What is NKX2-1 syndrome?

NKX2-1 syndrome is a disease caused by mutations – or genetic changes – in the NKX2-1 gene. The clinical symptoms may manifest as different presentations: The complete clinical picture – brain-lung-thyroid syndrome – involves all three organs. However, it is also possible to have a combination of manifestations in the brain and thyroid or even an isolated movement disorder with involuntary, irregular, and jerky movements called benign hereditary chorea.

How is NKX2-1 syndrome diagnosed?

Suspected Diagnosis

NKX2-1 syndrome is suspected with presentation of the following:

  • Non-progressive chorea (movement disorder with involuntary, irregular, and jerky movements) occurring during childhood with/without congenital hypothyroidism or respiratory distress syndrome

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

Genetic Diagnostics

The diagnosis of “NKX2-1 syndrome” is confirmed with detection of a mutation – or genetic change – in the NKX2-1 gene.

What is the risk of cancer?

There is a slightly higher risk of developing both lung and thyroid cancer, but it is yet to be precisely determined.

In addition, clinical manifestations of NKX2-1 syndrome may vary in severity. Both the full presentation involving all three organs (brain-lung-thyroid syndrome) as well as an isolated manifestation involving only one or two of these organs are possible. Complete brain-lung-thyroid syndrome occurs in approximately 50% of patients with an NKX2-1 mutation, with 30% of patients exhibiting symptoms affecting the brain and thyroid gland and 13% of patients exhibiting isolated chorea.

Neurological Manifestations

Chorea is characterized by involuntary, irregular, and 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.

In addition to chorea, other neurological abnormalities associated with an NKX2-1 mutation are also described, such as intention tremor (trembling when approaching a target), speech disorders and disorders of arbitrary facial expression, hearing loss, muscular weakness, decreased coordination, motor developmental delays, muscle twitching, and movement coordination disorders.

Respiratory Disorders

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

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

  • Neuroendocrine cell hyperplasia (a special form of interstitial lung disease (ILD) that occurs during childhood; ILD is a disease of the interstitial tissue of the lung and the alveoli): typically during childhood and improving with increasing age

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

  • Pulmonary fibrosis (increased formation of connective tissue in the lungs, which hinders the gas exchange): in older patients

Manifestations of the Thyroid

Thyroid dysfunction as part of NKX2-1 syndrome is caused by a malformation and can manifest as congenital hypothyroidism, reduced or absent production of the thyroid hormone, or compensated hypothyroidism (low to normal thyroid hormone and elevated TSH (thyroid-stimulating hormone)), whereby the thyroid may be smaller in size or completely absent.

What causes NKX2-1 syndrome?

NKX2-1 syndrome is caused by mutations – or genetic changes – in the NKX2-1 gene. This gene encodes for the NKX2-1 protein, which is necessary for reading and amplifying DNA – or genetic material – in our body, and it plays a special role in the development of organs, such as the lungs, thyroid glands, and specific brain structures.

Now if the NKX2-1 gene is altered, the NKX2-1 protein is not produced correctly and is no longer able to perform its correct function, which may result in the faulty development of the lung, thyroid, or brain.

So far NKX2-1 syndrome has been described in 50 people. As it can be passed on from parents to their children, it is inherited as an autosomal dominant disease. Spontaneous or new mutations – called de novo mutations – can also occur.

Is there a treatment?

Treatment of NKX2-1 syndrome should always be symptom-orientated and performed in collaboration with various specialist disciplines.

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

Respiratory distress syndrome, ILD, and asthma should be treated along the same lines as in patients who do not have NKX2-1 syndrome.

Taking L-thyroxin (thyroid hormone) is necessary if there is limited thyroid function.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

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

  • In patients without any lung manifestations or with minimal symptoms:
    an annual X-ray or CT of the lungs once the diagnosis has been made

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

Patients should be informed about their slightly increased risk of cancer. Specific cancer surveillance is not recommended.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as changes in movement or coordination, speech disorders, or hearing loss occur. Moreover, restrictions or changes in breathing should be noted and reported to a doctor as well. You should likewise go to a doctor right away if new anomalies or complaints develop.

Support Groups and Additional Information

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.