NKX2-1 syndrome (OMIM #610978) is a genetic disease caused by mutations in the NKX2-1 gene. Its clinical presentation may manifest all the symptoms of brain-lung-thyroid syndrome, or it may be a combination of manifestations in the brain and thyroid or isolated benign hereditary chorea (BHC).

Key Data

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Synonyms Brain-lung-thyroid syndrome
Choreoathetosis, hypothyroidism, and neonatal respiratory distress syndrome
Gene NKX2-1
Gene product Homeobox protein NKX2-1, also called thyroid transcription factor 1
Function Transcription factor, plays an important role in organogenesis of the basal ganglia, lungs, and thyroid
Heredity Autosomal dominant, de novo mutations possible (percentage as yet unknown)
Prevalence Unknown, around 50 cases have been described so far.
Genotype-phenotype correlation Large deletions lead to more severe phenotypic expressions than missense mutations.
Penetrance Unknown
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Suspected Diagnosis

NKX2-1 syndrome is suspected when the following findings apply:

  • Non-progressive chorea occurring in childhood, with/without congenital hypothyroidism or respiratory distress syndrome

  • Congenital hypothyroidism and (later) development of neurological manifestations and/or respiratory dysfunction

Genetic Diagnostics

The diagnosis of “NKX2-1” is confirmed by detection of a heterozygous germline mutation in the NKX2-1 gene through sequence analysis, deletion/duplication analysis or chromosomal microarray analysis. The use of panel examinations consisting of multiple genes as well as exome or genome sequencing may also be helpful.

Differential Diagnoses

  • Other causes of congenital hypothyroidism

  • Other causes of neonatal respiratory distress syndrome

  • Other causes of chorea

Clinical Presentation

The phenotypic spectrum of NKX2-1 syndrome includes benign hereditary chorea, congenital hypothyroidism, and neonatal respiratory distress syndrome. Both the full presentation of all three entities (brain-lung-thyroid syndrome) as well as an isolated manifestation of only one or two expressions is possible.

Complete brain-lung-thyroid syndrome is present in approximately 50% of patients with an NKX2-1 mutation, in 30% of patients exhibiting symptoms affecting the brain and thyroid and in 13% of patients exhibiting isolated chorea.

Neurological Manifestations

Chorea is characterized by involuntary, irregular, jerky movements and typically occurs for the first time in early infancy, at the end of the first year of life, or in late childhood to early adolescence. Chorea is progressive until the second decade of life, after which it usually stagnates or even exhibits regressive tendencies.

Besides chorea, other neurological abnormalities are also described as part of an NKX2-1 mutation, such as intention tremors, dysarthria, facial apraxia, sensory hearing loss, muscular hypotension, reduced coordination, motor developmental delays, myoclonus, dystonia, and ataxia.

Pulmonary Manifestations

After chorea, pulmonary dysfunction is the second most common manifestation associated with an NKX2-1 mutation and is described in approximately 50% of patients, with varying degrees of expression. The following diseases may occur:

  • Respiratory distress syndrome with or without pulmonary hypertension: most common manifestation during the neonatal period

  • Neuroendocrine cell hyperplasia: typically during childhood, improving with increasing age

  • Interstitial lung disease (ILD): occurring between 4 months and 7 years of age

  • Pulmonary fibrosis: in older patients

In addition, there is also a slightly increased risk of pulmonary carcinomas occurring in young adults with NKX2-1 syndrome. The exact risk is not yet known, however.

Manifestations of the Thyroid

Thyroid dysfunction as part of NKX2-1 syndrome is caused by dysmorphogenesis and can manifest as congenital hypothyroidism, the reduced or absent production of thyroid hormone, or compensated hypothyroidism (low to normal thyroid hormone level and elevated TSH), whereby the thyroid may exist in hypoplastic form or be completely absent.

It is presumed that the risk of papillary thyroid carcinomas is slightly increased and that the clinical progression is more aggressive with an NKX2-1 mutation.

Therapeutic Considerations

Treatment of NKX2-1 syndrome should always be symptom-orientated and interdisciplinary, with the involvement of the corresponding specialist disciplines.

When treating chorea, tetrabenazine is regarded as the treatment of choice, with levodopa being the second-line treatment. In addition, physical therapy also plays an important role in treatment.

Respiratory distress syndrome, ILD, and asthma should be treated as relatively sporadically occurring manifestations.

Substitution with L-thyroxin is necessary if there is limited thyroid function.

Surveillance Recommendations

Surveillance Recommendations

  • In patients without any neurological manifestation or with minimal symptoms:
    an annual neurological examination

  • In patients without any pulmonary manifestation or with minimal symptoms:
    an annual thoracic X-ray or CT once pulmonary dysfunction has been diagnosed

  • In patients without any thyroid manifestation or with minimal symptoms:
    an annual examination once thyroid dysfunction has been diagnosed

Patients should be made aware of their slightly increased risk of cancer. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with NKX2-1 syndrome that we can recommend to you for more information.

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with NKX2-1 syndrome. We will add new information as it becomes available.