Disease Overview
Synonyms
Signs & Symptoms
Causes
Affected Populations
Disorders with Similar Symptoms
Diagnosis
Standard Therapies
Clinical Trials and Studies
References
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Brain-Lung-Thyroid Syndrome

Last updated: 10/7/2024
Years published: 2024

Acknowledgment

NORD gratefully acknowledges Neha Potta, MD Candidate, UMKC School of Medicine, Alexis Poss, MS, CGC, University of North Carolina and Clara Hildebrandt, MD University of North Carolina, for the preparation of this report.

Disease Overview

Brain-lung-thyroid syndrome (BLT syndrome) is a genetic disease that affects the brain, lung and thyroid gland to variable degrees. The most severe form can cause abnormal movements (chorea), trouble breathing (respiratory distress syndrome) and thyroid problems from birth (congenital hypothyroidism)¹.

The severity of symptoms varies widely, even within families. Symptoms start in the newborn to early childhood period and get better over time². Life expectancy is reported to be normal³.

BLT syndrome is caused by genetic changes (pathogenic variants) in the NKX2-1 gene. Inheritance is autosomal dominant.

The chorea and thyroid deficiencies are treated with medication. Respiratory distress in newborns is managed with extra oxygen and sometimes requires a breathing machine². Some patients might have lung problems as they get older and need to see a lung doctor (pulmonologist)².

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Synonyms

BLT syndrome
CAHTP
choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction
choreoathetosis, hypothyroidism, and neonatal respiratory distress
choreoathetosis-hypothyroidism-neonatal respiratory distress
choreoathetosis-hypothyroidism-neonatal respiratory distress syndrome
NKX2-1-related disorder
TITF-1-related disorder

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Signs & Symptoms

The signs and symptoms of BLT syndrome can vary widely and affect just one part of the body or all three, the brain, lung and thyroid. About 50% of people have problems with all three, 30% with the brain and thyroid and 10-20% with just the brain². The movement problems get better during puberty and can even go away. The lung and thyroid problems usually improve too, but we don’t know much about how people are affected as they get older³.

Brain

The hallmark of the brain problems are jerky movements of the face, body, arms and legs, often said to look like a dance⁴. Thus, it is called chorea, which is Greek for “to dance.” People can also have trouble with balance (ataxia), twisting movements (athetosis), muscle stiffening (dystonia) and muscle twitches (myoclonus)³. These usually start with low muscle tone (hypotonia) and worsen in the first year of life⁵. Some other less common symptoms include speech problems (dysarthria), tremors, seizures, restless leg syndrome, learning disabilities and attention-deficit/hyperactivity disorder (ADHD)⁶. When people reach their 20s, the movement abnormalities stay stable and can even improve⁶.

Thyroid

The second most common problem is with the thyroid. The thyroid is a gland in the neck that makes hormones to help with growth and development. People with this syndrome often don’t have enough thyroid hormone from birth (congenital hypothyroidism)⁷. The gland itself is usually normal in size but can be smaller (hypoplastic) or even missing (aplastic)². Decreased thyroid hormone “slows” things down, leading to poor growth and development, constipation and low muscle tone (hypotonia).

Lung

The lung problems are the least common and can range from severe, life-threatening respiratory distress at birth⁴ to scarring of the lungs (interstitial lung disease in children and pulmonary fibrosis in adults)⁷. Individuals can also get lung infections more often and have a higher risk of lung cancer early in life⁸.

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Causes

BLT syndrome is caused by genetic changes (pathogenic variants) in the NKX2-1 gene. This gene’s job is to control other genes that help form the brain, lungs and thyroid gland⁹^,¹⁰. When the NKX2-1 gene does not work there are problems in normal development and function of these body systems¹¹^,¹². This causes the chorea, respiratory distress and congenital hypothyroidism¹.

It is still not understood why some people have problems with all three parts while others only have issues with one or two². Some studies report that a specific DNA change caused milder symptoms, but most agree that there is no clear pattern between the type of change and how severe the disease is⁷.

BLT syndrome is inherited in an autosomal dominant pattern ¹⁴. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Some patients with BLT syndrome were the first in their family to be affected, which means they had a new (de novo) mutation¹⁵^,¹⁶.

