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.
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.
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:
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.
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.