome
• A history of congenital hypothyroidism and (later) development of neurologic findings and/or respiratory dysfunction

Establishing the Diagnosis

The diagnosis of an NKX2-1-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in NKX2-1 identified by molecular genetic testing [Inzelberg et al 2011] (see Table 1).

Molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis (CMA), use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of NKX2-1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• Chromosomal microarray analysis (CMA) – if not already performed – may be obtained to detect genome-wide deletions/duplications (including NKX2-1). See Table 1, footnote 9.
• A multigene panel that includes NKX2-1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, whole mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes NKX2-1) fails to confirm a diagnosis in an individual with features of an NKX2-1-related disorder. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The clinical manifestations of NKX2-1-related disorders range from benign hereditary chorea (BHC) to congenital hypothyroidism to neonatal respiratory distress or any combination of brain, thyroid, and lung development. When all three organ systems are involved, this is also known as "brain-lung-thyroid syndrome" (see Figure 1).

Figure 1.

Phenotypic spectrum of NKX2-1-related disorders NKX2-1-related disorders may manifest as abnormalities in a single organ system or as any combination of brain, thyroid, and lung involvement. "Brain-lung-thyroid syndrome" refers to involvement of all three (more...)

In a review of 46 affected individuals Carré et al [2009] found that 50% had the full brain-lung-thyroid syndrome, 30% had involvement of only brain and thyroid, and 13% had isolated chorea only.

The prevalence of chorea in the NKX2-1-related disorders is unknown. In one study all 28 affected individuals from 13 families with a heterozygous NKX2-1 pathogenic variant had chorea and hypotonia [Gras et al 2012]. However, in a retrospective study of 21 individuals with an NKX2-1-related disorder presenting with pulmonary dysfunction, at least two unrelated individuals and three members of one family did not manifest neurologic symptoms [Hamvas et al 2013].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed as manifestations of NKX2-1-related disorders vary among individuals with the same NKX2-1 pathogenic variant even within the same family.

In general, the severity of the phenotype associated with a heterozygous NKX2-1 pathogenic variant depends on the type of variant (missense or nonsense), deletion size, or location within functional domains of NKX2-1 [Inzelberg et al 2011].

Larger (exon or whole-gene) deletions have been reported in infants with respiratory distress, congenital hypothyroidism, delayed achievement of motor milestones, and ataxia [McMichael et al 2013], including individuals with a contiguous deletion of NKX2-1 and PAX9 [Devos et al 2006]. Missense variants resulting in protein truncation have been related to milder phenotypes, though a systematic analysis of published cases revealed no clear correlation between variant type and protein functionality [Gras et al 2012, Monti et al 2015].

Penetrance

No studies have evaluated the penetrance of NKX2-1 pathogenic variants though observational case reports of families suggest a variable penetrance.

Nomenclature

Before its molecular basis was known, the disorder now known to be caused by a heterozygous pathogenic variant in NKX2-1 [Inzelberg et al 2011] was referred to as benign hereditary chorea (BHC) based on the original description of non-progressive, familial chorea in a five-generation African American family from rural Mississippi [Haerer et al 1967]. The broad phenotypic spectrum associated with pathogenic variants in NKX2-1 (including BHC and a variable combination of lung, thyroid, and neurologic abnormalities) identified in these studies led Willemsen et al [2005] to coin the term brain-lung-thyroid syndrome. In light of the varied manifestations of heterozygous mutation of NKX2-1, the authors suggest that these disorders be referred to as NKX2-1-related disorders.

Of note, NKX2-1 was previously known as TITF-1; thus, the early literature describing the molecular basis of this disorder uses this gene designation [Breedveld et al 2002, Kleiner-Fisman et al 2003, Costa et al 2005, Devos et al 2006, Kleiner-Fisman & Lang 2007, Glik et al 2008].