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Affected populations

BLT syndrome is a rare disorder, first described in 1998¹⁷. More than 120 individuals have been described in the medical literature since 2023, but the prevalence is unknown⁷. Males and females are affected equally.

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Diagnosis

Doctors might consider a diagnosis of brain-lung-thyroid syndrome (BLT syndrome) when they see movement or breathing problems in newborns. Some people with chorea can have abnormal findings on a brain scan (MRI)⁷.

Hypothyroidism is typically diagnosed on routine newborn screening. On laboratory testing, congenital hypothyroidism shows up as low thyroid hormone. This can raise suspicion for this syndrome when a baby also has movement or breathing issues⁷.

There are different ways to test for variants in the NKX2-1 gene that cause BLT syndrome:

Single gene testing: This looks at just the NKX2-1 gene for any changes⁷.
Multigene panel: This looks at several genes that can cause similar movement disorders⁷.
Comprehensive genomic testing (chromosomal microarray analysis (CMA), exome sequencing, genome sequencing): This looks at all or most of a person’s genes. It’s used when someone has unusual symptoms that don’t quite fit this syndrome⁷ and does not require the doctor to know which gene is likely involved Most of the changes found so far have been in the parts of genes that make proteins (exons), so looking at just those parts (called the exome) with exome sequencing is usually enough⁹^,¹². CMA can detect large sections of DNA that may be missing or duplicated. These changes are too big to be found with regular DNA sequencing tests. If a child has chorea and the genetic tests don’t find the cause, doctors may recommend this test.⁹

Clinical testing and work-up

The recommended testing and surveillance for BLT syndrome is divided by organ system:

Brain: Consultation with a neurologist and a brain scan (MRI)⁷
Lung: Consultation with a pulmonologist to check how well the lungs work and a chest X-ray or CT scan to screen for tumors⁷
Thyroid: Consultation with an endocrinologist to check thyroid levels (TSH, T3/T4). Starting at age 5, they should also check for thyroid cancer by feeling the thyroid gland⁷.
Development: Staring at around age 1, pediatricians or physical therapists can check how well a child moves and walks. Children should also be evaluated for ADHD and other mood problems⁷.

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Standard Therapies

There is no cure for brain-lung-thyroid syndrome (BLT syndrome) yet. Treatment is directed to the specific symptoms in the brain, lung and thyroid.

Brain

Chorea can be mostly controlled with medications. Tetrabenazine,deutetrabenazine, or valbenazine all work to decrease chemicals in the brain such as serotonin, norepinephrine and dopamine. By decreasing these, the brain sends less signals telling the body to move, controlling the abnormal movements in BLT syndrome²².
Another medication, levodopa, works by increasing dopamine to help in children that have trouble walking or repeated falls²³. It is recommended that all children still be followed by a neurologist. Early physical therapy is also recommended for children who have trouble walking⁷.

Lung

Breathing problems are treated as needed in newborns. This can include extra oxygen and sometimes a breathing machine. The RSV vaccine is also recommended to prevent infection⁷.
Other problems like asthma, infections and chronic lung disease are managed by pulmonologists with inhalers, steroids and antibiotics if needed²⁴. In the case of cancer, individuals should see a cancer doctor (oncologist) for early treatment⁷.

Thyroid

Hypothyroidism is treated with thyroid replacement medication levothyroxine⁷.

The medications called dopamine receptor blockers should be avoided because they can lead to a condition known as tardive dyskinesia. This condition causes uncontrollable movements, and in people who already have choreiform movements (jerky, involuntary movements), it can make their symptoms even worse.

Affected individuals and their families may benefit from follow up with a genetics expert, such as a genetic counselor or medical geneticist.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

Guillot L, Carré A, Szinnai G, et al. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”. Hum Mutat. 2010;31(2):E1146-E1162. doi:10.1002/humu.21183

Carré A, Szinnai G, Castanet M, et al. 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. doi:10.1093/hmg/ddp162

Gras D, Jonard L, Roze E, et al. 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. doi:10.1136/jnnp-2012-302505

Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144(3):794-804. doi:10.1378/chest.12-2502

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. 2018;6(1):34-39. Published 2018 Nov 9. doi:10.1002/mdc3.12690

Peall KJ, Kurian MA. Benign Hereditary Chorea: An Update. Tremor Other Hyperkinet Mov (N Y). 2015;5:314. Published 2015 Jul 14. doi:10.7916/D8RJ4HM5

Patel NJ, Jankovic J. NKX2-1-Related Disorders. 2014 Feb 20 [Updated 2023 Jun 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK185066/ Accessed Oct 3, 2024.

