NKX2-1 Syndrome – Definition
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).
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
Pattern of inheritance:
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
NKX2-1 Syndrome – Diagnosis
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.
Special Features of Treatment
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.
Diagnosis of NKX2-1 Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of NKX2-1 Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
- 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.
NKX2-1 Syndrome- Further Information
Additional Resources
Unfortunately, we are not yet aware of any support groups for patients with NKX2-1 syndrome. New information will be added as soon as it becomes available.