Prevalence

A prevalence of 1:500,000 was suggested by Harper [1978] in a study of individuals with clinically diagnosed benign hereditary chorea (BHC). However, the study was performed before the molecular basis of BHC was known; thus, it is unclear if all individuals included in the study had an NKX2-1 pathogenic variant. Additionally, persons with mild chorea and individuals without chorea as a presenting symptom were not included in the study [Kleiner-Fisman et al 2003].

NKX2-1-related disorders have primarily been described in Western European, Mediterranean, African American, and Japanese populations [Veneziano et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an NKX2-1-related disorder, the following evaluations are recommended:

For benign hereditary chorea*

• Consultation with a clinical geneticist and/or genetic counselor

For brain-lung-thyroid syndrome (choreoathetosis*, congenital hypothyroidism, and neonatal respiratory distress)

• Lung
  • Pulmonary function testing, if not performed at the time of diagnosis
  • Pulmonary consultation for further evaluation and treatment of pulmonary dysfunction
  • Screening for pulmonary malignancy with chest x-ray or CT scan of the chest
• Thyroid
  • Thyroid function testing (TSH, T₃, T₄) for evaluation of possible hypothyroidism, if not performed at the time of diagnosis
  • Endocrinology consultation for further evaluation and treatment of thyroid abnormalities
  • Consider evaluation for thyroid malignancy by physical examination that includes thyroid palpation.
• Consultation with a clinical geneticist and/or genetic counselor

*Note that brain MRI is typically obtained as part of the diagnostic evaluation.

Treatment of Manifestations

A multidisciplinary approach to the management of individuals with NKX2-1-related disorders is recommended.

Chorea. Tetrabenazine, which has been reported to reduce chorea in low doses [Jankovic 2009, Salvatore et al 2010, Jankovic & Clarence-Smith 2011, Gras et al 2012, Jimenez-Shahed & Jankovic 2013], is a first-line treatment for chorea. Starting at low doses and gradually increasing to the dose most effective in controlling symptoms is recommended.

• Children: 0.5 mg/kg/day starting dose divided into 2-3 doses
• Adults: 37.5 mg/day starting dose divided in 2-3 doses

Levodopa therapy has been reported to improve chorea in four children and can be considered as second-line therapy for the treatment of chorea [Asmus et al 2005, Rosati et al 2015]. Rosati et al [2015] and Asmus et al [2005] noted a dramatic and substantial improvement in gait symptoms (specifically falls) in the same four children with levodopa therapy; this medication can be used as first-line therapy in children with gait impairment.

Of note:

• Although Devos et al [2006] found a beneficial effect of methylphenidate on chorea in one patient, methylphenidate is not recommended as first-line therapy for the treatment of chorea.
• Although Glik et al [2008] reported amelioration of choreic movements in an individual with benign hereditary chorea treated with olanzapine for psychosis, dopamine receptor blockers are not recommended as first-line therapy for the treatment of chorea.

Other neurologic manifestations. Gross motor and gait abnormalities can occur during early development [Harper 1978]; physical therapy is recommended to address delays in motor and gait development identified in childhood.

Pulmonary dysfunction. Treat asthma and interstitial lung disease as needed.

Hypothyroidism. Thyroid hormone replacement therapy is recommended.

Prevention of Primary Manifestations

Neonatal screening for thyroid-stimulating hormone, thyroxine (T₄) levels with appropriate thyroid replacement can prevent systemic sequelae of congenital hypothyroidism.

Prevention of Secondary Complications

Screening and treatment of hypothyroidism can prevent the systematic sequelae of congenital hypothyroidism.

Early and aggressive medical intervention for respiratory infections and asthma can prevent respiratory distress, intubation and/or death.

Early intervention for motor development delays with physical therapy and/or medication for the treatment of chorea can improve function.

Annual screening for pulmonary and thyroid cancer can reduce morbidity and mortality associated with malignancy with NKX2-1 related disorders.

