Last updated:
10/7/2024
Years published: 2024
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.
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 time.² Life expectancy is reported to be normal.³
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
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 brain.² 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 older.³
Brain
The hallmark of the brain problems are jerky movements of the face, body, arms and legs, often said to look like a dance.⁴ 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 life.⁵ 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 improve.⁶
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 life.⁸
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 gland.⁹,¹⁰ When the NKX2-1 gene does not work there are problems in normal development and function of these body systems.¹¹,¹² This causes the chorea, respiratory distress and congenital hypothyroidism.¹
It is still not understood why some people have problems with all three parts while others only have issues with one or two.² 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 is.⁷
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) variant.¹⁵,¹⁶
BLT syndrome is a rare disorder, first described in 1998.¹⁷ More than 120 individuals have been described in the medical literature since 2023, but the prevalence is unknown.⁷ Males and females are affected equally.
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 issues.⁷
There are different ways to test for variants in the NKX2-1 gene that cause BLT syndrome:
Clinical testing and work-up
The recommended testing and surveillance for BLT syndrome is divided by organ system:
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
Lung
Thyroid
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.
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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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
View reportMedlinePlus has information about this condition that may include a description, frequency, causes, inheritance, and links to more information. The information is written for the public, including patients, caregivers and families. MedlinePlus is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).
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