NKX2-1-Related Disorders

Clinical characteristics: NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark feature of NKX2-1-related disorders, may or may not be associated with pulmonary disease or congenital hypothyroidism. Age of onset of chorea varies from early infancy (most commonly) to late childhood or adolescence and may progress into the second decade, after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older individuals. The risk for pulmonary carcinoma is increased in young adults with NKX2-1-related disorders. Thyroid dysfunction, occurring as a result of thyroid dysgenesis, can present as congenital or compensated hypothyroidism. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had brain and thyroid involvement only, and 13% had chorea only.

Diagnosis/testing: The diagnosis of NKX2-1-related disorders is established in a proband with a heterozygous pathogenic variant in NKX2-1 identified by molecular genetic testing.

Management: Treatment of manifestations: Tetrabenazine, deutetrabenazine, or valbenazine starting at low doses and gradually increasing to control chorea. Levodopa, reported to improve chorea in children with gait abnormalities (including frequent falls), can be considered as second-line therapy for the treatment of chorea and as first-line therapy in children with gait impairment. Pulmonary manifestations are treated per standard recommendations including respiratory support as needed during the neonatal period, RSV vaccination in infancy, and early treatment of asthma and interstitial lung disease. Standard treatment for pulmonary carcinoma. Thyroid replacement therapy for hypothyroidism. Early intervention and physical therapy for motor and gait abnormalities. Standard treatments for neuropsychiatric issues.

Surveillance: Annual neurologic evaluation or more frequently as needed, depending on symptoms. Annual pulmonary evaluations including pulmonary function tests and chest x-ray or chest CT scan to screen for pulmonary malignancy. Annual endocrine evaluations including thyroid function tests (serum thyroxine and thyroid-stimulating hormone) and physical examination (including thyroid palpation) to screen for thyroid cancer.

Agents/circumstances to avoid: Dopamine receptor blockers due to the risk of developing tardive dyskinesia, which can worsen choreiform movements.

Evaluation of relatives at risk: Testing at-risk relatives prenatally or as soon as possible after birth for early identification and treatment of infants at risk for congenital hypothyroidism (and associated neurodevelopmental consequences) as well as pulmonary disease.

Pregnancy management: Prior to pregnancy or early in gestation, assess the safety of medications used for the treatment of chorea.

Genetic counseling: NKX2-1-related disorders are inherited in an autosomal dominant manner. Most individuals with an NKX2-1-related disorder have an affected parent. Each child of an individual with an NKX2-1-related disorder has a 50% chance of inheriting the pathogenic variant. Once the NKX2-1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.