Surveillance

The following are appropriate:

• For individuals with no neurologic manifestations or minimal symptoms: annual neurologic evaluation
• For individuals with no pulmonary manifestations or minimal symptoms: annual evaluation starting at the time of diagnosis for pulmonary dysfunction (pulmonary function tests) and pulmonary malignancy with chest x-ray or CT scan of the chest
• For individuals with no manifestations of thyroid disease or minimal symptoms: annual evaluation starting at the time of diagnosis for thyroid dysfunction (serum concentration of thyroid stimulating hormone) and for thyroid cancer (physical examination that includes thyroid palpation)

Agents/Circumstances to Avoid

No agents or circumstances are known to trigger or exacerbate NKX2-1-related disorders.

Evaluation of Relatives at Risk

Evaluation of at-risk relatives prenatally or as soon as possible after birth enables early identification of infants at high risk for congenital hypothyroidism and pulmonary disease, permitting early diagnosis and management, and particularly, prevention of the neurodevelopmental consequences of untreated hypothyroidism.

Evaluations can include:

• Molecular genetic testing if the NKX2-1 pathogenic variant in the family is known;
• If a pathogenic variant has not been identified, assessment of thyroid function in a family with benign hereditary chorea or brain-lung-thyroid syndrome.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no known increased risk during pregnancy for a woman with an NKX2-1-related disorder.

Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine the safety for the fetus of the use of any medication she is taking for chorea.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NKX2-1-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with an NKX2-1-related disorder have an affected parent.
• A proband with an NKX2-1-related disorder may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
• Although most individuals diagnosed with an NKX2-1-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members due to mild symptomatology, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

• If a parent of the proband is affected, the risk to the sibs is 50%.
• If the NKX2-1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with an NKX2-1-related disorder has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, members of the parent's family may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic family members requires prior identification of the pathogenic variant in the family. Benign hereditary chorea and brain-lung-thyroid syndrome rarely develop in an asymptomatic adult, but there is a suggested increased risk of malignancy (pulmonary and thyroid) in those with germline NKX2-1 pathogenic variants.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the NKX2-1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Cancer and Benign Tumors

NKX2-1 somatic variants have been recognized as a tumor marker in both sporadic papillary thyroid and sporadic pulmonary carcinomas [Ngan et al 2009, Matsuse et al 2011, Watanabe et al 2013, Tsai et al 2014].

Somatic NKX2-1 expression in thyroid cancers is reduced, further implicating NKX2-1 for an increased risk for thyroid cancer [Kimura 2011].

Author Notes

www.jankovic.org

Revision History

• 29 July 2016 (ha) Comprehensive updated posted live
• 20 February 2014 (me) Review posted live
• 9 September 2013 (np) Original submission

