"NKX2-1 Syndrome" – What Is It?
NKX2-1 syndrome is a disease caused by mutations, i.e., genetic changes in the NKX2-1 gene. It can manifest itself clinically in different forms: In the complete picture of brain-lung-thyroid syndrome, all three organs are affected, but a combination of manifestations in the brain and thyroid gland or an isolated movement disorder with involuntary, irregular and jerky movements, so-called benign hereditary chorea, can also occur.
How Is "NKX2-1 Syndrome" Diagnosed?
Suspected Diagnosis
NKX2-1 syndrome is suspected if the following findings are present:
- Non-progressive chorea (movement disorder with involuntary, irregular, and jerky movements) occurring in childhood with/without congenital hypothyroidism or respiratory distress syndrome
- Congenital hypothyroidism and (later) development of neurological manifestations and/or respiratory disorders
Genetic Diagnostics
The “NKX2-1 syndrome” diagnosis is confirmed when a mutation, i.e., genetic change, is detected in the NKX2-1 gene.
What Is the Risk of Cancer?
The risk is slightly increased for both lung and thyroid cancer but cannot yet be precisely quantified.
In addition, other clinical manifestations of varying severity can occur as part of NKX2-1 syndrome. The full picture of all three organ involvement is possible (brain-lung-thyroid syndrome) and an isolated manifestation of only one or two forms. Around 50% of patients with NKX2-1 mutations have complete brain-lung-thyroid syndrome, 30% of patients have brain and thyroid involvement, and 13% have isolated chorea.
Neurological Manifestations
Chorea is characterized by involuntary, irregular, and jerky movements. It 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 progresses until the second decade of life, after which it usually stagnates or shows a regressive tendency.
In addition to chorea, other neurological abnormalities such as intention tremor (trembling when approaching a target), speech and voluntary facial expression disorders, hearing loss, muscular weakness, reduced coordination, motor developmental delay, muscle twitching, cramped posture, and movement coordination disorders have been described in the context of an NKX2-1 mutation.
Respiratory Disorders
Respiratory disorders are the second most common manifestation of an NKX2-1 mutation after chorea and are described in around 50% of patients, although the degree of severity can vary. The following diseases can occur:
- Respiratory distress syndrome with or without pulmonary hypertension: most common manifestation in the neonatal period
- Neuroendocrine cell hyperplasia (a specific form of interstitial lung disease (ILD) that occurs in childhood; ILD is a disease of the interstitial lung tissue and alveoli): Typically in childhood, improves with age
- Interstitial lung disease (ILD), see above: Occurs between 4 months and 7 years of age
- Pulmonary fibrosis (increased formation of connective tissue in the lungs, which impedes gas exchange): In older patients
Manifestations of the Thyroid Gland
Thyroid dysfunction in the context of NKX2-1 syndrome is based on maldevelopment. It can manifest itself as congenital hypothyroidism, reduced or absent production of thyroid hormones, or compensated hypothyroidism (low to normal thyroid hormones and increased TSH (thyroid-stimulating hormone)). The thyroid gland may be smaller or completely absent.
What Is Known About the Development of "NKX2-1 Syndrome"?
NKX2-1 syndrome is caused by mutations, i.e., genetic changes in the NKX2-1 gene. This gene codes for the NKX2-1 protein, which is necessary for reading and replicating the DNA, i.e., the genetic material, in our body. It plays a unique role in the organ development of the lungs, thyroid gland, and specific brain structures.
If the NKX2-1 gene is now present in an altered form, the NKX2-1 protein is also not produced correctly and can no longer fulfill its actual function. This can lead to defective organ development in the lungs, thyroid, or brain.
To date, NKX2-1 syndrome has been described in 50 people and can be passed on from parents to their children. The inheritance is autosomal dominant. Spontaneous or new mutations, known as de novo mutations, are also possible.
Is There Any Form of Treatment Available?
Treatment of NKX2-1 syndrome should always be symptom-oriented and carried out in collaboration with various specialist disciplines.
In the treatment of chorea, tetrabenazine is the treatment of choice, and levodopa is a second-line therapy. Physiotherapy also plays a vital role in the treatment.
Respiratory distress syndrome, ILD, and asthma should be treated as in patients without NKX2-1 syndrome.
The intake of L-thyroxine (thyroid hormone) is necessary if the function of the thyroid gland is impaired.
Diagnosis of " NKX2-1 Syndrome" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Diagnosis of " NKX2-1 Syndrome" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Medical Measures for Early Detection
- For patients without neurological manifestations or with minimal symptoms:
Annual neurological examination - In patients without manifestations in the lungs or with minimal symptoms:
From the diagnosis of a respiratory disorder, X-ray or CT lung annually - For patients without thyroid manifestations or with minimal symptoms:
Annual examination from the time a thyroid dysfunction is diagnosed
Patients should be made aware of a slightly increased risk of cancer. Targeted cancer screening is not recommended.
NKX2-1 Syndrome – What You Can Do Yourself
You Should Pay Attention to This
You should consult a doctor as soon as changes in movement or coordination, speech disorders, or hearing loss occur. In addition, any restrictions or changes in breathing should be noticed and reported to a doctor. You should also consult a doctor if you notice any new abnormalities or complaints.
Further Information
Unfortunately, we are unaware of any support groups for patients with NKX2-1 syndrome. As soon as we have new information, we will add it here. However, patients can also register for the CPS registry at any time or have this done by the doctors in charge.
Any further questions?
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