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. doi:10.1002/mds.22215

Devos D, Vuillaume I, de Becdelievre A, et al. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord. 2006;21(12):2237-2240. doi:10.1002/mds.21135

Teissier R, Guillot L, Carré A, et al. 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. doi:10.1159/000337214

Invernizzi F, Zorzi G, Legati A, et al. Benign hereditary chorea and deletions outside NKX2-1: What’s the role of MBIP?. Eur J Med Genet.2018;61(10):581-584. doi:10.1016/j.ejmg.2018.03.011

Villamil-Osorio M, Yunis LK, Quintero L, et al. Brain-lung-thyroid syndrome in a newborn with deletion 14q12-q21.1. Andes Pediatr. 2021;92(6):930-936. doi:10.32641/andespediatr.v92i6.3287

Ferrara AM, De Michele G, Salvatore E, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18(9):1005-1009. doi:10.1089/thy.2008.0085

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. The Journal of Pediatrics. 2004;145(2):190-193. doi:10.1016/j.jpeds.2004.04.011

Liang R, Ou S, Ding Y, Liu C. A case of brain-lung-thyroid syndrome. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022;47(3):396-400. doi:10.11817/j.issn.1672-7347.2022.200998

Willemsen MA, Breedveld GJ, Wouda S, et al. 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. doi:10.1007/s00431-004-1559-x

Devriendt K, Vanhole C, Matthijs G, de Zegher F. Deletion of Thyroid Transcription Factor-1 Gene in an Infant with Neonatal Thyroid Dysfunction and Respiratory Failure. The New England Journal of Medicine. 1998;338(18):1317-1318. doi:10.1056/nejm199804303381817

Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign hereditary chorea–entity or syndrome?. Mov Disord. 2000;15(2):280-288. doi:10.1002/1531-8257(200003)15:2<280::aid-mds1011>3.0.co;2-q

Hisama FM, Friedman J, Raskind WH, et al. ADCY5 Dyskinesia. 2014 Dec 18 [Updated 2020 Jul 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK263441/ Accessed Oct 7, 2024.

Whitsett JA, Wert SE, Weaver TE. Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol. 2015;10:371-393. doi:10.1146/annurev-pathol-012513-104644

Bishara J, Keens TG, Perez IA. The genetics of congenital central hypoventilation syndrome: clinical implications. Appl Clin Genet. 2018 Nov 15;11:135-144. doi: 10.2147/TACG.S140629. PMID: 30532577; PMCID: PMC6241683.

Bashir H, Jankovic J. Treatment options for chorea. Expert Rev Neurother. 2018;18(1):51-63. doi:10.1080/14737175.2018.1403899

Asmus F, Horber V, Pohlenz J, et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology. 2005;64(11):1952-1954. doi:10.1212/01.WNL.0000164000.75046.CC

Nattes E, Lejeune S, Carsin A, et al. Heterogeneity of lung disease associated with NK2 homeobox 1 mutations. Respir Med. 2017;129:16-23. doi:10.1016/j.rmed.2017.05.014

Brain-lung-thyroid syndrome. Orphanet. April 2011. https://www.orpha.net/en/disease/detail/209905 Accessed Oct 7, 2024.

Brain-lung-thyroid syndrome. MedGen UID: 369694. Concept ID: C1970269. https://www.ncbi.nlm.nih.gov/medgen/369694 Accessed Oct 7, 2024.

Choreoathetosis and Congenital Hypothyroidism with or without Pulmonary Dysfunction. Online Mendelian Inheritance in man (OMIM). 02/02/2022. https://omim.org/entry/610978#:~:text=less%20severe%20manifestations.-,Description,triad%20of%20features%20in%20infancy. Accessed Oct 7, 2024.

Brain-lung-thyroid syndrome. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/12163/x Accessed Oct 7, 2024.

Brain-lung-thyroid syndrome: MedlinePlus Genetics. updated January 1, 2017. https://medlineplus.gov/genetics/condition/brain-lung-thyroid-syndrome/ Accessed Oct 7, 2024.

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