Literature Cited

• 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;64:1952–4. [PubMed: 15955952]
• Barnett CP, Mencel JJ, Gecz J, Waters W, Kirwin SM, Vinette KM, Uppill M, Nicholl J. Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2-1. Am J Med Genet A. 2012;158A:3168–73. [PubMed: 23169673]
• 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;11:971–9. [PubMed: 11971878]
• Burns J, Neuhauser G, Tomasi L. Benign hereditary non-progressive chorea of early onset. Clinical genetics of the syndrome and report of a new family. Neuropadiatrie. 1976;7:431–8. [PubMed: 1036766]
• 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;18:2266–76. [PubMed: 19336474]
• Chang FC, Westenberger A, Dale RC, Smith M, Pall HS, Perez-Duenas B, Grattan-Smith P, Ouvrier RA, Mahant N, Hanna BC, Hunter M, Lawson JA, Max C, Sachdev R, Meyer E, Crimmins D, Pryor D, Morris JG, Carss KL, Raymond L, Kurian MA, Klein C, Fung VS. Phenotypic insights into ADCY5-associated disease. Mov Disord. 2016;31:1033–40. [PMC free article: PMC4950003] [PubMed: 27061943]
• Chen PM, Wu TC, Cheng YW, Chen CY, Lee H. NKX2-1 mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKß/NF-ĸB activation. Oncotarget. 2015;6:14274–89. [PMC free article: PMC4546466] [PubMed: 25881545]
• Costa MC, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, Segeiros J, Maciel P. Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics. 2005;6:209–15. [PubMed: 16220345]
• Damasio H, Antunes L, Damasio AR. Familial nonprogressive involuntary movements of childhood. Ann Neurol. 1977;1:602–3. [PubMed: 883778]
• de Gusmao CM, Kok F, Casella EB, Waugh JL. Benign hereditary chorea related to NKX2-1 with ataxia and dystonia. Neurol Genet. 2015;2:e40. [PMC free article: PMC4817908] [PubMed: 27066577]
• Devos D, Vuillaume I, de Becdelievre A, de Martinville B, Dhaenens CM, Cuvellier JC, Cuisset JM, Vallee L, Lemaitre MP, Bourteel H, Hachulla E, Wallaert B, Destee A, Defebvre L, Sablonniere B. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord. 2006;21:2237–40. [PubMed: 17044090]
• 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;145:190–3. [PubMed: 15289765]
• Fagman H, Nilsson M. Morphogenetics of early thyroid development. J Mol Endocrinol. 2011;46:R33–42. [PubMed: 21322126]
• 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;57:106–10. [PubMed: 11445636]
• Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, Del Prete G, Fenzi G, Filla A, Macchia PE. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18:1005–9. [PubMed: 18788921]
• Flandin P, Kimura S, Rubenstein JL. The progenitor zone of the ventral medial ganglionic eminence requires Nkx2-1 to generate most of the globus pallidus but few neocortical interneurons. J Neurosci. 2010;30:2812–23. [PMC free article: PMC2865856] [PubMed: 20181579]
• Galambos C, Levy H, Cannon CL, Vargas SO, Reid LM, Cleveland R, Lindeman R, deMello DE, Wert SE, Whitsett JA, Perez-Atayde AR, Kozakewich H. Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome. Am J Respir Crit Care Med. 2010;182:549–54. [PMC free article: PMC2937244] [PubMed: 20203240]
• Gillett ES, Deutsch GH, Bamshad MJ, McAdams RM, Mann PC. Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate. J Perinatol. 2013;33:157–60. [PubMed: 23361500]
• 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;23:1744–7. [PubMed: 18661567]
• Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, Rodriguez D, Louha M, Caubel I, Kemlin I, Lion-Francois L, Goizet C, Guillot L, Moutard ML, Epaud R, Heron B, Charles P, Tallot M, Camuzat A, Durr A, Polak A, Devos D, Sanlaville D, Vuillaume I, Billette de Villemeur 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;83:956–62. [PubMed: 22832740]
• Guala A, Falco V, Breedveld G, De Filippi P, Danesino C. Deletion of PAX9 and oligodontia: a third family and review of the literature. Int J Paediatr Dent. 2008;18:441–5. [PubMed: 18445003]
• Guillot L, Carre A, Szinnai G, Castanet M, Tron E, Jaubert F, Broutin I, Counil F, Feldmann D, Clement A, Polak M, Epaud R. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in "Brain-Lung-Thyroid Syndrome". Hum Mutat. 2010;31:E1146–62. [PubMed: 20020530]
• Haerer AF, Currier RD, Jackson JF. Hereditary nonprogressive chorea of early onset. N Engl J Med. 1967;276:1220–4. [PubMed: 4225827]
• Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halnower A, Planer B, Stephan MJ, Uchinda DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, Nogee LM. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144:794–804. [PMC free article: PMC3760742] [PubMed: 23430038]
• Harper PS. Benign hereditary chorea. Clinical and genetic aspects. Clin Genet. 1978;13:85–95. [PubMed: 624192]
• Inoue Y, Matsuura S, Kurabe N, Kahyo T, Mori H, Kawase A, Karayama A, Funai K, Shinmura K, Suda T, Sugimura H. J Thorac Oncol. 2015;10:1590–600. [PubMed: 26536195]
• Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: an update. Parkinsonism Relat Disord. 2011;17:301–7. [PubMed: 21292530]
• Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T. Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J Pediatr. 2000;137:272–6. [PubMed: 10931427]
• Jankovic J, Clarence-Smith K. Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders. Expert Rev Neurother. 2011;11:1509–23. [PubMed: 22014129]
• Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol. 2009;8:844–56. [PubMed: 19679276]
• Jendrzejewski J, Liyanarachchi S, Nagy R, Senter L, Wakely PE, Thomas A, Nabhan F, He H, Li W, Sworczak K, Ringel M, Kirschner LS, de la Chapelle A. Papillary thyroid carcinoma: Association between germline DNA varieant markers and clinical parameters. Thyroid. 2016;26:1276–84. [PMC free article: PMC5036310] [PubMed: 27342578]
• Jimenez-Shahed J, Jankovic J. Tetrabenazine for treatment of chorea associated with Huntington’s disease. Expert Opin Orphan Drugs. 2013;1:423–36.
• Kimura S. Thyroid-specific transcription factors and their roles in thyroid cancer. J Thyroid Res. 2011;2011:710213. [PMC free article: PMC3112524] [PubMed: 21687604]
• Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: a journey to understanding. Mov Disord. 2007;22:2297–305. [PubMed: 17702033]
• 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;54:244–7. [PubMed: 12891678]
• Kleinlein B, Griese M, Liebisch G, Krude H, Lohse P, Aslanidis C, Schmitz G, Pters J, Holzinger A. Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis. Arch Dis Child Fetal Neonatal Ed. 2011;96:F453–6. [PubMed: 20584796]
• 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;260:207–13. [PubMed: 22825795]
• Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, Defelice M, Von Deimling A, Van Langeghem F, Dilauro R, Gruters A. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest. 2002;109:475–80. [PMC free article: PMC150790] [PubMed: 11854319]
• Kusakabe T, Kawaguchi A, Hoshi N, Kawaguchi R, Hoshi S, Kimura S. Thyoid-specific enhancer-binding protein/ NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid. Mol Endocrinol. 2006;20:1796–809. [PMC free article: PMC2588428] [PubMed: 16601074]
• Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, Robitaille Y, Vuissoz JM, Payot A, Laberge S, Van Vliet G, Deladoey J. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endocrinol Metab. 2009;94:197–203. [PubMed: 18957494]
• Matsuse M, Takashashi M, Mitsutake N, Nishihara E, Hirokawa M, Kawaguchi T, Rogonovitch T, Saenko V, Bychkov A, Suzuki K, Matsuo K, Tajima K, Miyauchi A, Yamada R, Matsuda F, Yamashita S. The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population. J Med Genet. 2011;48:645–8. [PubMed: 21730105]
• 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;56:506–9. [PubMed: 23911641]
• Montanelli L, Tonacchera M. Genetics and phenomics of hypothyroidism and thyroid dys- and agenesis due to PAX8 and TTF1 mutations. Mol Cell Endocrinol. 2010;322:64–71. [PubMed: 20302910]
• Monti S, Nicoletti A, Cantasano A, Krude H, Cassio A. NKX2.1- Related Disorders: a novel mutation with mild clinical presentaotin. Ital J Pediatr. 2015;41:45. [PMC free article: PMC4477322] [PubMed: 26103969]
• Moya CM, Perez de Nanclares G, Castano L, Potau N, Bilbao JR, Carrascosa A, Bargada 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;91:1832–41. [PubMed: 16507635]
• Ngan ES, Lang BH, Liu T, Shum CK, So MT, Lau DK, Leon TY, Cherny SS, Tsai SY, Lo CY, Khoo US, Tam PK, Garcia-Barceló MM. A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst. 2009;101:162–75. [PubMed: 19176457]
• 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 NK2-1: expansion of genotypic and phenotypic spectrum. Dev Med Child Neurol. 2014;56:642–8. [PubMed: 24171694]
• Peca D, Petrini S, Tzialla C, Boldrini R, Morini F, Stronati M, Carnielli VP, Cogo PE, Danhaive O. Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect. Respir Res. 2011;12:115. [PMC free article: PMC3179724] [PubMed: 21867529]
• Pincus JH, Chutorian A. Familial benign chorea with intention tremor: a clinical entity. J Pediatr. 1967;70:724–9. [PubMed: 4225654]
• 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 TITF 1 gene mutations. Dev Med Child Neurol. 2015;57:777–9. [PubMed: 25412988]
• Salvatore E, Di Maio L, Filla A, Ferrara AM, Rinaldi C, Sacca F, Peluso S, Macchia PE, Pappata S, De Michele G. Benign hereditary chorea: clinical and neuroimaging features in an Italian family. Mov Disord. 2010;25:1491–6. [PubMed: 20544814]
• Schady W, Meara RJ. Hereditary progressive chorea without dementia. J Neurol Neurosurg Psychiatry. 1988;51:295–7. [PMC free article: PMC1031549] [PubMed: 2964512]
• Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign hereditary chorea--entity or syndrome? Mov Disord. 2000;15:280–8. [PubMed: 10752577]
• Shimohata T, Hara K, Sanpei K, Nunomura J, Maeda T, Kawachi I, Kasuga K, Miyashita A, Kuwano R, Hirota K, Tsuji S, Onodera O, Nishizawa M, Honma Y. Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. Brain. 2007;130:2302–9. [PubMed: 17405764]
• Suchowersky O, Hayden MR, Martin WR, Stoessl AJ, Hildebrand AM, Pate BD. Cerebral metabolism of glucose in benign hereditary chorea. Mov Disord. 1986;1:33–44. [PubMed: 2973557]
• Teissier R, Guillot L, Carre A, Melina 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 prove amplification improves the detection rate of NKX2.1 Mutations in patients affected by brain-lung-thyroid syndrome. Horm Res Paediatr. 2012;77:146–51. [PubMed: 22488412]
• Thorwarth A, Schnitter-Hubener S, Schrumpf P, Muller I, Jyrch S, Dame C, Biebermann H, Katchanov J, Schuelke M, Ebert G, Steininger A, Bonnemann C, Brockmann K, Christen HJ, Crock P, deZegher F, Griese M, Hewitt J, Huber C, Kapelari K, Plecko B, Rating D, Stoeva I, Ropers HH, Gruters A, Ullmann R, Krude H. Comprehensive genotyping and clinical characterization reveals 27 novel KNX2-1 mutations and expand the phenotypic spectrum. J Med Genet. 2014;51:375–87. [PMC free article: PMC5240655] [PubMed: 24714694]
• Tsai LH, Chen PM, Cheng YW, Chen CY, Sheu GT, Wu TC, Lee H. LKB1 loss by alteration of the NKX2-1/p53 pathway promotes tumor malignancy and predicts poor survival and relapse in lung adenocarcinomas. Oncogene. 2014;33:3851–60. [PubMed: 23995788]
• Uematsu M, Haginoya K, Kikuchi A, Nakayama T, Numata Y, Kobayashi T, Hino-Fukuo N, Fujiwara I, Kure S. Hypoperfusion in caudate nucei in patients with brain-lung-thyroid syndrome. J Neurol Sci. 2012;315:77–81. [PubMed: 22166853]
• 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;13:588–95. [PMC free article: PMC4155168] [PubMed: 24930029]
• Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, Peng S, Snyder EL, Tata PR, Izzo F, Schinzel AC, Cho J, Hammerman PS, Verhaak RG, Hahn WC, Rajagopal J, Jacks T, Meyerson M. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO2 as a functional transcription target. Genes Dev. 2013;27:197–210. [PMC free article: PMC3566312] [PubMed: 23322301]
• 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;164:28–30. [PubMed: 15517377]
• Young LR, Deutsch GH, Bokulic R, Brody A, Nogee LM. A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy (NEHI). Chest. 2013;144:1199–206. [PMC free article: PMC3787915] [PubMed: 23787483]